DALLAS – Aug. 01, 2024 – Targeting a protein called ZFP574 suppressed leukemia in a mouse model of the disease, UT Southwestern Medical Center researchers showed in a new study. Their findings, published in PNAS (Proceedings of the National Academy of Sciences), could lead to new treatments for leukemias and lymphomas in cancer patients.

Jin Huk Choi, Ph.D., is Assistant Professor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern.

“Effective treatments exist for B-cell malignancies such as leukemias and lymphomas. But in a significant portion of patients, these treatments stop working and their disease recurs, leaving them with no viable treatment options. Targeting ZFP574 could eventually fill an unmet need, either as a primary or backup therapeutic,” said Jin Huk Choi, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Immunology.

Dr. Choi co-led the study with Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine. The study’s first author is Xue Zhong, Ph.D., Instructor in the Center for the Genetics of Host Defense and of Immunology. Drs. Choi and Zhong are former postdoctoral researchers in the Beutler Lab.

Bruce Beutler, M.D., is Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine at UT Southwestern. A Nobel Laureate, Dr. Beutler is a Regental Professor and holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.

Dr. Beutler shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of pathogen sensors known as Toll-like receptors found on immune cells. He has long used mutagenesis – introducing mutations into the genes of animal models through exposure to a chemical called N-ethyl-N-nitrosourea (ENU) – as a key tool for discovering the function of genes. Recently, the Beutler Lab pioneered a method known as automated meiotic mapping (AMM) that traces unusual features in mutant mice, thereby identifying genes needed to maintain the normal physiologic state.

Combining these techniques in mice, Drs. Choi, Beutler, and Zhong and their colleagues searched for genes that might play important roles in the development of B cells. These are white blood cells that fight infections as part of the adaptive immune system. The team quickly homed in on a gene called Zfp574, which produces the ZFP574 protein that previously was not known to have any function in immunity.

Xue Zhong, Ph.D., is Instructor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern.

Experiments showed that mutating this gene in embryos prevented development, suggesting that it’s essential to life. When the researchers used a genetic technique to control its activity in healthy adult mice, they found that switching Zfp574 off dramatically decreased the number of B cells, making the animals immunodeficient. Further experiments showed that ZFP574 appears to be responsible for controlling an important part of the cell cycle, the process by which cells multiply.

Because many cancer drugs work by inhibiting the cell cycle – preventing malignant cells from their characteristic rapid division – the scientists wondered whether inhibiting ZFP574 could be a way to treat B-cell cancers such as leukemia and lymphoma. Tests in a mouse model of leukemia showed that mutating or deleting Zfp574, or using pharmaceuticals to degrade ZFP574, reduced the amount of malignant B cells by as much as 92%. Normal B cells were largely spared due to their significantly slower cell division, Dr. Choi explained.

“Not only leukemias and lymphomas, but perhaps many cancers will respond to inhibition of ZFP574,” said Dr. Beutler, a member of the Cellular Networks in Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “The use of a random germline mutagen to discover a new and essential component of the cell cycle – despite the fact that the cell cycle has been intensively studied for many years – suggests there may still be plenty of new targets to exploit in controlling cancer cell proliferation.”

Future studies will focus on ZFP574’s atomic structure and how it controls B-cell cycling, knowledge that could help pharmaceutical companies eventually develop drugs targeting ZFP574 to treat leukemias, lymphomas, and potentially other cancers.

Dr. Beutler, a Regental Professor, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.

Other UTSW researchers who contributed to this study are James J. Moresco, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Biophysics; Jeffrey A. SoRelle, M.D., Assistant Professor of Pathology and Pediatrics; Eva Marie Y. Moresco, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Immunology; Ran Song, Ph.D., Mylinh T. Nguyen, M.S., and Jianhui Wang, M.S., Senior Research Scientists; Chun Hui Bu, Ph.D., Computational Biologist; and Yiao Jiang, Ph.D., postdoctoral researcher.

This research was funded by the National Institutes of Health (AI125581 and CA258602).

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – July 31, 2024 – Researchers at UT Southwestern Medical Center have discovered that a diet free of the amino acid tryptophan can effectively halt the growth of liver cancer in mice. Their findings, published in Nature Communications, offer new insights for dietary-based cancer treatments and highlight the critical role of the tryptophan metabolite indole 3-pyruvate (I3P) in liver tumor development.

Maralice Conacci-Sorrell, Ph.D., is Associate Professor of Cell Biology and Children's Medical Center Research Institute at UT Southwestern (CRI) and a member of the Cellular Networks in Cancer Research Program of the Harold C. Simmons Comprehensive Cancer Center. She holds the John P. Perkins, Ph.D. Distinguished Professorship in Biomedical Science.

“This work demonstrates that tailored dietary modulation may serve as a powerful adjuvant in cancer treatment,” said study leader Maralice Conacci-Sorrell, Ph.D., Associate Professor of Cell Biology and Children’s Medical Center Research Institute at UT Southwestern (CRI) and a member of the Cellular Networks in Cancer Research Program of the Harold C. Simmons Comprehensive Cancer Center. “It builds on our lab’s discovery that the universal oncogene MYC increases the demand for tryptophan in liver tumors.”

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide, according to 2020 data from the World Health Organization, with limited options for effective treatment and a five-year survival rate of about 30%. The study shows that growth of liver cancers driven by the MYC oncogene is particularly dependent on tryptophan, which is converted into I3P as well as other metabolites.

By removing tryptophan from the diet of mice, researchers stopped the growth of MYC-driven liver tumors and restored normal gene expression in liver cells. Notably, this dietary intervention did not affect protein synthesis in normal cells, suggesting a targeted therapeutic approach that spares healthy tissues.

“Liver tumors require large amounts of tryptophan to generate the oncometabolite I3P,” Dr. Conacci-Sorrell said. “A tryptophan-free diet prevents liver tumor growth by a mechanism that depends on I3P but is independent of translation, the process by which proteins are synthesized from amino acid building blocks. Because tryptophan is the amino acid with the lowest abundance in the proteome, short-term dietary manipulation is safe for healthy tissues but not for cancer cells.”

Among foods high in tryptophan are turkey, red meat, pork, chicken, tofu, milk, soybeans (including edamame), quinoa, oats, and fish.

The research highlights the complex role of tryptophan metabolism in cancer. While tryptophan is known to be metabolized into several important compounds, including the neurotransmitter serotonin and kynurenine, a precursor of the B vitamin niacin, the study showed that MYC-driven liver tumors preferentially utilize tryptophan to produce I3P rather than kynurenine. This shift underscores the potential for targeting specific metabolic pathways in cancer treatment.

The researchers also found that supplementation with I3P restored the growth of tryptophan-starved liver cancer cells, further emphasizing the critical role of this metabolite in cancer development. These findings suggest that targeting I3P or its production pathway could be a viable therapeutic strategy.

“This study not only advances understanding of liver cancer biology but also suggests a promising approach for developing personalized cancer therapies,” Dr. Conacci-Sorrell said.

The study’s co-first authors are Niranjan Venkateswaran, M.S., former research associate; Roy Garcia, B.S., graduate student researcher; Maria del Carmen Lafita Navarro, Ph.D., and Yi-Heng Hao, Ph.D., both Instructors of Cell Biology; and Lizbeth Perez-Castro, Ph.D., and Pedro A. S. Nogueira, Ph.D., both postdoctoral fellows in the Sorrell Lab.

Other UTSW researchers who contributed to this study are Ashley Solmonson, Ph.D., Assistant Professor in the Cecil H. and Ida Green Center for Reproductive Biology Sciences and of Obstetrics and Gynecology; Andrew Lemoff, Ph.D., Assistant Professor of Biochemistry; Nick V. Grishin, Ph.D., Professor of Biophysics and Biochemistry; Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and of Pediatrics; Noelle S. Williams, Ph.D., Professor of Biochemistry; Jerry W. Shay, Ph.D., Professor of Cell Biology and a Distinguished Teaching Professor; Ralph J. DeBerardinis, M.D., Ph.D., Professor in CRI and the Eugene McDermott Center for Human Growth and Development and of Pediatrics; Hao Zhu, M.D., Professor in CRI and of Internal Medicine and Pediatrics; Jessica A. Kilgore, B.S., Research Scientist; Shun Fang, M.D., Ph.D., postdoctoral fellow in the Sorrell Lab; Isabella N. Brown, B.S., graduate student researcher; Li Li, M.D., Senior Research Scientist; Emily Parks, B.S., graduate and medical student researcher; Igor Lopes dos Santos, M.S., graduate student researcher; Mahima Bhaskar, Green Fellow and Laboratory Technician; Jiwoong Kim, M.S., Computational Biologist; and Lisa Kinch, Ph.D., bioinformatics specialist in the Orth Lab.

Dr. Conacci-Sorrell holds the John P. Perkins, Ph.D. Distinguished Professorship in Biomedical Science. Dr. DeBerardinis holds the Joel B. Steinberg, M.D. Distinguished Chair in Pediatrics and is co-leader of the Cellular Networks in Cancer Research Program of the Simmons Cancer Center, an Investigator of the Howard Hughes Medical Institute, and a Sowell Family Scholar in Medical Research. Dr. Grishin holds the Cecil H. and Ida M. Green Chair in Biomedical Science. Dr. Shay holds The Southland Financial Corporation Distinguished Chair in Geriatrics. Dr. Zhu is co-leader of the Development and Cancer Research Program in the Simmons Cancer Center and holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.

Drs. Conacci-Sorrell and Grishin are Virginia Murchison Linthicum Scholars in Medical Research. Drs. Shay, Williams, and Xu are also members of Simmons Cancer Center.

This study was funded by the American Cancer Society (724003), the Cancer Prevention and Research Institute of Texas (RP220046, RP210041), National Cancer Institute (NCI) (R35CA22044901, R01CA245548, R01 CA251928), The Welch Foundation (I-2058-20210327), National Institute of General Medical Sciences (GM145744-01), a Circle of Friends Award, Simmons Comprehensive Cancer Center Cancer & Obesity Translational Pilot Award, Mark Foundation (21-003-ELA), National Science Foundation (2022344499), a Mary Kay postdoctoral fellowship, the HHMI Gilliam Fellows Program, and a NCI Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – July 30, 2024 – More educated people who are skilled at finding reliable information through social media don’t always see cancer as fatal while those with less schooling and social media awareness hold more fatalistic beliefs about the disease, researchers at UT Southwestern Medical Center found. Their study, published in Cancer Causes & Control, could help enhance public health efforts to increase cancer screening and prevention.

People with a fatalistic view of cancer, meaning they believe it is unavoidable, are less likely to be screened and may not notice symptoms until it is too late to treat the disease adequately.

Lead author Jim Stimpson, Ph.D., is Professor in the Peter O'Donnell Jr. School of Public Health and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“Our study emphasizes the importance of improving social media users’ ability to evaluate online health information, especially for those with lower education levels, to reduce negative attitudes toward cancer prevention and treatment,” said Jim Stimpson, Ph.D., Professor in the Peter O’Donnell Jr. School of Public Health and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

UTSW researchers examined data from the Health Information National Trends Survey to assess adults’ knowledge of cancer risk factors, attitudes toward cancer screening, and prevention and screening behaviors. Only adult respondents who had used social media within the previous year and completed the survey between March and November 2022 were included for analysis.

The survey measured cancer fatalism by asking participants if they believe everything causes cancer, if they think there’s nothing they can do to prevent it, and if there are too many recommendations about cancer prevention. 

Researchers measured social media awareness by asking participants about the difficulty in judging the truthfulness of health information. Participants were recognized as having high social media awareness if they agreed that they could tell whether health information was true or false. Researchers also examined how participants’ views related to their education level.

Dr. Stimpson and his colleagues found that people with at least a college education and high media awareness were less likely to hold fatalistic views about cancer. In contrast, higher percentages of those without a college degree and with low media awareness held fatalistic beliefs.

Participants who struggled to evaluate health information on social media were 9% more likely to believe that everything causes cancer, 6% more likely to think they cannot lower their chances of getting cancer, and 21% more likely to feel overwhelmed by the number of cancer prevention recommendations.

Sixty percent of the group with a college education and high awareness of social media information accuracy agreed that “everything causes cancer,” compared with 74% among those with lower education and media awareness. Additionally, the educated and media-aware group was less likely to agree that there’s nothing one can do to lower the chances of developing cancer and that there are too many cancer prevention recommendations.

Enhancing the ability of social media users to judge the reliability of online health information could decrease fatalistic views about cancer prevention and treatment, the study authors said. “We should invest in digital media literacy for patients to help them better understand quality and fact-based information available online and in social media,” Dr. Stimpson added.

Public health efforts could also help educate people about the spread of health misinformation and disinformation on social media, focusing particularly on populations with low social media awareness and education levels.

UT Southwestern’s Moncrief Cancer Institute in Fort Worth, which is part of the Simmons Cancer Center, places a sharp focus on cancer prevention, education, and screenings. In addition to prevention education sessions, Moncrief offers free screenings for breast, cervical, colorectal, lung, and prostate cancers to rural and medically underserved populations across 67 counties in Texas. UTSW also has a Cancer Answer Line, available from 8 a.m. to 5 p.m. Monday through Friday, to answer questions about cancer and cancer care.

UTSW researcher Miguel Cano, Ph.D., Associate Professor in the O’Donnell School of Public Health and a member of the Simmons Cancer Center, contributed to this study.

This research was funded by the National Institute on Minority Health and Health Disparities at the National Institutes of Health (R01MD018727).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – July 25, 2024 – Liver cells have a vital metabolic inflexibility during regeneration to starve dysfunctional cells and keep damage from spreading, according to new research from Children’s Medical Center Research Institute at UT Southwestern (CRI) published in Science.

CRI Associate Professor Prashant Mishra, M.D., Ph.D., Xun Wang, Ph.D., and colleagues have found that hepatocytes, the cells responsible for most liver function, normally use their mitochondria to process fatty acids, a key energy source during regeneration. When their mitochondria are damaged, hepatocytes turn on PDK4 – a metabolic enzyme that restricts cells from shifting to an alternative energy source – and cells die.

“There are good and bad sides of metabolic flexibility. Although metabolic flexibility has been largely described as beneficial because it gives cells the ability to tolerate shifting environments or alternative nutritional sources, our findings suggest flexibility can also be detrimental by allowing damaged cells to survive,” Dr. Mishra said. “With mitochondrial damage, liver cells actively suppress flexibility – a good thing if it prevents the damage from spreading.”

Prashant Mishra, M.D., Ph.D., is Associate Professor in Children's Medical Center Research Institute at UT Southwestern. He is a member of CRI's Genetic and Metabolic Disease Program, CRI's Tissue Regeneration Program, and the Cellular Networks in Cancer Research Program of the Harold C. Simmons Comprehensive Cancer Center at UTSW.

CRI scientists initially studied the mitochondria of healthy liver cells, both under normal and regenerative conditions. Their analyses showed fatty acids from other parts of the body were transported through the blood to the liver to fuel regeneration. When researchers blocked fatty acid transit, heathy livers were flexible and shifted to other energy sources, including sugars like glucose.

Researchers then examined livers from mice with mutations in their mitochondrial genes. Damaged liver cells were unable to use fatty acids during regeneration and did not shift to other energy sources, preventing livers from regenerating.

To understand why the flexibility was suppressed by mitochondrial mutations, Mishra Lab members examined genes that control a cell’s ability to use alternate energy sources. Results showed increased levels of the PDK4 gene – a negative regulator of a pathway needed to generate energy from glucose. When researchers blocked PDK4, damaged cells in the liver became metabolically flexible and were able to use other energy sources to spread and duplicate.

“The liver has an amazing capacity to regenerate after injury, but it is important that only the healthy cells multiply. We found that metabolic inflexibility can be useful by eliminating unhealthy cells,” Dr. Mishra said.

Previous Mishra Lab research showed that healthy mitochondria are critical in the liver for proper organ function and fatty acid metabolism. This new research illustrates how regenerating livers regulate cell proliferation and how disabling the key regulator PDK4 results in unhealthy livers with fat accumulation and steatosis, also commonly known as fatty liver disease.

“Mitochondrial damage is often observed in common human diseases, including cancer,” Dr. Mishra said. “We hope that by identifying the mechanisms cells use to prevent damage from spreading, we can harness these processes to potentially combat disease and prolong health.”

Dr. Mishra is a member of CRI’s Genetic and Metabolic Disease Program (GMDP), CRI’s Tissue Regeneration Program (TRP), and the Cellular Networks in Cancer Research Program of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He collaborated on this research with GMDP Director Ralph DeBerardinis, M.D., Ph.D., and TRP Director Hao Zhu, M.D.

Dr. Mishra is also an Associate Professor of Pediatrics at UT Southwestern. His research focuses on how to improve understanding and find new insights into mitochondrial diseases in order to develop clinical tools and therapeutic options.

Dr. DeBerardinis is a Professor in CRI, in the Eugene McDermott Center for Human Growth and Development at UTSW, and of Pediatrics, and he co-leads the Cellular Networks in Cancer Research Program of the Simmons Cancer Center. He holds the Joel B. Steinberg, M.D. Distinguished Chair in Pediatrics and is a Sowell Family Scholar in Medical Research. Dr. DeBerardinis is also a Howard Hughes Medical Institute Investigator. 

Dr. Zhu is a Professor in CRI, of Internal Medicine and Pediatrics, and he co-leads the Development and Cancer Research Program of the Simmons Cancer Center. He holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.

Dr. Wang is an Assistant Instructor in CRI’s Mishra Lab.

Research was supported by grants from the National Institutes of Health, National Cancer Institute, Moody Medical Research Institute, National Science Foundation, Human Frontier Science Program, Pollack Foundation, Simmons Comprehensive Cancer Center Cancer & Obesity Translational Pilot Award, and an Emerging Leader Award from the Mark Foundation for Cancer Research.

About CRI

Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology and metabolism.

X/Twitter | LinkedIn | Instagram | YouTube | Facebook | Website

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year. 

DALLAS – July 24, 2024 – Socioeconomic factors can influence the diagnosis and treatment of children in Texas with malignant solid tumors, increasing the risk of the cancer’s spread and lowering the five-year survival rate, according to researchers at UT Southwestern Medical Center. The study, published in Journal of the American College of Surgeons, identifies vulnerable populations in an effort to improve outreach and distribution of resources for better health outcomes for pediatric patients.

Dai Chung, M.D., is Professor of Surgery at UT Southwestern and Chief Medical Executive at Children's Health. Dr. Chung holds the Helen J. and Robert S. Strauss and Diana K. and Richard C. Strauss Chair in Pediatric Surgery.

“Despite significant progress in the treatment of pediatric cancer, socioeconomic factors continue to cause outcome disparities, including lower five-year survival among children with malignant solid tumors who live in socioeconomically disadvantaged neighborhoods compared to those from more affluent areas,” said study co-author Dai Chung, M.D., Professor of Surgery at UT Southwestern and Chief Medical Executive at Children’s Health.

Low socioeconomic status is a well-established factor associated with poor health outcomes for children. In this study, Dr. Chung and his team evaluated Texas Cancer Registry records of 3,863 children diagnosed with malignant tumors between 1995 and 2019. The average age at diagnosis was 4.5 years.

The researchers’ primary outcome measure was to determine overall patient survival after five years. However, since pediatric malignant tumors often metastasize before they’re found, the team also evaluated for delays in diagnosis and treatment, which can affect patient survival.

UTSW researchers used the Area Deprivation Index (ADI), which measures 17 neighborhood socioeconomic characteristics, including education levels and housing availability, to assess patients’ backgrounds. Higher ADI scores indicate greater economic uncertainty. They compared ADI scores and other patient demographic information, including sex, race, ethnicity, and household location, to determine the effects on clinical outcomes.

Dr. Chung and colleagues found that non-white pediatric cancer patients had a higher risk of death than their white counterparts. The study showed that with each point increase in ADI, the risk of death within five years of diagnosis increased by 4%. 

Minority patients living in affluent neighborhoods also had an increased risk of death compared with the overall risk for patients with the lowest ADI scores. Rural and impoverished patients residing in affluent counties in Texas also had higher mortality rates at year five after diagnosis.

During the study period, 52% of the children with solid tumors were diagnosed with metastatic cancer. Those who lived in affluent pockets surrounded by impoverished neighborhoods, non-white children, and those living in rural areas or areas near the Texas-Mexico border had an increased risk of metastatic disease.

Lower socioeconomic status was also associated with later treatment initiation, which can increase the risk of cancer metastasis and death. Among sarcoma patients, for example, the median time between diagnosis and the start of treatment for all children in the study was three days. But the investigators found that treatment began more than 51 days later among Black patients compared with white patients. Children living in rural counties began treatment 34 days later than those living in metropolitan areas, the study showed.

“Determining which populations are at the highest risk and where to direct resources can be difficult,” Dr. Chung explained. “Our hope is that our study findings can motivate improvements in racial and socioeconomic diversity in pediatric cancer clinical trials, increase funding for disparities in outcomes research, and implement ground-level changes that will make health care more accessible for all patients.”

Other UTSW investigators who contributed to this study are first author Elizabeth D. Cochran, M.D., a general surgical resident who recently completed a pediatric research fellowship in Dr. Chung’s lab; Jingbo Qiao, Ph.D., Assistant Professor of Surgery; and Jillian Jacobson, M.D., a general surgery resident. Sullivan McCreery, B.A., a medical student at UT-Health Houston McGovern Medical School, and Mithin Nehrubabu, B.S., also contributed to this work.

This study was supported by a grant from the National Institutes of Health (R01 DK61470).

Dr. Chung holds the Helen J. and Robert S. Strauss and Diana K. and Richard C. Strauss Chair in Pediatric Surgery.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – July 23, 2024 – James J. Collins III, Ph.D., Associate Professor of Pharmacology at UT Southwestern Medical Center who leads groundbreaking research into the parasitic disease schistosomiasis, has been named a Howard Hughes Medical Institute (HHMI) Investigator.

Dr. Collins was among 26 distinguished scientists nationwide named today as new HHMI Investigators and the only one in Texas. With his appointment, UT Southwestern now has 14 HHMI Investigators, the most of any institution in Texas. Each new investigator will receive $11 million in support over a seven-year period, which is renewable pending a scientific review by HHMI, a philanthropic organization created to advance basic biomedical research and science education for the benefit of humanity.

“By unraveling the basic biological processes of the parasite responsible for schistosomiasis, a devastating infectious disease, Dr. Collins aims through the use of powerful genomic approaches to identify vulnerabilities that can lead to the development of new therapies for a disease that affects hundreds of millions of people globally,” said Daniel K. Podolsky, M.D., President of UT Southwestern. “We are delighted that Dr. Collins has been selected for this high honor and is joining the ranks of 13 other HHMI scientists at UT Southwestern whose bold ideas and research hold great promise for future advances.”  

Schistosomes live in certain types of freshwater snails and enter an individual when skin encounters contaminated freshwater through wading, swimming, bathing, or drinking. These parasites infect people in parts of South America and Asia, but the most infections occur in sub-Saharan Africa. 

Second only to malaria as the most devastating parasitic disease, schistosomiasis progresses as female parasitic worms lay millions of eggs inside the host, causing debilitating inflammatory responses and scarring as eggs get trapped in the liver, intestines, or even the brain. After years of infection, the parasite can also damage the intestines, lungs, and bladder and cause anemia, malnutrition, and learning difficulties in children.   

The Collins Lab studies schistosomes from multiple angles using a variety of modern molecular approaches. Dr. Collins was the first to set up the culture conditions to monitor the reproductive cycle of the worms without having to pass it through a host. In doing so, he has transformed the understanding of schistosomes by discovering and isolating the pheromone, or signal, that male worms use to control female sexual development and egg production. Experts think that understanding and isolating this signal provides a great new direction for the field and may bring relief to the millions of people the tropical disease affects each year in developing nations.   

“I am honored to be selected as an HHMI Investigator and grateful to my lab members, collaborators, my UT Southwestern colleagues, and Chair, David Mangelsdorf, Ph.D., for their tremendous support,” Dr. Collins said. “Schistosomiasis is a neglected disease by virtually every measure, particularly in terms of our understanding of basic schistosome biology. Thus, this generous and flexible support from HHMI will allow us to take our understanding of these parasites in new and exciting directions with the ultimate goal of developing new treatments for this terrible disease.”

Dr. Collins received his B.S. in biology from Southeast Missouri State University and Ph.D. from Washington University in St. Louis. He did postdoctoral work at the University of Illinois with Phillip Newmark, Ph.D., who is also an HHMI Investigator. A Rita C. and William P. Clements, Jr. Scholar in Biomedical Research, Dr. Collins has received the Burroughs Wellcome Fund’s Investigator in the Pathogenesis of Infectious Disease award and the 2023 Edith and Peter O’Donnell Award in Biological Sciences from the Texas Academy of Medicine, Engineering, Science and Technology (TAMEST). He holds the Jan and Bob Bullock Distinguished Chair for Science Education and the Jane and Bud Smith Distinguished Chair in Medicine at UT Southwestern and is a member of the Harold C. Simmons Comprehensive Cancer Center.

Other Howard Hughes Medical Institute Investigators at UT Southwestern are: 

• Zhijian “James” Chen, Ph.D., Professor of Molecular Biology and in the Center for the Genetics of Host Defense, who holds the George L. MacGregor Distinguished Chair in Biomedical Science.
• Ralph DeBerardinis, M.D., Ph.D., Professor in Children’s Medical Center Research Institute at UT Southwestern, the Eugene McDermott Center for Human Growth and Development, and the Department of Pediatrics, and Director of the Genetic and Metabolic Disease Program at CRI, who holds the Joel B. Steinberg, M.D. Distinguished Chair in Pediatrics and is a Sowell Family Scholar in Medical Research.
• Helen Hobbs, M.D., Professor and Director of the Eugene McDermott Center for Human Growth and Development and Professor of Internal Medicine and Molecular Genetics, who holds the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development, the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Chair in Developmental Biology, and the 1995 Dallas Heart Ball Chair in Cardiology Research.
• Lora Hooper, Ph.D., Chair and Professor of Immunology, Professor of Microbiology and in the Center for the Genetics of Host Defense, who holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology, and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in Honor of Dr. Bill S. Vowell.
• Youxing Jiang, Ph.D., Professor of Physiology and Biophysics, who holds the Rosewood Corporation Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research.
• David Mangelsdorf, Ph.D., Chair and Professor of Pharmacology and Professor of Biochemistry, who holds the Alfred G. Gilman Distinguished Chair in Pharmacology and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.
• Joshua Mendell, M.D., Ph.D., Professor of Molecular Biology, who holds the Charles Cameron Sprague, M.D. Chair in Medical Science.
• Sean Morrison, Ph.D., Professor and Director of Children’s Medical Center Research Institute at UT Southwestern and Professor of Pediatrics, who holds the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern and the Mary McDermott Cook Chair in Pediatric Genetics.
• Kim Orth, Ph.D., Professor of Molecular Biology and Biochemistry, who holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research.
• Duojia Pan, Ph.D., Chair and Professor of Physiology, who holds the Fouad A. and Val Imm Bashour Distinguished Chair in Physiology.
• Michael K. Rosen, Ph.D., Chair and Professor of Biophysics, who holds the Mar Nell and F. Andrew Bell Distinguished Chair in Biochemistry.
• Vincent Tagliabracci, Ph.D., Associate Professor of Molecular Biology, who is a Michael L. Rosenberg Scholar in Medical Research.
• Benjamin Tu, Ph.D., Professor of Biochemistry, who holds the Martha Steiner Professorship in Medical Research and is a UT Southwestern Presidential Scholar and a W.W. Caruth, Jr. Scholar in Biomedical Research.

Dr. Podolsky holds the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration and the Doris and Bryan Wildenthal Distinguished Chair in Medical Science.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – July 18, 2024 – Cancer cells salvage purine nucleotides to fuel tumor growth, including purines in foods we eat, an important discovery with implications for cancer therapies from research by Children’s Medical Center Research Institute at UT Southwestern published in Cell.

CRI Assistant Professor Gerta Hoxhaj, Ph.D., and her team have challenged the long-standing belief that tumors primarily acquire purine nucleotides – building blocks for DNA, which is required for cellular growth and function – by constructing them from scratch via de novo synthesis. The Hoxhaj Lab’s newest research shows tumors also significantly use the more efficient salvage, or recycling, pathway to acquire purines.

“For more than 70 years, drugs targeting purine nucleotides have been a cornerstone of cancer treatment, but these treatments have limitations, and drug resistance often develops,” Dr. Hoxhaj said. “Our research illuminates the contributions of both pathways – de novo and salvage – and highlights the crucial, yet previously overlooked, role the salvage pathway plays in tumor growth.”

The study's co-first authors are, from left, Senior Research Scientist Diem Tran, Ph.D., postdoctoral fellow Rushendhiran Kesavan, Ph.D., and UT Southwestern graduate student
Dohun Kim, B.S.

Dr. Hoxhaj, with co-authors Diem Tran, Ph.D., Rushendhiran Kesavan, Ph.D., and Dohun Kim, B.S., used isotope tracing to follow the de novo and salvage purine pathways across normal mouse tissues and a variety of cancer types, including breast, kidney, colon, and liver cancers.

Normal tissue analyses showed the kidney salvaged the most purines, which could explain why people with kidney disease are at higher risk for gout. Gout, a type of arthritis linked to uric acid buildup, may be caused by the kidney’s inability to process uric acid, a purine byproduct.

When conducting the same analyses on tumors, CRI researchers discovered cancer cells use both de novo and salvage pathways to fulfill their constant need for purines. Additionally, tumors grew faster in mice given a high dose of oral nucleotides, indicating purines from the diet contribute to cancer growth.

This illustration shows nucleotides from dietary sources being salvaged by a tumor cell. (Credit: DRAWIMPACTS)

“While our food provides sugars, proteins, and fats, it also supplies purine nucleotides, especially from meat products. Our research could pave the way for doctors to include dietary interventions when creating a treatment strategy for cancer patients – restricting nucleotide availability could be a new tool to slow cancer progression,” Dr. Hoxhaj said.

Dr. Hoxhaj is also an Assistant Professor of Pediatrics and Biochemistry at UT Southwestern. She is a Pew-Stewart Scholar, Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, V Foundation Scholar, American Cancer Society (ACS) Scholar, and 2024 recipient of the Vilcek Prize for Creative Promise in Biomedical Science. She is also a member of Harold C. Simmons Comprehensive Cancer Center.

This research was supported by National Institutes of Health grants, CPRIT, ACS Scholar award, V Foundation Award, Welch Foundation grant, TSC Alliance grant, and a pilot UTSW Kidney Cancer SPORE grant.

Research was also conducted and supported by CRI Metabolomics Shared Facility, UT Southwestern Quantitative Light Microscopy Core, and the UT Southwestern Whole Brain Microscopy Facility.

Dr. Tran is a CRI Senior Research Scientist, Dr. Kesavan is a CRI postdoctoral fellow, and Mr. Kim is pursuing a Ph.D. in cancer biology at UT Southwestern. All three work in CRI’s Hoxhaj Lab.

About CRI

Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology and metabolism.

X/Twitter | LinkedIn | Instagram | YouTube | Facebook | Website

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year. 

DALLAS – July 17, 2024 – A team led by UT Southwestern Medical Center researchers has discovered a new way that cells regulate senescence, an irreversible end to cell division. The findings, published in Cell, could one day lead to new interventions for a variety of conditions associated with aging, including neurodegenerative and cardiovascular diseases, diabetes, and cancer, as well as new therapies for a collection of diseases known as ribosomopathies.

Joshua Mendell, M.D., Ph.D., is Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He is a Howard Hughes Medical Institute Investigator and holds the Charles Cameron Sprague, M.D. Chair in Medical Science.

“There is great interest in reducing senescence to slow or reverse aging or aging-associated diseases. We discovered a noncoding RNA that when inhibited strongly impairs senescence, suggesting that it could be a therapeutic target for conditions associated with aging,” said Joshua Mendell, M.D., Ph.D., Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He is also a Howard Hughes Medical Institute Investigator.

Dr. Mendell led the study with co-first authors Yujing Cheng, Ph.D., recent graduate of the Genetics, Development, and Disease graduate program, and Siwen Wang, M.D., a former postdoctoral researcher, both in the Mendell Lab.

Cellular senescence is a “double-edged sword,” Dr. Mendell explained. Cells sometimes undergo senescence when a cancer-causing mutation arises, halting uncontrolled cell division and preventing tumors from developing. On the other hand, too much senescence contributes to aging and degenerative diseases.

The Mendell Lab has long studied noncoding RNAs, finding new roles for these molecules in both health and disease. In this newest study, he and his colleagues used a technique for regulating gene activity called CRISPR interference to individually inactivate thousands of noncoding RNAs in human cells that carried a cancer-causing mutation. Usually, this mutation prompts cells to become senescent; however, inactivating a noncoding RNA involved in senescence caused the cells to continue dividing.

These experiments quickly revealed a previously unrecognized regulator of senescence called SNORA13, a member of a family of noncoding RNAs known as small nucleolar RNAs that are thought largely to function as guides for chemical modification of other RNA molecules. A series of additional experiments showed that SNORA13 plays another important and unexpected role: slowing down the construction of ribosomes, cellular machines that synthesize proteins.

Dr. Mendell explained that cellular stress – prompted by a cancer-causing mutation, for example – can perturb ribosome assembly and push cells into senescence. However, removing SNORA13 caused cells to ramp up ribosome assembly, blocking the quality control that would normally trigger senescence and allowing cells to continue dividing.

Learning more about this process could eventually help researchers control it, Dr. Mendell said. For example, developing drugs that push cells into senescence could offer a new way to treat cancer. Conversely, developing drugs that prevent senescence could slow aging and diseases that typically accompany it, such as cardiovascular diseases, neurodegenerative diseases, and diabetes.

In addition, because of SNORA13’s essential function in regulating ribosome assembly, targeting this noncoding RNA could someday be used to treat ribosomopathies, diseases characterized by abnormal ribosome production or function, such as Treacher Collins syndrome or Diamond-Blackfan anemia.

Other UTSW researchers who contributed to this study are Michael Buszczak, Ph.D., Professor of Molecular Biology; Hao Zhu, M.D., Professor in Children’s Medical Center Research Institute at UT Southwestern and of Internal Medicine and Pediatrics and co-leader of the Development and Cancer Research Program in the Simmons Cancer Center; Asha Acharya, Ph.D., and Tsung-Cheng Chang, Ph.D., Assistant Professors of Molecular Biology; Jong-Sun Lee, Ph.D., Assistant Instructor of Molecular Biology; He Zhang, Ph.D., Computational Biologist III; Chunyang Ni, Ph.D., Research Associate; Eric Chen, B.S., graduate student researcher; and Jason Guo, B.S., medical student.

Dr. Mendell holds the Charles Cameron Sprague, M.D. Chair in Medical Science. Dr. Buszczak holds the Lillian B. and Tom B. Rhodes Professorship in Stem Cell Research and is an E.E. and Greer Garson Fogelson Scholar in Medical Research. Dr. Zhu holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research. Drs. Buszczak and Zhu are also Simmons Cancer Center members. Dr. Zhu is supported by an Emerging Leader Award from the Mark Foundation for Cancer Research.

This study was funded by grants from the Cancer Prevention and Research Institute of Texas (RP220309), The Welch Foundation (I-1961-20210327 and I-1961-20240404), the Mark Foundation for Cancer Research (21-003-ELA), the Department of Defense (W81XWH2110815), and the National Institutes of Health (R01CA282036, R01CA251928, R35GM144043, R01AG079513, and P30 CA142543).

Dr. Mendell is a scientific adviser for Ribometrix Inc. and owns equity in Orbital Therapeutics Inc., both of which are developing RNA-based therapies. Dr. Zhu is academic co-founder of Quotient Therapeutics and Jumble Therapeutics, has sponsored research agreements with Alnylam Pharmaceuticals and Chroma Medicine, and serves on the scientific advisory boards for NewLimit and Ubiquitix. UTSW has filed a provisional patent on the inhibition of SNORA13 as a strategy to increase ribosome biogenesis.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – July 15, 2024 – UT Southwestern Medical Center is the No. 1 hospital in Dallas-Fort Worth for the eighth consecutive year and ranks among the nation’s top hospitals for care in 11 specialties – the most of any hospital in Texas, according to U.S. News & World Report’s annual Best Hospitals list released today.

Six specialties are ranked in the top 25: cancer; cardiology, heart, and vascular surgery; diabetes and endocrinology; neurology and neurosurgery; pulmonology and lung surgery; and rehabilitation. In addition, UT Southwestern is rated “High Performing” in 19 out of 20 procedures and conditions, from aortic valve surgery and hip replacement to back surgery (spinal fusion) and stroke care.

“Our collaborative multidisciplinary approach to patient care, as in our overall mission to educate, discover, and heal, continues to drive innovation at UT Southwestern and produce exceptional outcomes for the patients and families we are privileged to serve,” said Daniel K. Podolsky, M.D., President of UT Southwestern. “In parallel with ensuring that our patients have access to the most advanced technologies and treatments, we remain hyperfocused on providing the best care experience for them and their families. In the search for an even better tomorrow, our campus community is committed to translating scientific discoveries into improved treatments not only for our patients but also for patients worldwide.”

Among the 4,500 hospitals reviewed by U.S. News, UT Southwestern is ranked among the top 50 nationwide in the following 11 specialties – the most of any hospital in Texas:

• 15: Diabetes & Endocrinology
• 15: Rehabilitation
• 17: Pulmonology & Lung Surgery
• 19 (tie): Neurology & Neurosurgery
• 21 (tie): Cardiology, Heart & Vascular Surgery
• 25: Cancer
• 26: Otolaryngology – Ear, Nose & Throat
• 27: Geriatrics
• 30: Gastroenterology & GI Surgery
• 33 (tie): Urology
• 49: Orthopaedics

UT Southwestern, ranked No. 2 among all hospitals in Texas, also earned “High Performing” designations for 19 of the 20 procedures and conditions included in the U.S. News rankings: abdominal aortic aneurysm repair; aortic valve surgery; back surgery (spinal fusion); chronic obstructive pulmonary disease (COPD); colon cancer surgery; diabetes; gynecological cancer surgery; heart attack; heart bypass surgery; heart failure; hip fracture; hip replacement; kidney failure; leukemia, lymphoma, and myeloma; lung cancer surgery; pneumonia; prostate cancer surgery; stroke; and transcatheter aortic valve replacement (TAVR). 

The Southwestern Health Resources network – which aligns the strengths of UT Southwestern with those of Texas Health Resources – has five of the 10 top-ranked hospitals in Dallas-Fort Worth. In addition to UT Southwestern at No. 1, Texas Health Presbyterian Hospital Dallas ranked No. 4, Texas Health Harris Methodist Hospital Southwest Fort Worth ranked No. 5, Texas Health Harris Methodist Hospital Fort Worth tied for No. 6, and Texas Health Presbyterian Hospital Plano tied for No. 8. The patient-centered, clinically integrated network of 31 hospital locations and more than 7,000 physicians and other providers cares for more than 750,000 individuals across 16 counties in North Texas. Children’s Medical Center Dallas, where the UT Southwestern Pediatric Group practices, was rated among the nation’s best pediatric hospitals by U.S. News for 2023-24 and was the only pediatric hospital in North Texas ranked in all 10 specialties. (This year’s pediatric rankings will be released in the fall.) 

Growing to meet today’s needs and those of the future

UT Southwestern continues to expand to meet the health care needs of patients now and for decades to come. Earlier this year, UT Southwestern and Children’s Health announced plans for a transformative $5 billion pediatric campus in Dallas’ Southwestern Medical District across from William P. Clements Jr. University Hospital and connected by bridge. The approximately 2 million-square-foot hospital will have two 12-story towers and one eight-story tower to replace the existing Children’s Medical Center Dallas, significantly expanding inpatient, surgical, and ambulatory capacity to meet the needs of one of the country’s fastest-growing and largest metropolitan areas. 

On the other end of the UTSW campus, construction of the state’s newest psychiatric hospital is well underway. The Texas Behavioral Health Center at UT Southwestern is a collaborative project of the Texas Health and Human Services Commission, UT Southwestern, and Children’s Health. The adult portion of the facility is slated to open in late 2025, with a pediatric wing to follow in 2026. 

In 2023, UT Southwestern opened a regional medical center in Coppell, broadening its reach to seven satellite locations in DFW, including Frisco, Fort Worth, and Richardson/Plano. 

In 2022, UT Southwestern opened a 12-story Cancer Care Outpatient Building to serve patients of the Harold C. Simmons Comprehensive Cancer Center and also opened UT Southwestern Medical Center at RedBird to improve access to care for those living and working in southwestern Dallas County. 

Last fall, the Peter O’Donnell Jr. School of Public Health, the first new school at UT Southwestern in 50 years, started inaugural classes in the Master of Public Health (M.P.H.) program and in the combined Doctor of Medicine/Master of Public Health (M.D./M.P.H.) program. A Ph.D. program will begin later this year. The school is training a new generation of leaders who can respond to emerging public health needs.

Other recent national distinctions

• Clements University Hospital was honored earlier this year with Press Ganey’s Pinnacle of Excellence Award and its Guardian of Excellence Award in the patient satisfaction category.
• UT Southwestern Medical School was ranked No. 24 nationally among the best medical schools for research and No. 26 for best medical school for primary care (tie), by U.S. News. The UT Southwestern Graduate School of Biomedical Sciences and the School of Health Professions also have nationally rated programs.
• UT Southwestern is ranked No. 3 among global health care institutions in the 2023 Nature Index for its published research.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – July 15, 2024 – A protein receptor called PAQR4 found within fat cells appears to act as a sensor for ceramides, waxy lipids whose overabundance has been linked to a variety of metabolic disorders and cancers, a study led by UT Southwestern Medical Center researchers suggests. Their findings, published in Nature Metabolism, could eventually lead to drugs that reduce cellular ceramide levels, much like statins reduce cholesterol levels.

Philipp Scherer, Ph.D., is Professor of Internal Medicine and Cell Biology and Director of the Touchstone Center for Diabetes Research at UT Southwestern.

“Rising ceramides in the cell are responsible for inflammation, insulin resistance, and cell death,” said study leader Philipp Scherer, Ph.D., Professor of Internal Medicine and Cell Biology and Director of the Touchstone Center for Diabetes Research at UT Southwestern. “Just like cholesterol, excessive levels of ceramides are particularly bad for the cell and metabolism at large. Defining a cellular mechanism by which levels of ceramides are sensed is therefore quite important.”

Ceramides play critical roles in tissues throughout the body. They help the skin form a moisture-retaining barrier and insulate nerves, for example. However, their overabundance is tied to several conditions, including Type 2 diabetes, cardiovascular disease, and multiple malignancy types including skin, non-small cell lung, prostate, and breast cancers.

For the last three decades, the Scherer Lab has studied molecular pathways related to adiponectin, a hormone with roles in various metabolic processes. The hormone is also known for its healthful insulin-sensitizing and anti-inflammatory effects. Adiponectin exerts these effects by binding to two receptors known as PAQR1 and PAQR2 present on the surface of fat cells. PAQR4, a receptor in the same protein family, has an extremely similar structure; however, its function has been unknown.

Wondering whether PAQR4 might also interact with adiponectin to provide health benefits, the researchers investigated its role by genetically modifying lab mice so that they overproduced PAQR4. Despite no change in their food intake, these animals lost weight when carrying higher levels of PAQR4.

Qingzhang Zhu, Ph.D., is first author on the study and Instructor of Internal Medicine at UT Southwestern.

While weight loss is often an indicator of improved metabolic health, these animals were far from healthy. Their blood sugar and insulin production sharply increased, suggesting that they had developed diabetes, and their livers became loaded with excess fat.

When Qingzhang Zhu, Ph.D., first author on the study and Instructor of Internal Medicine at UTSW, genetically modified other lab mice to shut off PAQR4 production, their metabolic health improved. Similar effects occurred when using a drug to block cellular production of ceramides. Additional experiments showed that PAQR4 appears to detect the quantity of ceramides in fat cells. In turn, by mediating the stability of proteins that synthesize ceramides, PAQR4 regulates how much of these lipids are present in cells, hence acting as an important sensor for the levels of cellular ceramides.

Dr. Scherer said further research will look at ways to target PAQR4 with drugs that decrease its function and consequently stymie ceramide production, which could treat or prevent these conditions.

Other UTSW researchers who contributed to this study include Ruth Gordillo, Ph.D., Associate Professor of Internal Medicine; Christine M. Kusminski, Ph.D., and Daeseok Kim, Ph.D., Assistant Professors of Internal Medicine; Christy Gliniak, Ph.D., Instructor of Internal Medicine; Shiuhwei Chen, M.S., Senior Research Associate; Jan-Bernd Funcke, Ph.D., Qian Lin, Ph.D., and Line Pedersen, Ph.D., postdoctoral researchers; and Chanmin Joung, B.S., graduate student researcher.

Dr. Scherer holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research and the Touchstone/West Distinguished Chair in Diabetes Research. Dr. Scherer is also a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

This study was funded by grants from the National Institutes of Health (RC2-DK118620, R01-DK55758, R01-DK099110, R01-DK127274, P01-AG051459, R01-DK131537, P30-DK127984, and R00-AG068239), a DFG Walter Benjamin Fellowship (444933586), and an American Heart Association Career Development Award (855170).

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – June 26, 2024 – Researchers at UT Southwestern Medical Center developed nanoparticles that successfully edited the disease-causing gene in the lungs of a mouse model of cystic fibrosis (CF), swapping a mutated form with a healthy one that persisted in stem cells. Their findings, reported in Science, could offer hope for people with CF and other debilitating genetic lung diseases.

Daniel Siegwart, Ph.D., is Professor of Biomedical Engineering and Biochemistry and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

“If these findings in mice can be translated to humans, the discovery suggests that single-dose genome-editing therapy may provide years to a lifetime of therapeutic benefit in people with CF,” said study leader Daniel Siegwart, Ph.D., Professor of Biomedical Engineering and Biochemistry and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Gene editing – a group of technologies designed to correct disease-causing mutations in the genome – has the potential to revolutionize medicine, Dr. Siegwart explained. Targeting these technologies to specific organs, tissues, or cell populations will be necessary to effectively and safely treat patients.

In 2020, the Siegwart Lab reported a new approach that it named Selective Organ Targeting, or SORT, that uses specific components in the lipid nanoparticles (LNPs) that encapsulate gene-editing molecules to target certain organs. Although researchers demonstrated that SORT could deliver gene-editing machinery to the lungs, it was unknown whether this strategy could successfully edit lung stem cells.

Because the lining of the lungs renews itself every few months, editing the disease-causing genes in stem cells is essential to providing a long-lasting therapy, Dr. Siegwart said. Such a treatment would be especially beneficial for the roughly 10% of people with CF whose disease is caused by rare mutations in a gene called CFTR or a specific CFTR mutation type known as “nonsense” mutations, such as R553X. Their disease cannot be treated by Trikafta, a drug that’s the current gold-standard therapy for CF.

The researchers initially worked with healthy mice that were genetically manipulated so the cells that undergo gene editing would glow red. They then intravenously delivered SORT LNPs containing gene-editing machinery aimed at the lungs. A persistent red glow in the lungs showed that cells with edited genes remained present for at least 22 months. Further investigation showed that more than 70% of the animals’ lung stem cells had undergone gene editing.

In another experiment, researchers used the SORT system on lung cells isolated from people with CF that were grown at an air-liquid interface, a scenario that mimics the biology of the lung and is considered a strong predictor of therapeutic efficacy in humans. Tests showed that mutant genes in most cells were corrected, leading to a restoration of functional activity comparable with what can be achieved when eligible patients are treated with Trikafta.

Next, the researchers worked with mice carrying the R553X mutation. Although mouse models of CF don’t experience the respiratory symptoms characteristic of human CF, they do have distinct physiological differences compared with healthy mice. Experiments showed that gene editing was also successful in this disease model.

Taken together, Dr. Siegwart said, these findings suggest that gene editing using SORT holds promise to treat CF and possibly other genetic lung diseases long term. More research will be necessary to investigate this approach in animal models that share CF symptoms and to ensure the safety of this prospective therapy.

Other UTSW researchers who contributed to this study are co-first authors Yehui Sun, M.S., graduate student researcher, and Sumanta Chatterjee, Ph.D., Instructor of Biomedical Engineering; Raksha Jain, M.D., Professor of Internal Medicine and Medical Director of the Adult Cystic Fibrosis Program; Pratima Basak, Ph.D., Lab Manager; Xu Wang, Ph.D., Senior Research Associate; postdoctoral researchers Xizhen Lian, Ph.D., Yufen Xiao, Ph.D., Yun-Chieh Sung, Ph.D., Minjeong Kim, Ph.D., and Sang M. Lee, Ph.D.; and graduate student researchers Stephen Moore, B.S., and Shiying Wu, B.S.

Dr. Siegwart holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research. Dr. Jain is a Dedman Family Scholar in Clinical Care.

This research was funded by the Cystic Fibrosis Foundation (SIEGWA18XX0, SIEGWA21XX0, HODGES19R1, and CONLON18G0), the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1), and a Sponsored Research Agreement with ReCode Therapeutics. The UTSW Small Animal Imaging Shared Resource is supported in part by a National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543) and the Cancer Prevention and Research Institute of Texas (CPRIT) (RP210099).

Dr. Siegwart is a co-founder and member of the scientific advisory board of ReCode Therapeutics, which has licensed intellectual property from UTSW. Dr. Siegwart has financial interests in ReCode Therapeutics, Signify Bio, and Tome Biosciences. Dr. Jain previously served on the ReCode clinical advisory committee.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

The Cancer Care Outpatient Building at UT Southwestern in Dallas, Texas, is part of the Harold C. Simmons Comprehensive Cancer Center.

DUARTE, Calif. – June 12, 2024 – AccessHope, LLC, a company changing the way leading-edge cancer expertise is delivered, today announced that UT Southwestern Harold C. Simmons Comprehensive Cancer Center will become the seventh National Cancer Institute (NCI)-designated center in the AccessHope network. Through this collaboration, more people living with complex cancer will have access to insights on targeted treatments and potential clinical trials from oncology experts at Simmons Cancer Center based in Dallas.

“Since its inception, AccessHope’s mission has been to deploy the latest cancer care knowledge to the places and people who need it most, when it is most valuable – ensuring that every member, no matter where they live, has access to the best treatment knowledge to meet their unique needs,” said AccessHope CEO Brad Kreick. “The addition of Simmons Cancer Center to our growing roster of foundational partners further extends our ability to help more people with cancer. Working together, we can ensure more members benefit from the latest research, clinical insights, and effective treatment plans recommended by leading experts in the field.”

Carlos L. Arteaga, M.D., is Professor and Director of Simmons Cancer Center and Associate Dean of Oncology Programs at UT Southwestern.

Cancer specialists from Simmons Cancer Center will provide expert clinical insights for AccessHope’s employer plan members and their treating oncologists in Texas, Arkansas, Louisiana, and Oklahoma.

Simmons Cancer Center draws its 265 clinical and research members from 36 departments across UT Southwestern, one of the premier medical centers in the U.S. It is the only NCI-Designated Comprehensive Cancer Center in North Texas and is ranked among the nation’s top 20 hospitals for cancer care by U.S. News & World Report. With Specialized Programs of Research Excellence (SPOREs) in kidney and lung cancer, over $110 million in total cancer-focused research funding, and 15 multidisciplinary disease-oriented teams, Simmons Cancer Center conducts laboratory, clinical, and population-based research, leading to new drugs and treatments designed to improve patient care and ultimately save lives.

“Through our groundbreaking research and exceptional patient care, we strive to ease the burden of cancer in North Texas and beyond‚” said Carlos L. Arteaga, M.D., Professor and Director of Simmons Cancer Center and Associate Dean of Oncology Programs at UT Southwestern. “By joining forces with AccessHope, we are able to further broaden our impact by providing more patients with recommendations of the most up-to-date and impactful treatments.”

In addition to Simmons Cancer Center, AccessHope has partnered with six other NCI-Designated Comprehensive Cancer Centers: City of Hope, Dana-Farber Cancer Institute, Emory Healthcare and Winship Cancer Institute of Emory University, Fred Hutch Cancer Center, Johns Hopkins Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Northwestern Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Patients who receive care at an NCI-Designated Cancer Center have significantly better outcomes, including improved long-term survival and strengthened treatment guideline adherence, yet only 20% of patients have access to these elite facilities. AccessHope’s ability to connect members to remote cancer support services aims to extend oncology expertise across the United States, in every state and ZIP code, reducing cancer health disparities while allowing plan members to stay close to home.

About AccessHope

AccessHope, LLC, believes in putting the ever-growing body of cancer knowledge to work for the greater good. The company delivers a revolutionary cancer benefit that is changing the way leading-edge expertise is delivered. Through collaborations with City of Hope, Dana-Farber Cancer Institute, Emory Healthcare and Winship Cancer Institute of Emory University, Fred Hutch Cancer Center, Johns Hopkins Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Northwestern Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, and UT Southwestern Medical Center and its Harold C. Simmons Comprehensive Cancer Center, AccessHope shares the latest discoveries in cancer care with employees' plans and local oncologists to help as they develop precise plans for treatment. The company brings the vast expertise of major medical centers to benefit people near and far. They never have to switch doctors. They never have to leave home. It's simply a better approach to treating cancer. An organization founded by City of Hope, AccessHope offers the benefit to approximately seven million members through more than 400 employers, including over 60 Fortune 500 companies. For more information about AccessHope, visit myaccesshope.org and follow us on LinkedInand Twitter.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

Rapalogs (or rapamycin analogs) are used to treat renal cell carcinoma (RCC) and other tumor types, but their utility is hindered because tumors become resistant over time. Why this occurs has remained unknown since the drugs were first introduced for kidney cancer treatment in 2007.

Resistance to targeted therapies, such as rapalogs, often involves mutations in the drug target that interfere with drug binding. However, mTOR, the drug target, is not mutated when RCC tumors become resistant.

James Brugarolas, M.D., Ph.D., is Professor of Internal Medicine in the Division of Hematology and Oncology and founding Director of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D.

To model resistance to rapalogs, investigators in the Brugarolas Lab leveraged their SPORE-funded tumorgraft program, one of the largest such programs worldwide. As they had done previously when evaluating resistance against HIF2α-blocking drugs (another class of FDA-approved drugs for RCC), they treated mice transplanted with patient RCC tumors with rapamycin until resistance developed. While the drug target is often reactivated when resistance develops, unexpectedly, mTOR remained suppressed in tumor cells.

Previous experiments with HIF2α-blocking drugs revealed that drug resistance resulted from a mutation in HIF2α that allowed it to remain active even in drug-treated tumor cells, and the same results were subsequently found in drug resistant patients’ tumors.

However, when resistance against rapamycin developed, the drug still blocked mTOR activity in tumor cells. Strikingly, however, mTOR became reactivated in cells around the tumor, known as the tumor microenvironment (TME).

To determine the role of the TME, investigators engineered mice to make a form of mTOR that was resistant to rapamycin. The researchers hypothesized that if suppression of mTOR in the TME was important for rapalog activity, patient tumors should be less responsive to the drug when transplanted into these mice.

Inhibition of the tumor microenvironment (TME) by rapalog drugs is essential for their anti-tumor activity.

The investigators found that rapamycin was far less effective at killing transplanted RCC tumors in these mice. Thus, even though mTOR was readily inhibited in the transplanted human tumor cells, failure to inhibit mTOR in the TME, which develops from the host mice, caused drug resistance.

These studies merged two traditional but distinct approaches to cancer modeling – tumor transplantation and genetic engineering – and showed that the TME plays a critical role in mediating the activity of rapalogs.

The findings pave the way for novel therapeutic strategies that target the tumor microenvironment. “By implicating tumor support cells in drug resistance, this study addresses a longstanding question since the first rapalog approval nearly two decades ago,” said lead author James Brugarolas, M.D., Ph.D., Professor of Internal Medicine in the Division of Hematology and Oncology and founding Director of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

The study was supported by a National Cancer Institute Specialized Program of Research Excellence (SPORE) grant (P50CA196516) and the National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

Other UTSW researchers who contributed to this study are Payal Kapur, M.D., Professor of Pathology and Urology; Robert E. Hammer, Ph.D., Professor of Biochemistry; postdoctoral fellows Ramesh Butti, Ph.D., and Arijit Mal, Ph.D.; Vanina Toffessi Tcheuyap, M.S., Research Associate; Mylinh Nguyen, M.S., Senior Research Scientist; Alana Christie, M.S., Biostatistical Consultant; and Jiwoong Kim, M.S., Computational Biologist. 

Dr. Brugarolas holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. Dr. Hammer holds the Graydon Heartsill Professorship in Medical Science. Dr. Kapur holds the Jan and Bob Pickens Distinguished Professorship in Medical Science, in Memory of Jerry Knight Rymer and Annette Brannon Rymer, and Mr. and Mrs. W.L. Pickens.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – June 11, 2024 – In a large clinical trial, UT Southwestern Medical Center researchers developed a robust model for testing strategies to prevent health problems in patients with multiple chronic conditions. The study, published in the New England Journal of Medicine, addressed a lack of research on the effectiveness of guideline-directed therapies and included patients from racial groups who are typically underrepresented in clinical trials.

Miguel Vazquez, M.D., is Professor of Internal Medicine and Clinical Director of the Division of Nephrology at UT Southwestern. He is also Chief of Nephrology at Parkland Health.

Miguel Vazquez, M.D., Professor of Internal Medicine and Clinical Director of the Division of Nephrology at UT Southwestern, said the trial was notable for taking place under real-world conditions. “We proved that it was possible to conduct a rigorous trial where patients from multiple large health care clinics are receiving care to test interventions for overlapping diseases that can cause serious complications and death,” he said.

Dr. Vazquez led the study with Robert Toto, M.D., Professor of Internal Medicine, Director of the Center for Translational Medicine, Medical Director of UT Southwestern’s Multi-Specialty Clinic, and Associate Dean of the UT Southwestern Clinical and Translational Science Award (CTSA) Program.

The co-occurrence of chronic health conditions is increasingly common in the U.S. Therapies based on clinical guidelines are often used to decrease hospitalizations and death for these patients, but there are barriers to receiving guideline-directed therapies, including physicians who are overwhelmed by the many demands of their patients.

The researchers evaluated whether providing physicians with additional support would improve health for patients living with a kidney-dysfunction triad of chronic kidney disease, Type 2 diabetes, and hypertension, which together pose a high risk for major cardiovascular issues and kidney failure.

Robert Toto, M.D., is Professor of Internal Medicine and in the Peter O'Donnell Jr. School of Public Health, Director of the Center for Translational Medicine, Medical Director of UT Southwestern's Multi-Specialty Clinic, and Associate Dean of the UT Southwestern Clinical and Translational Science Award (CTSA) Program. A Distinguished Teaching Professor, Dr. Toto holds the Mary M. Conroy Professorship in Kidney Disease.

They enrolled 11,000 adults with the kidney-dysfunction triad who were being treated at 141 primary care practices, including through Parkland Health, Texas Health Resources, and the VA North Texas Health Care System, all in Dallas-Fort Worth.

All patients had access to guideline-directed therapies such as blood pressure targets, immunizations, and education as a typical part of their care. Half of the patients received these therapies with the addition of an electronic algorithm to identify patients and practice facilitators assigned to support primary care providers at participating clinics.

“The interventions we tested are treatments that patients should be receiving, but they may not be,” Dr. Vazquez explained. “It’s difficult to address multiple complex problems at primary care practices where patients are seen for a short amount of time with limited resources.”

The team predicted that having facilitators support physicians and patient care would reduce health problems in kidney-dysfunction triad patients. However, there was no significant difference in outcomes between the two groups. Hospitalizations were reported in 20.7% of the intervention group and 21.1% in the usual-care group. Rates of emergency room visits were 24.3% for the intervention group and 22.6% for the usual-care group. Other outcomes – cardiovascular events, dialysis, and death – occurred at similar rates for both groups.

The project addressed the lack of research on the practical effects of guideline-based interventions in health care settings. Partnering with a private nonprofit, a public safety-net health care system, a veterans health care system, and a private health care system made the findings in this study broadly relevant to patients from diverse socioeconomic groups and racial/ethnic groups.

“We performed this study to gain insight on testing interventions to prevent health outcomes that are meaningful for patients, their families, and caregivers,” Dr. Toto said. “We’ve learned a lot about overcoming barriers to conducting a large, high-fidelity trial in a real-world situation and developed a platform that others can use to conduct similar studies.”

Other UTSW researchers from the Department of Internal Medicine who contributed to this study are Perry Bickel, M.D., Associate Professor and Chief of the Division of Endocrinology; Samir M. Parikh, M.D., Professor and Chief of the Division of Nephrology; Richard T. “Tyler” Miller, M.D., Professor of Internal Medicine and Vice Chair of the VA North Texas Health Care System; Susan Hedayati, M.D., Professor and Associate Vice Chair for Research in Internal Medicine; Jeffrey Hastings, M.D., Associate Professor of Internal Medicine in the Division of Cardiology and Chief of Staff at the VA North Texas Health Care System; and Blake Barker, M.D., Associate Professor of Internal Medicine and Associate Dean of Student Affairs for UT Southwestern Medical School. Other UTSW contributors from the Peter O’Donnell Jr. School of Public Health are Chul Ahn, Ph.D., Professor and Director of Biostatistics Shared Resource at the Harold C. Simmons Comprehensive Cancer Center, and Song Zhang, Ph.D., Professor and Director of Biostatistics, Epidemiology, and Research Design for the CTSA Program.

Dr. Vazquez is also the Chief of Nephrology at Parkland Health. Dr. Toto is also Professor in the O’Donnell School of Public Health. Dr. Hedayati is Director of Nephrology Clinical and Population Health Research.

A Distinguished Teaching Professor, Dr. Toto holds the Mary M. Conroy Professorship in Kidney Disease. Dr. Bickel holds the Daniel W. Foster, M.D. Distinguished Chair in Internal Medicine. Dr. Miller, who is also a Professor in the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, holds the Jacob Lemann, M.D. Professorship in Calcium Transport. Dr. Parikh holds the Robert Tucker Hayes Distinguished Chair in Nephrology, in Honor of Dr. Floyd C. Rector, Jr. and the Ruth W. and Milton P. Levy, Sr. Chair in Molecular Nephrology.

The trial was funded by the National Institutes of Health, which included a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NCT02587936).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

About Parkland Health

Parkland Health is one of the largest public hospital systems in the country. Premier services at the state-of-the-art Parkland Memorial Hospital include the Level I Rees-Jones Trauma Center, the only burn center in North Texas verified by the American Burn Association for adult and pediatric patients, and a Level III Neonatal Intensive Care Unit. The system also includes two on-campus outpatient clinics – the Ron J. Anderson, MD Clinic and the Moody Outpatient Center – as well as more than 30 community-based clinics and numerous outreach and education programs. By cultivating its diversity, inclusion, and health equity efforts, Parkland enriches the health and wellness of the communities it serves. For more information, visit parklandhealth.org.

DALLAS – June 4, 2024 – Two genes working in tandem play a critical role in shaping the identity and behavior of prostate cancer cells and their response to treatment, UT Southwestern Medical Center researchers report. The findings, published in Cancer Discovery, offer crucial insights into how cancer cells evade the current standard-of-care treatments and provide a potential target for the development of novel prostate cancer therapies.

Ping Mu, Ph.D., Assistant Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, is a Deborah and W. A. “Tex” Moncrief, Jr. Scholar in Medical Research.

“Our study reveals a new genetic and molecular process that controls how tumor cells change their type and respond to treatment,” said study leader Ping Mu, Ph.D., Assistant Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “These important discoveries enhance our understanding of what drives drug resistance and introduce a new approach for treating prostate cancer.”

Nearly 1 out of every 8 men will get prostate cancer during their lifetime, making it the most common cancer among men, according to the American Cancer Society.

Prostate cancer’s ability to adapt has proved a formidable challenge, with therapy resistance emerging as a significant obstacle. Advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), is particularly difficult due to its capacity to develop resistance to conventional therapies, such as androgen receptor (AR) inhibitors.

This resistance can arise due to lineage plasticity, where cancer cells undergo “identity switches,” enabling them to evade targeted treatments. Lineage plasticity allows cancer cells to switch from their original luminal lineage, driven by androgen receptor (AR) signaling, to alternative lineages, such as neuroendocrine or stem-like phenotypes, which are resistant to AR-targeted therapies originally designed to target their previous identities.

In this study, researchers identified a deficiency of Zinc Finger Protein 397 (ZNF397) as a critical trigger for this transformation in prostate cancer cells. This deficiency prompts a shift from a reliance on AR signaling for cell growth (the luminal lineage) to increased dependence on activity involving the gene Ten Eleven Translocation 2 (TET2), which encodes an enzyme that regulates DNA methylation, a critical epigenetic mechanism. The transition consequently renders cancer cells more flexible and adaptable, ultimately leaving them resistant to therapies targeting AR signaling.

The research also revealed the pivotal role of TET2 in driving epigenetic rewiring, which contributes to lineage plasticity and therapy resistance in prostate cancer, shedding light on how prostate cancer cells can adapt through epigenetic reprogramming. In addition, the study demonstrates that inhibiting TET2 can reverse resistance to AR-targeted therapies in ZNF397-deficient tumors. By genetically and pharmacologically inactivating TET2, the researchers effectively reversed resistance to AR-targeted therapies in ZNF397-deficient tumors.

The study builds upon previous research from the Mu Lab, furthering the understanding of lineage plasticity and drug resistance mechanisms and paving the way for personalized treatment strategies tailored to combat lineage plasticity-driven therapy resistance in prostate cancer.

“The possibility of reversing this type of resistance by targeting TET2 with drugs offers new paths for developing treatments for patients with advanced prostate cancer,” Dr. Mu said. “These insights could lead to clinical trials testing TET2 inhibitors in treating metastatic castration-resistant prostate cancer patients, potentially improving treatment results and increasing survival rates.”

Other UTSW researchers who contributed to this study include Ganesh V. Raj, M.D., Ph.D., Professor of Urology and Pharmacology; Carlos L. Arteaga, M.D., Professor and Director of the Simmons Cancer Center and Associate Dean of Oncology Programs; Ariella B. Hanker, Ph.D., Assistant Professor in the Simmons Cancer Center and of Internal Medicine; Tao Wang, Ph.D., Associate Professor in the Peter O’Donnell Jr. School of Public Health and the Center for the Genetics of Host Defense; Su Deng, Ph.D., Instructor of Molecular Biology; postdoctoral researchers Yaru Xu, Ph.D., Xiang Li, Ph.D., Xiaoling Li, Ph.D., and Quanhui Xu, Ph.D.; graduate student researchers Yuqiu Yang, M.S., Choushi Wang, B.S., Julisa Gonzalez, B.S., Atreyi Mukherji, B.S., Carla Rodriguez-Tirado, B.S., and Mia Hofstad, B.S.; Yuyin Jiang, B.S., Research Technician; and Lauren A. Metang, M.S., Senior Research Associate.

Dr. Mu is a Deborah and W. A. “Tex” Moncrief, Jr. Scholar in Medical Research at UTSW.

This study was funded by grants from the National Cancer Institute/National Institutes of Health (5R00CA218885 and 1R37CA258730, 1R01CA258584, T32C124334, 1F31CA261019-01A1), the U.S. Department of Defense (W81XWH-18-1-0411 and W81XWH21-1-0520, W81XWH21-1-0418), the Cancer Prevention & Research Institute of Texas (RR170050, RP220473, RP230363), the Prostate Cancer Foundation (17YOUN12 and 21YOUN10), The Welch Foundation (I-2005-20190330), a UT Southwestern Harold C. Simmons Comprehensive Cancer Center Pilot Award, the Simmons Cancer Center Data Science Shared Resource, the Terry Fox New Frontiers Program Project Grant (PPG19-1090), the National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543), and the Life Sciences Research Foundation.

Disclosures are listed in the study.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – May 29, 2024 – When cancer cells metastasize, breaking away from the primary tumor and spreading to blood, tissue, or lymph nodes, the disease is at its most lethal. In 2021, researchers at UT Southwestern Medical Center used artificial intelligence and deep machine learning to analyze 1.7 million raw images of patient-derived tumor samples, pinpointing a key distinction between skin cancer cells with high and low potential to metastasize – a discovery that could ultimately mean the difference between life or death for patients.

Gaudenz Danuser, Ph.D., Professor of Cell Biology and inaugural Chair of the Lyda Hill Department of Bioinformatics, is the Patrick E. Haggerty Distinguished Chair in Basic Biomedical Science.

The algorithm that helped make this possible is just one example of how AI is propelling UT Southwestern research and discoveries forward in laboratories, clinics, and classrooms across campus.

With AI assisting, UTSW physician-scientists are zeroing in on the most effective medications for depression, predicting insulin resistance in Type 2 diabetes, and grading medical students on simulated encounters with patients. AI is also playing a vital role in advancing personalized radiotherapy and cancer treatments as well as putting complex and costly genetic research well within reach.

AI catapulted heavily into the public consciousness in 2023 with the introduction of ChatGPT, a form of generative AI that astounded the public with its ability to churn out Shakespearean-style sonnets and surrealistic visuals in a matter of seconds. While much of the media attention surrounding AI has focused on these parlor tricks and the potential risks that this technology might pose to jobs, privacy, and society as a whole, its ability to accelerate biomedical research cannot be overstated.

Steve Jiang, Ph.D., is Professor, Vice Chair for Digital Health and AI, and Chief of the Division of Medical Physics and Engineering, in the Department of Radiation Oncology at UT Southwestern. He holds the Barbara Crittenden Professorship in Cancer Research.

“Medicine is one of the fastest-growing areas of AI research, and its effects could be life-changing,” said Gaudenz Danuser, Ph.D., Professor of Cell Biology and inaugural Chair of the Lyda Hill Department of Bioinformatics, who led the study on metastatic skin cancer.

Eric Peterson, M.D., M.P.H., Vice Provost and Senior Associate Dean for Clinical Research at UT Southwestern, holds the Adelyn and Edmund M. Hoffman Distinguished Chair in Medical Science.

AI is broadly defined as technology that autonomously reasons within machines and thus can come up with insights alternative to human thinking. But what individual researchers consider true AI can vary from algorithms trained to perform sophisticated pattern recognition to programs that mimic the neural wiring of human brains, said Steve Jiang, Ph.D., Professor, Vice Chair for Digital Health and AI, and Chief of the Division of Medical Physics and Engineering in the Department of Radiology Oncology at UTSW. He is also Director of the Medical Artificial Intelligence and Automation (MAIA) Lab.

These types of AI tools can make important contributions to health care, with many applications already in use or being rapidly developed at UTSW.

“I have no doubt,” said Dr. Jiang, “AI in health care will impact millions of lives.”

Two recent developments provide further proof that the era of AI is well underway at UT Southwestern.

In March 2024, UT Southwestern joined more than a dozen of the country’s top academic medical centers and Microsoft to form the Trustworthy & Responsible AI Network (TRAIN), a consortium designed to set quality and safety standards for the use of AI in health care and explore frameworks for collaboration and knowledge sharing.

And on May 30-31, UTSW will host the inaugural UT System AI Symposium in Health Care, bringing together scientists, clinicians, educators, and students from across the state to explore AI’s revolutionary potential.

“We are just beginning to see how much artificial intelligence can speed up the pace of scientific discovery,” said Eric Peterson, M.D., M.P.H., Vice Provost and Senior Associate Dean for Clinical Research at UT Southwestern, who is moderating the symposium. “At UT Southwestern, every day we’re finding new ways to harness AI to analyze vast amounts of data, enhance our biomedical research, and, ultimately, deliver the most advanced treatments to our patients.”  

Dr. Danuser is the Patrick E. Haggerty Distinguished Chair in Basic Biomedical Science. Dr. Jiang holds the Barbara Crittenden Professorship in Cancer Research. Dr. Peterson holds the Adelyn and Edmund M. Hoffman Distinguished Chair in Medical Science. Drs. Danuser and Jiang are members of the Harold C. Simmons Comprehensive Cancer Center. 

To see examples of how UT Southwestern is using AI, visit the MedBlog.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – May 24, 2024 – As the warm weather and summer vacations draw more people outdoors, a UT Southwestern Medical Center cancer specialist is reminding everyone to stay vigilant of potential sun damage.

Skin cancer is mainly caused by ultraviolet radiation from the sun. And while it is the most common of all cancers in the U.S., it is also one of the most avoidable forms of the disease.

Rohit Sharma, M.D., is Associate Professor of Surgery at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center.

“Overexposure to ultraviolet radiation is the most preventable risk factor for skin cancer, but skin cancer’s incidence rates continue to rise,” says Rohit Sharma, M.D., Associate Professor of Surgery at UT Southwestern, who specializes in melanoma, soft-tissue sarcoma, and other complex skin cancers. Dr. Sharma is also a member of the Harold C. Simmons Comprehensive Cancer Center.

About 1 in 5 Americans will get skin cancer by the age of 70, according to the Skin Cancer Foundation. People with fair skin as well as those with naturally blond or red hair are at greater risk. People who use tanning beds or spend time exposed to the sun without protection are also more vulnerable.

To be safe in the sun, Dr. Sharma recommends:

• Generously apply sunscreen to all exposed skin each day using a broad-spectrum sunscreen that protects against both UVA and UVB rays and has an SPF of at least 30.
• Be sure to use enough sunscreen for adequate protection. The skin should be reasonably saturated to assure coverage.
• Pay attention to the water-resistant rating of the sunscreen. When exercising or swimming, you will need to observe the time frame for reapplication. At a minimum, reapply every two hours, even on cloudy days. This applies to both lotions and sprays.
• Avoid tanning outdoors or using tanning beds indoors. Ultraviolet light from tanning beds and the sun causes damage such as skin cancer and wrinkling. Use a sunless self-tanning product instead.
• Wear protective clothing, including long sleeves, sunglasses, and a wide-brimmed hat that shades the face, ears, and neck when outdoors.
• Check whether any medications you take cause extra sensitivity to the sun’s rays.
• Seek shade and remember that the sun’s rays are strongest between 10 a.m. and 4 p.m.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – May 22, 2024 – The number of mutations in the DNA of cancerous tumors may not be an indicator of how well patients will respond to immune checkpoint inhibitors (ICIs), a commonly prescribed type of immunotherapy, a team led by UT Southwestern Medical Center researchers reported in a retrospective study. The findings, published in Nature Cancer, upend long-held conventional wisdom and could lead to more effective ways of deciding which patients will benefit most from this type of treatment.

“Our study challenges the paradigm that tumor mutational burden is a universal marker of how immunogenic a cancer will be. Current standards that rely on this assumption could lead to both undertreatment and overtreatment of patients,” said study leader David Hsieh, M.D., Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

David Hsieh, M.D., is Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

ICIs have revolutionized therapy for several cancer types since the first drug in this category was approved by the U.S. Food and Drug Administration in 2011. Seven other ICIs have since joined the U.S. market. They all work by blocking protein checkpoints that prevent the immune system from attacking cancer cells.

Although ICIs can significantly extend survival, clinical trials have shown that they work in only a fraction of patients, with the number of mutations present in cancer cells thought to be a reliable predictor of ICI success. For example, pembrolizumab – an ICI commonly prescribed to treat a range of cancers including melanoma, non-small cell lung cancer, and renal cell carcinoma – is approved for patients whose tumors have 10 or more mutations per million base pairs of DNA and whose cancers have progressed on standard treatments.

However, Dr. Hsieh said, the idea that tumor mutation burden (TMB), or the number of mutations present in a tumor, is a consistent marker of how well ICIs will work could be a faulty assumption. The studies forming the basis for this idea were relatively small and included a limited number of cancer types. In addition, he said, the cutoff of 10 or more mutations used to prescribe pembrolizumab was based on weak evidence.

To determine how TMB relates to outcomes with ICI, Dr. Hsieh and his colleagues relied on a database managed by the Caris Precision Oncology Alliance, a group of more than 80 leading cancer centers and academic medical centers, including UT Southwestern. The database includes de-identified genetic information on hundreds of thousands of malignant tumors derived from patients with many different cancer types.

The researchers used this database to analyze TMB in 70,698 tumors of 27 different types of cancer. The data involved 14,736 patients treated with ICIs that target an immune checkpoint protein known as PD-1/L1 and 55,962 who never received an ICI. The researchers then compared TMB with patient outcomes in both groups.

Results showed that TMB predicted ICI benefit in only 12 of the 27 cancer types. Among those 12 cancer types, the TMB thresholds for ICI benefits were far fewer than 10 mutations per million base pairs of DNA and varied widely between cancer types, suggesting that the cutoff for pembrolizumab use was arbitrary. In some cancer types examined in the study, TMB was associated with improved survival for patients who never received an ICI. In others, survival was worse, suggesting that mutation burden may have independent effects on patients’ prognoses regardless of whether they received immunotherapy.

Since TMB was thought to stimulate immune activity, Dr. Hsieh explained, doctors have often used immune factors – such as whether a tumor had relatively high numbers of infiltrating immune cells or produced more PD-1/L1 – as proxies for TMB. To determine whether these assumptions were accurate, the researchers compared TMB with information in the Caris database from tumor biopsies. While some tumors with high TMBs had features suggesting increased immune activity, others didn’t, suggesting that these features weren’t reliable proxies.

Dr. Hsieh said that these findings showed that TMB is not a reliable indicator of whether ICIs will improve outcome – a potential paradigm shift for the field. More research is necessary, he added, to boost cancer patient outcomes with ICI.

Other UTSW researchers who contributed to this study are first author Maishara Muquith, a medical student; Hao Zhu, M.D., Professor in the Children’s Medical Center Research Institute at UT Southwestern as well as in Internal Medicine and Pediatrics; and Magdalena Espinoza, M.D., Clinical Assistant Professor of Internal Medicine.

Dr. Zhu is co-Leader of the Development and Cancer Research Program in the Simmons Cancer Center and holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.

Dr. Hsieh is supported by a Cancer Prevention and Research Institute of Texas (CPRIT) Early Clinical Investigator Award (RP200549) and the Josephine Hughes Sterling Foundation.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – May 21, 2024 – Researchers at UT Southwestern Medical Center have developed a novel artificial intelligence (AI) model to improve the detection of breast cancer metastasis, which could reduce the need for needle or surgical biopsies.

The noninvasive model uses standard magnetic resonance imaging (MRI), paired with machine learning AI, to detect axillary metastasis – the presence of cancer cells in the lymph nodes under the arms.

Basak Dogan, M.D., is Professor of Radiology, Director of Breast Imaging Research, and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“Most breast cancer deaths are due to metastatic disease, and the first site is usually an axillary lymph node,” said study leader Basak Dogan, M.D., Professor of Radiology, Director of Breast Imaging Research, and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “Determining nodal status is critical in guiding treatment decisions, but traditional imaging techniques alone do not have enough sensitivity to rule out axillary metastasis. That often requires patients to undergo invasive procedures that involve radioisotope and dye injection followed by surgery to remove and test whether the axillary nodes harbor cancer cells.”

The research, published in Radiology: Imaging Cancer, showed that the AI model was significantly better at identifying patients with axillary metastasis than MRI or ultrasound. In clinical practice, the AI model would have helped avoid 51% of benign (noncancerous) or unnecessary surgical sentinel node biopsies while correctly detecting 95% of patients with axillary metastasis.

“That’s an important advancement because surgical biopsies have side effects and risks, despite having a low probability of a positive result confirming the presence of cancer cells,” Dr. Dogan noted. “Improving our ability to rule out axillary metastasis during a routine MRI – using this model – can reduce that risk while enhancing clinical outcomes.”

The retrospective study used dynamic contrast-enhanced breast MRI exams from 350 newly diagnosed breast cancer patients at UT Southwestern and the Moody Center for Breast Health, which is located on Parkland Health’s main campus in Dallas. All had known nodal status. The images, along with a range of clinical measures, were used to train the AI model to identify axillary metastasis using machine learning techniques.

Because the model is used in conjunction with standard imaging exams, it can also eliminate the stress and expense of additional testing for many patients.

“Patients with benign findings from traditional MRI exams or needle biopsies are often subjected to sentinel lymph node biopsy because those tests can miss a significant proportion of metastasis,” Dr. Dogan explained. “Our research demonstrates that it’s possible to identify – with a high degree of accuracy – patients who are nonmetastatic, which benefits the patient and also allows the physician to tailor treatment.” 

The research builds on previous studies at UT Southwestern related to breast cancer imaging and the development of predictive tools to detect metastasis. 

“Our study is a testament to UT Southwestern’s commitment to impactful research that addresses real-world health care challenges,” Dr. Dogan said. “The development and validation of AI models for medical imaging holds great promise in helping us in the fight against breast and other cancers, and this new tool is a significant step forward.”

Researchers are continuing to refine the image analysis process and are looking to include more varied data to validate their findings.

Other UTSW researchers who contributed to this study are first author Dogan Polat, M.D., a second-year resident in Radiology; Albert Montillo, Ph.D., Assistant Professor in the Lyda Hill Department of Bioinformatics and in Biomedical Engineering; Keith Hulsey, Ph.D., Instructor of Radiology; and Liqiang Wang, Ph.D., Faculty Associate, and Son Nguyen, Ph.D., postdoctoral researcher, in the Lyda Hill Department of Bioinformatics. 

Dr. Dogan is a Eugene P. Frenkel, M.D. Scholar in Clinical Medicine. 

This research was supported by the Simmons Cancer Center, the National Institutes of Health (NIH) National Institute of General Medical Sciences (R01GM144486), NIH National Institute of Aging (R01AG059288), NIH National Cancer Institute (U01 CA207091), the King Foundation, and the Lyda Hill Foundation.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

About Parkland Health

Parkland Health is one of the largest public hospital systems in the country. Premier services at the state-of-the-art Parkland Memorial Hospital include the Level I Rees-Jones Trauma Center, the only burn center in North Texas verified by the American Burn Association for adult and pediatric patients, and a Level III Neonatal Intensive Care Unit. The system also includes two on-campus outpatient clinics – the Ron J. Anderson, MD Clinic and the Moody Outpatient Center, as well as more than 30 community-based clinics and numerous outreach and education programs. By cultivating its diversity, inclusion, and health equity efforts, Parkland enriches the health and wellness of the communities it serves. For more information, visit parklandhealth.org.

DALLAS – May 16, 2024 – A unique collaboration between two UT Southwestern Medical Center labs – one that studies bacteria and another that studies viruses – has identified two immune proteins that appear key to fighting infections. The findings, published in PLOS Pathogens, could lead to new strategies for treating microbial infections and even cancer, the authors said.

Don Gammon, Ph.D., is Assistant Professor of Microbiology at UT Southwestern and is a W.W. Caruth, Jr. Scholar in Biomedical Research.

“By studying how bacterial proteins can promote viral replication, we discovered new factors that block virus replication in organisms ranging from moths to humans,” said Don Gammon, Ph.D., Assistant Professor of Microbiology at UT Southwestern. Dr. Gammon co-led the study with Neal Alto, Ph.D., Professor of Microbiology and a member of the Harold C. Simmons Comprehensive Cancer Center at UTSW, and first author Aaron Embry, B.A.Sc., a graduate student researcher mentored in the Gammon Lab and the Alto Lab.

Neal Alto, Ph.D., is Professor of Microbiology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He holds the Lorraine Sulkin Schein Distinguished Professorship in Microbial Pathogenesis and is a Rita C. and William P. Clements, Jr. Scholar in Medical Research and a UT Southwestern Presidential Scholar.

Dr. Gammon’s lab uses molecules known as immune evasion proteins produced by viruses. Studying these proteins, which disable portions of the immune system to allow viruses to replicate in cells, can shed light on how the immune system targets viral infections. Like viruses, some bacteria also replicate inside the cells of other organisms with the help of proteins known as effectors, many of which thwart immune responses, Dr. Alto explained. Identifying bacterial effector proteins is one focus of his lab.

Drs. Gammon and Alto reasoned that by combining their expertise, they might be able to identify immune mechanisms that organisms use to tackle both bacterial and viral infections. They used a genetic technique to prompt moth cells to individually produce 210 bacterial effectors that are collectively produced by seven different bacterial pathogens. They then tested the ability of these altered cells to allow replication by four types of arboviruses, which are responsible for millions of human infections each year. Although arboviruses are typically transmitted by bloodsucking insects, such as mosquitoes, they usually can’t replicate in moth cells.

Using this method, the researchers identified six effectors that allowed all four arboviruses to multiply inside moth cells. While each of the four arboviruses could replicate somewhat in human cells, genetically altering human cells to produce these effectors significantly boosted viral reproduction.

Singling out just one of these effectors – a protein called IpaH4 isolated from a human-infecting bacterium called Shigella flexneri – in further experiments showed that this protein prevented cellular immune mechanisms from thwarting viral replication by degrading two proteins called SHOC2 and PSMC1, which had not previously been connected to antimicrobial immunity. Because both moth and human cells produce these proteins, Dr. Alto said, they appear to have arisen early in evolution in an ancestor common to both organisms. Thus, these proteins probably play a broad role in innate immunity in many organisms across the animal kingdom.

These images show how human cancer cells (labeled with a blue CellTracker dye) expressing the bacterial effector protein IpaH4 (right column) are more susceptible to viral infection (green indicates viral infection) than cells not expressing the bacterial effector (left column).

Future research into how SHOC2 and PSMC1 operate within the immune system could lead to new designs for antibacterial and antiviral drugs, Dr. Gammon said. It also might pave the way for new therapies to treat other diseases, including cancer, he added. Like moth cells, which are naturally resistant to replication of some viruses, certain types of cancer cells also thwart viral reproduction, preventing effective use of a cancer treatment known as oncolytic therapy, in which viral infections are used to kill cancer cells.

The researchers plan to continue studying how the IpaH4 protein and some other bacterial effectors affect antimicrobial immunity.

Other UTSW researchers who contributed to this study include Diana Tomchick, Ph.D., Professor of Biophysics and Biochemistry; Maarten de Jong, Ph.D., Senior Research Scientist; and Nina Baggett, graduate student researcher.

Dr. Alto holds the Lorraine Sulkin Schein Distinguished Professorship in Microbial Pathogenesis and is a Rita C. and William P. Clements, Jr. Scholar in Medical Research and a UT Southwestern Presidential Scholar. Dr. Gammon is a W.W. Caruth, Jr. Scholar in Biomedical Research.

This study was funded by grants from the National Institutes of Health (1R35GM137978-01, 1R21AI169558-01A1, R01AI083359, and T32 AI007520), the UTSW Endowed Scholars Program, The Welch Foundation (I-1704), and the Burroughs Wellcome Fund (1011019).

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – May 14, 2024 – By completely or even partially depleting a protein called midnolin in B cells, UT Southwestern Medical Center researchers suppressed leukemia and lymphoma in a mouse model genetically prone to these cancers. Their findings, reported in the Journal of Experimental Medicine, could lead to new treatments for these diseases that avoid the serious side effects of current therapies.

“We used a purely genetic method to find a drug target, and that target turns out to be sensational in that B-cell leukemias and lymphomas are strongly dependent on it, while most tissues of the host are not,” said study leader Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine at UT Southwestern.

Bruce Beutler, M.D., is Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine at UT Southwestern. A Nobel Laureate, Dr. Beutler is a Regental Professor and holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.

Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of pathogen sensors known as Toll-like receptors found on immune cells, has long used mutagenesis – introducing mutations into the genes of animal models through exposure to a chemical called N-ethyl-N-nitrosourea (ENU) – as a key tool for discovering the function of genes. Recently, the Beutler Lab pioneered a method known as automated meiotic mapping (AMM) that traces unusual features in mutant mice to the causative mutations, thereby identifying genes needed to maintain the normal physiologic state.

Mutagenesis often causes genetic diseases to develop in animals, providing insight into the function of affected genes by studying the animals’ abnormalities. However, Dr. Beutler explained, mutations can also provide protection from disease. Examples include mutations that protect HIV-infected individuals, or those with inherited sickle cell disease, from developing symptoms. The mechanisms behind some protective mutations have inspired drugs to treat various health conditions.

Searching for protective mutations for immune disorders, the researchers screened mutant mice for those that had immune cells with unusual features. In multiple sets of animals with unusually low numbers of B cells – an important component of the adaptive immune system responsible for the production of antibodies – the researchers used AMM to trace this deficit to mutations in midnolin, a protein found primarily in B cells. Although animals with complete absence of midnolin die during development before birth, milder mutations, including some introduced using a genetic technique that allows deletion of the gene during adulthood, caused no apparent harm.

Jin Huk Choi, Ph.D., is Assistant Professor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern.

The researchers significantly reduced or completely eliminated midnolin in mice genetically predisposed to B-cell leukemias and lymphomas, cancers in which B cells divide out of control. Although mice with normal midnolin died from these diseases by 5 months of age, most of those with less or no midnolin never developed the malignancies.

Xue Zhong, Ph.D., is Instructor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern.

Additional experiments revealed that midnolin’s role in B cells is to stimulate the activity of proteasomes, cellular organelles that dispose of proteins that are damaged or no longer useful. Some therapies currently used for B-cell leukemias and lymphomas work by inhibiting proteasome activity, much like ridding cells of midnolin does, explained Dr. Beutler. However, unlike these drugs, which have numerous and potentially serious side effects, eliminating or reducing midnolin in animal models appeared to have no ill effects. Future research will focus on developing midnolin-inhibiting drugs that could eventually serve as the basis for new B-cell cancer therapies.

Other UTSW researchers who contributed to this study include first author Xue Zhong, Ph.D., Instructor in the Center for the Genetics of Host Defense and of Immunology; Nagesh Peddada, Ph.D., Instructor in the Center for the Genetics of Host Defense and of Immunology; James J. Moresco, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Biophysics; Jonathan J. Rios, Ph.D., Associate Professor in the Eugene McDermott Center for Human Growth and Development and of Orthopaedic Surgery and Pediatrics; Eva Marie Y. Moresco, Ph.D., and Jin Huk Choi, Ph.D., both Assistant Professors in the Center for the Genetics of Host Defense and Immunology; Jianhui Wang, M.S., Senior Research Scientist; and Yiao Jiang, Ph.D., postdoctoral researcher.

Dr. Beutler, a Regental Professor, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. Drs. Beutler and Rios are members of the Harold C. Simmons Comprehensive Cancer Center.

This study was funded by grants from the National Institutes of Health (AI125581 and CA258602).

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – May 13, 2024 – A team led by researchers at UT Southwestern Medical Center developed deep learning models to identify a simple set of rules that govern the activity of promoters – regions of DNA that initiate the process by which genes produce proteins. Their findings, published in Science, could lead to a better understanding of how promoters contribute to gene regulation in health and disease.

Jian Zhou, Ph.D., Assistant Professor in the Lyda Hill Department of Bioinformatics at UT Southwestern, is a Lupe Murchison Foundation Scholar in Medical Research and a member of the Harold C. Simmons Comprehensive Cancer Center.

“Although promoters are essential for the function of every gene, our understanding of how these genetic elements operate is incomplete despite decades of study that have defined many of their features. Our research sheds new light on how these sequences work in humans and other mammals,” said Jian Zhou, Ph.D., Assistant Professor in the Lyda Hill Department of Bioinformatics at UT Southwestern. Dr. Zhou co-led the study with first author Kseniia Dudnyk, a graduate student in the Zhou Lab, and Jian Xu, Ph.D., a former researcher at the Children’s Medical Center Research Institute at UT Southwestern.

Creating the proteins that cells use to perform their activities starts with a process known as transcription. That’s when an RNA polymerase protein latches onto a DNA strand and copies – or transcribes – the encoded information into an RNA molecule. The region where the RNA polymerase attaches to begin transcription is called the promoter. In humans, promoters are typically composed of hundreds of base pairs, the units that make up DNA. Although researchers have identified common base pair sequences shared among some regions of DNA that are promoters, these sequences are often absent in human promoters, leaving the rules of how DNA sequence directs the transcription process unclear.

Kseniia Dudnyk is a graduate student in the Zhou Lab at UT Southwestern.

To better define promoters in humans and how they operate, the researchers developed a machine learning program they named Puffin. After analyzing data from tens of thousands of recognized human promoters, the program determined that they are made of three types of sequence patterns: motifs, initiators, and trinucleotides.

Puffin showed that depending on how these elements are arranged, they can activate or repress transcription of a gene. Puffin also can predict how the arrangement of these elements can direct RNA polymerase to preferentially transcribe a single strand of DNA or transcribe both strands simultaneously toward opposite directions. This bidirectional transcription is common in human genes.

The program further showed that mice and other mammals shared similar rule sets for governing promoter operation. In addition, Puffin allowed the researchers to predict whether and how transcription would occur if they mutated promoters, findings that closely matched those from experiments.

The study authors suggested that Puffin could help them understand how promoters work in healthy cells as well as how disease-associated alterations in promoters could lead to changes in gene transcription. This program is available on a free web server (tss.zhoulab.io) so that other researchers can test any promoter sequence of interest. They added that using a similar machine learning approach could offer insights into other facets of the genome that are still not well understood.

Additional UTSW researchers who contributed to this study are Donghong Cai, Ph.D., a joint postdoctoral fellow with the Xu Lab, and Chenlai Shi, M.S., Data Scientist.

This study was funded by grants from the National Institutes of Health (DP2GM146336, R01DK111430, R01CA230631, and R01CA259581); the Cancer Prevention and Research Institute of Texas (RR190071); and a Leukemia & Lymphoma Society Scholar award.

Dr. Zhou is a Lupe Murchison Foundation Scholar in Medical Research and a member of the Harold C. Simmons Comprehensive Cancer Center.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

Blue light improves bladder cancer detection across races

White light cystoscopy (WLC) – a procedure in which doctors illuminate a patient’s bladder with a white light and peer into it with a tiny camera – has long been a gold standard for diagnosing bladder cancer, the sixth most common cancer diagnosis in the U.S. Blue light cystoscopy (BLC), a related procedure that uses a blue light to activate a drug that makes bladder tumors fluoresce, has improved bladder cancer diagnosis in several clinical trials. However, because most patients in these trials were Caucasian, it has been unclear whether this diagnostic improvement applied to all races. Using data from nearly 1,300 Caucasian, African American, Asian, and Hispanic patients with suspected bladder cancer from multiple medical institutions, a team that included UT Southwestern reported in Cancers that combining WLC with BLC improved diagnosis by an average of 10% across all races compared with WLC alone. Asian patients benefited the most from the combined technique’s ability to spot potential tumors, and Hispanic patients benefited the most from its ability to rule tumors out. These findings suggest that supplementing WLC with BLC helps improve bladder cancer diagnoses across races.

UTSW researcher Yair Lotan, M.D., Professor of Urology, Chief of Urologic Oncology, and a member of the Harold C. Simmons Comprehensive Cancer Center, contributed to the study. Dr. Lotan is a paid consultant for Photocure, the company that developed the fluorescent drug used with BLC.

Gamma waves distinguish goal-oriented movements

Movements guided by vision (such as touching an elevator button) and those guided by sensing the body’s position in space (such as reaching to scratch one’s face) are driven by different brain activity. Characterizing this activity has been a challenge. Researchers from UT Southwestern and other institutions report in the Journal of Neural Engineering that these movement types spark irregularities in brain waves called gamma oscillations in different parts of the brain. They monitored brain activity in patients who received an implant for deep brain stimulation as they repeatedly touched a clinician’s finger (visually guided) and their own chins (proprioception). In these tests, researchers found more gamma wave irregularities in the motor cortex during the visually guided movements and more irregularities in the posterior parietal cortex during proprioception movements. Monitoring gamma waves also helped them identify connections among brain regions involved in these movements.

UTSW researchers Nader Pouratian, M.D., Ph.D., Chair and Professor of Neurological Surgery and Investigator in the Peter O’Donnell Jr. Brain Institute, and Jeong Woo Choi, Ph.D., Senior Research Scientist, contributed to the study.

Giving abnormal bone formation a closer look

The inappropriate formation of bone within muscle, tendon, and other soft tissues, called heterotopic ossification (HO), is a common consequence of joint replacements and traumatic injuries. Although researchers have traced the origin of HO to aberrant transformation of stem cells known as mesenchymal progenitor cells (MPCs) led by a protein called HIF-1a, the molecular mechanism behind this phenomenon has been unclear. A team of scientists led by UTSW researchers shows in Bone Research that this transformation is caused by changes in the role MPCs play in organizing the extracellular matrix, a mixture of proteins and carbohydrates that surrounds cells and provides structural and biochemical support. By selectively deleting the gene for HIF-1a in MPCs, researchers determined that this protein appears to cause MPCs to consume more blood sugar. This increases the production of enzymes called PLOD2 and LOX involved in making collagen, the predominant component of the extracellular matrix. In addition to HIF-1a, PLOD2 and LOX could eventually serve as targets for drugs to prevent or treat HO.

UTSW researchers contributing to this study include Benjamin Levi, M.D., Associate Professor of Surgery and Division Chief of Burn, Trauma, Acute and Critical Care Surgery; Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health; Robert Tower, Ph.D., Assistant Professor of Surgery; Lei Guo, Ph.D., Computational Biologist; Senior Research Scientists Heeseog Kang, Ph.D., and Yuxiao Sun, Ph.D.; medical student Conan Juan; Research Assistants Ji Hae Choi and Michael Woodard; and Chase A. Pagani, graduate student researcher.

Dissecting the HIV-1 transcriptional circuitry

Developing a cure for HIV-1, the primary virus that causes AIDS, has been difficult due to the virus’s ability to lie dormant in T cells and its potential to reactivate. As reported in Viruses, researchers from UT Southwestern investigated transcription, a process necessary for HIV-1 to produce RNAs and proteins needed for viral reactivation and spread in cells. During reactivation, HIV-1 becomes transcribed, which has two layers of control. First, human proteins activate the virus (called the “host phase”), which leads to expression of the Tat protein, turning on the “viral phase” where Tat drives the high levels of transcription required to replicate and perpetuate infection. Because this process happens in a sequential feedback loop, it has been difficult to understand the contributions of either phase to HIV-1 reactivation, limiting therapeutic approaches. Researchers used CRISPR gene editing to create HIV-1 integrated T cell clones with mutations in the tat gene. By comparing them to paired control T cell clones, researchers teased apart molecular contributions from the host and viral phases of HIV-1 transcription. This study provides a novel tool that could lead to new drugs for treating HIV-1 more effectively.  

UTSW researchers contributing to the study include Usman Hyder, Ph.D., first author and a former graduate student; Ivan D’Orso, Ph.D., Professor of Microbiology; Ashutosh Shukla, Ph.D., Instructor of Internal Medicine; and Ashwini Challa, M.S., Research Associate.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – May 02, 2024 – A drug that targets a protein known as phosphatidylserine boosted the response rate for hepatocellular carcinoma (HCC) patients receiving immunotherapy without compromising their safety, according to results of a phase two clinical trial conducted by UT Southwestern Medical Center. The findings, published in Nature Communications, show the potential benefits of augmenting immunotherapy for this and other forms of cancer.

David Hsieh, M.D., is Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Experimental Therapeutics Research Program of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“This study shows the promise of improving the success of cancer immunotherapies by targeting other immunomodulating proteins simultaneously,” said study leader David Hsieh, M.D., Assistant Professor of Internal Medicine in the Division of Hematology and Oncology and a member of the Experimental Therapeutics Research Program of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

HCC is the most common form of liver cancer and the fourth most frequent cause of cancer-related deaths worldwide. For many years, the only existing treatment for tumors of this kind that can’t be surgically removed was a drug called sorafenib. It works by slowing the growth of tumor-feeding blood vessels. Although this targeted therapy drug was groundbreaking when it was approved by the U.S. Food and Drug Administration in 2007, it extends survival by only a few months.

More recently, immunotherapies – treatments that spur the immune system to fight tumors – have emerged as the most effective treatments for HCC patients. However, only a fraction of patients responded to these drugs when delivered alone, and combining multiple immunotherapies increased the likelihood of serious and occasionally deadly side effects.

Several years ago, researchers discovered that phosphatidylserine, a fatty substance called a phospholipid sometimes present on the surface of cancer cells, appeared to interact with immune cells to prevent them from attacking tumors. An antibody drug called bavituximab that neutralizes phosphatidylserine showed no effect on tumor response, progression, or survival when administered alone across multiple cancer types or when combined with sorafenib in HCC. But bavituximab had never been tested in combination with immunotherapy agents.

Toward that end, Dr. Hsieh and his colleagues recruited 28 patients with HCC receiving care at UT Southwestern and Parkland Health. These patients, whose cancers couldn’t be surgically removed, received imaging of their tumors at the start of the study. They then received a combination of bavituximab and pembrolizumab, an immunotherapy drug approved in 2016 to treat various cancers. While receiving both therapies, these patients had periodic imaging to determine whether their tumors shrank, stopped growing, or continued to grow and multiply. The researchers followed these patients for an average of 28.5 months.

Although previous clinical trials had shown that only about 16% of HCC patients responded to pembrolizumab alone, nine patients, or 32%, responded to the combined therapy. Two of them had a complete response, with no evidence of disease on imaging at the end of the trial. The combined therapy halted progression in another 32% of patients. For responders, the two drugs continued to shrink their tumors for a median time of 13.3 months, and four patients were still responding to the combination therapy when the study ended.

Researchers noted that adding bavituximab did not appear to increase side effects over those taking pembrolizumab alone based on data from prior trials – an important point showcasing this combination’s safety.

These results suggest that adding agents that target phosphatidylserine to immunotherapy regimens could increase the likelihood of response in HCC and potentially other cancers in which this protein might affect anti-cancer immunity.

Other UTSW researchers who contributed to this study include co-first author Muhammad S. Beg, M.D., Adjunct Associate Professor of Internal Medicine; Radhika Kainthla, M.D., Assistant Professor of Internal Medicine; Jay Lohrey, M.D., Assistant Professor of Internal Medicine and Medical Director of the Simmons Cancer Center located at the Moncrief Cancer Institute in Fort Worth; Syed M. Kazmi, M.D., Associate Professor of Internal Medicine; Anil K. Pillai, M.D., Professor of Radiology and Chief of Vascular Interventional Radiology; Rolf Brekken, Ph.D., Professor of Surgery and Pharmacology and in the Hamon Center for Therapeutic Oncology Research; Chul Ahn, Ph.D., Professor in the Peter O’Donnell Jr. School of Public Health and Director of the Biostatistics Shared Resource in the Simmons Cancer Center; Amit G. Singal, M.D., M.S., Professor of Internal Medicine and in the O’Donnell School of Public Health, Medical Director of the Liver Tumor Program, and Chief of Hepatology; Hao Zhu, M.D., Professor in the Children’s Medical Center Research Institute at UT Southwestern (CRI) as well as in Internal Medicine and Pediatrics, co-leader of the Development and Cancer Research Program in the Simmons Cancer Center, and Director of the CRI Tissue Regeneration Program; Yujin Hoshida, M.D., Ph.D., Professor of Internal Medicine and Director of Liver Tumor Translational Research; Adam C. Yopp, M.D., Professor of Surgery, Chief of the Division of Surgical Oncology, and Surgical Director of the Liver Tumor Program; Leticia Khosama, M.S.N., Advanced Practice Registered Nurse; Mary Claire Maxwell, M.S.N., Advanced Practice Registered Nurse; Heather Kline, M.S., Advanced Practice Registered Nurse; Courtney Katz, M.S., Research Associate; and Ellen Siglinsky, B.S., Clinical Research Manager.

Dr. Brekken is an Effie Marie Cain Research Scholar. Dr. Hoshida holds the H. Ray and Paula Calvert Chair in Gastroenterology Oncology in Honor of Udit Verma, M.D. Dr. Kazmi is a Eugene P. Frenkel, M.D. Scholar in Clinical Medicine. Dr. Singal is a Dedman Family Scholar in Clinical Care and holds the Willis C. Maddrey, M.D. Distinguished Chair in Liver Disease. Dr. Yopp holds The Occidental Chemical Chair in Cancer Research. Dr. Zhu holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.

Drs. Ahn, Brekken, Hoshida, Hsieh, Kazmi, Singal, Yopp, and Zhu are all members of the Simmons Cancer Center.

For this study, Merck provided funding along with pembrolizumab while OncXerna Therapeutics supplied bavituximab. Dr. Hoshida is supported by grants from the National Cancer Institute (CA233794, CA255621), the European Commission (ERC-AdG-2020-101021417), and the Cancer Prevention and Research Institute of Texas (RR180016). This study was also supported by the National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

Author financial disclosures can be found in the manuscript.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – April 29, 2024 – By examining which genes were turned on and off in a mix of cell types from breast cancer biopsies, a team led by UT Southwestern Medical Center researchers developed a tool that can accurately predict which patients with breast cancer will respond to immunotherapies. Their findings, reported in Cell Reports Medicine, could offer a new way to perform precision medicine, which directs the most effective therapies to individual patients.

“Immunotherapies have made incredible strides in extending survival for cancer patients, but they only work about 20% of the time. To make immunotherapies more beneficial, we need to have a much better understanding of the cellular composition of specific tumors and how those cells interact with each other,” said Isaac Chan, M.D., Ph.D., Assistant Professor of Internal Medicine and Molecular Biology and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Isaac Chan, M.D., Ph.D., is Assistant Professor of Internal Medicine and Molecular Biology and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Dr. Chan explained that over the past several decades, researchers have had a growing understanding that malignant tumors aren’t just made of cancer cells but have a variety of cell types, including immune cells that can either hinder or help tumors thrive. Existing immunotherapies take advantage of this phenomenon by stimulating T cells present in and around tumors to attack cancer cells. 

However, T cells aren’t the only cancer-fighting cells present in tumors that change after interacting with cancer cells, Dr. Chan noted. Natural killer (NK) cells, part of the innate immune system, can also help fight cancer. But the Chan Lab and others have shown that interactions between cancer cells and NK cells can exhaust or even reprogram – or corrupt – NK cells to promote tumors instead of killing them. Dr. Chan and his team were able to identify these reprogrammed NK cells in breast tumors in previous research. Patients who had high levels of reprogrammed NK cells had worse outcomes, suggesting the potential for therapeutically targeting these cells.

To better understand how cancer cells interact with immune cells, Dr. Chan and his colleagues took advantage of a method called single cell RNA sequencing (scRNA-seq), which evaluates gene expression in each individual cell. By combining several publicly available scRNA-seq databases, they created a new dataset that included 119 tumor samples from 88 breast cancer patients. Using this larger database, the researchers were able to analyze data from 236,363 cells, far more than any breast cancer scRNA-seq analysis thus far.

Using a computational technique, the team grouped together cancer cells in which similar sets of genes were turned on or off and found there were actually 10 categories of breast cancer cells. Just three categories of breast cancer cells (hormone positive, HER2 positive, and triple negative) are typically used to determine appropriate therapy. The distribution of the 10 categories of cancer cells varied among tumors; nearly all tumors had a mix of different subtypes, Dr. Chan said.

By analyzing which immune cells appeared to interact with categories of cancer cells based on this gene expression, the researchers used outcomes data to show that patients with certain combinations of subtypes had worse outcomes than others. This analysis also offered insight on the important clinical cancer cell interactions with other immune cell types – a finding that Dr. Chan and his colleagues leveraged to create a tool they named InteractPrint. Demonstrating its value, InteractPrint accurately predicted the response to immunotherapy in a large, ongoing clinical trial testing immunotherapy in breast cancer patients.

Dr. Chan noted that this approach – evaluating interactions between cancer and immune cells through their gene expression – could assess the likelihood of response to different immunotherapies across a wide variety of cancer types, helping doctors choose patients for whom this treatment will be the most successful.

Other UTSW researchers who contributed to this study include first authors Lily Xu, a medical student, Shao-Po Huang, a Medical Scientist Training Program student and Perot Family Scholar, and Kaitlyn Saunders, former UT Dallas graduate student researcher who worked in the Chan Lab; Heather McArthur, M.D., M.P.H., Associate Professor of Internal Medicine and Clinical Director of the Breast Cancer Program in the Simmons Cancer Center; Sangeetha M. Reddy, M.D., Assistant Professor of Internal Medicine and in the Simmons Cancer Center; Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health, of Pediatrics, and in the Simmons Cancer Center; Kenian Chen, Ph.D., Computational Biologist; and graduate student researchers Kenneth Martinez Algarin and Isabella Terrazas.

This study was supported by funding from METAvivor, Susan G. Komen (CCR231010879), the National Institutes of Health (1K08CA270188-01A1), the Peter Carlson Trust, Theresa’s Research Foundation, and a National Cancer Institute Cancer Center Support Grant (P30 CA142543).

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.