87 members representing 18 departments and centers at UT Southwestern
The Experimental Therapeutics (ET) Program provides an organized integrated infrastructure that enables both clinical translation of basic and population science research from Simmons research programs and identification of clinically relevant hypotheses for testing by the Center’s basic science programs. The Program is the main hub of cancer clinical trials in the SCCC.
The four program specific aims focus on therapeutic development and biomarker discovery, where members work collectively to: Develop molecular therapeutic sensitizers by focusing on the development of unique tumor-selective agents that enhance existing therapies; Target tumor microenvironment with immunotherapy by modulating the role of immune cells in tumor progression; Advance imaging and drug delivery by developing novel imaging and nanotechnology delivery platforms to enhance cancer diagnosis and therapy; and Exploit cancer vulnerabilities by leveraging synthetic lethalities as new “targeted” therapy for cancer.
Develop Molecular Therapeutic Sensitizers
Under the mentorship of co-leader, Ganesh Raj, M.D., Ph.D., Benjamin Chen, Ph.D., found that drugs targeting DNA-PKc block DNA damage repair, resulting in sustained DNA damage (as measured by persistent γ-H2ax foci). To enable clinical translation, they developed a hypoxia-activated prodrug (SN38023) that targets DNA-PKc. This drug is activated by reductases in the hypoxic tumor environment. and radiosensitizes hypoxic tumors. While the active agent (IC87361) radiosensitizes in both hypoxia and normoxia, the prodrug (SN38023) has radiosensitizing effects only in hypoxic tumors. In contrast, normoxic tissues will not have the activated form of prodrug providing a “therapeutic window” for radiosensitization. Clinical translation of this pro-drug is ongoing.
Target the Tumor Microenvironment with Immunotherapy
Yang-Xin Fu, M.D., Ph.D., is leading a multipronged investigation to understand the mechanisms underlying ionizing radiation-induced resistance and to test newly developed personalized immunotherapies to overcome this resistance. These include the role of host cell PD-L1 expression, efficacy of dual innate and adaptive checkpoints, the role of IFNα targeting, tumor-reprogrammed resident T cells, targeting tertiary lymphoid structures, strategies to facilitate T cell infiltration in tumor microenvironment, and synergistic interactions between radiation and checkpoint blockade. Together, they provide the basis for a rapidly expanding program of immuno-oncology translational studies and clinical trials at Simmons Cancer Center.
Advance Imaging and Drug Delivery
Theme co-leader, Jinming Gao, Ph.D., has collaborated with Zhijian “James” Chen, Ph.D., to develop nanoparticle vaccines to activate the STING pathway to boost antitumour immunity and the response to cancer immunotherapy. This nanovaccine, comprising a simple physical mixture of an antigen and a synthetic polymeric nanoparticle enhances antigen delivery and cross-presentation, generates a strong cytotoxic T-cell response with low systemic cytokine expression, and leads to potent tumor growth inhibition in melanoma, colon cancer and HPV tumor models.
Exploit Cancer Cell-Autonomous and Non-Autonomous Vulnerabilities
Recognizing the major unmet need presented by this common disease subset (approximately 25% of NSCLC), ET has brought together program members for preclinical development and clinical translation (overseen by co-leaders John Minna, M.D., and David Gerber, M.D.). Lung Disease-Oriented Team investigators have worked with the Cancer Vulnerabilities theme to develop numerous IITs in this space. Our Phase II clinical trial of (FAK inhibition was the first in KRAS mutant lung cancer to assign patient cohorts according to co-mutations in p16/ARF and p53.
Choi, C. et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 2012; 18: 624-9. PMCID: PMC3615719.
Gerber, D.E. et al. Phase 1 study of ARQ 761, a beta-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis. Br J Cancer 2018; 119: 928-36. PMCID: PMC6203852.
Kim, J. et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature 2016; 538: 114-7. PMCID: PMC5161658.
Khan, S.A. et al. Prevalence of Autoimmune Disease Among Patients With Lung Cancer: Implications for Immunotherapy Treatment Options. JAMA Oncol 2016; 2: 1507-8. PMCID: PMC5656433.
Liu, Z. et al. Catalytic-Independent Functions of PARP-1 Determine Sox2 Pioneer Activity at Intractable Genomic Loci. Mol Cell 2017; 65: 589-603 e9. PMCID: PMC5319724.