Publications

Raj Lab Publications

Prostate Cancer

          A novel lncRNA situated within the LCK gene that may serve as an oncogene in PCA.

          Sphingosine kinase signaling underlies LPS-induced matriptase activation and PCa cell invasion.

          BRD4 is a central player in the repair of DNA DSBs, with significant implications for cancer therapy.

          Deficiencies in the understanding of the mechanisms underlying prostate cancer pathogenesis s preventing hormonal agent success in clinical trials.

  • Thoreson GR, Gayed BA, Chung PH, Raj GV. Emerging therapies in castration resistant prostate cancer. Can J Urol. 2014 Apr;21(2 Supp 1):98-105. Review. PubMed PMID: 24775731.

    Emerging therapies need time to be fully integrated into clinical practice in order to impact the survival for patients with metastatic prostate cancer.
  • Kothari V, Goodwin JF, Zhao SG, Drake JM, Yin Y, Chang SL, Evans JR, Wilder-Romans K, Gabbara K, Dylgjeri E, Chou J, Sun G, Tomlins SA, Mehra R, Hege K, Filvaroff EH, Schaeffer EM, Karnes RJ, Quigley DA, Rathkopf DE, He HH, Speers C, Spratt DE, Gilbert LA, Ashworth A, Chinnaiyan AM, Raj GV, Knudsen KE, Feng FY. DNA-Dependent Protein Kinase Drives Prostate Cancer Progression through Transcriptional Regulation of the Wnt Signaling Pathway. Clin Cancer Res. 2019 Sep 15;25(18):5608-5622. doi: 10.1158/1078-0432.CCR-18-2387. Epub 2019 Jul 2. PMID: 31266829; PMCID: PMC6744969.DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.
  • Wang S, Kollipara RK, Humphries CG, Ma SH, Hutchinson R, Li R, Siddiqui J, Tomlins SA, Raj GV, Kittler R. The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer. 2016 Oct 4;7(40):64921-64931. doi: 10.18632/oncotarget.11915. PubMed PMID: 27626314; PubMed Central PMCID: PMC5323126.

    ERG upregulates TRIM25 expression which is mitigated by the expression of the deubiquitinase USP9X
  • Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E, Freeman E, Humphries CG, Kapur P, Lotan Y, Fazli L, Gleave ME, Plymate SR, Raj GV, Hsieh JT, Kittler R. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer.Proc  Natl Acad Sci U S A. 2014 Mar 18;111(11):4251-6. doi: 10.1073/pnas.1322198111. Epub 2014 Mar 3. PubMed PMID: 24591637; PubMed Central PMCID: PMC3964108.

    USP9X is a potential therapeutic target in prostate cancer cells and established WP1130 as a lead compound for the development of ERG-depleting drugs.
  • Welti J, Sharp A, Yuan W, Dolling D, Nava Rodrigues D, Figueiredo I, Gil V, Neeb A, Clarke M, Seed G, Crespo M, Sumanasuriya S, Ning J, Knight E, Francis JC, Hughes A, Halsey WS, Paschalis A, Mani RS, Raj GV, Plymate SR, Carreira S, Boysen G, Chinnaiyan AM, Swain A, de Bono JS; International SU2C/PCF Prostate Cancer Dream Team.. Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC).Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571. Epub 2018 Mar 19. PubMed PMID: 29555663.

    Targeting bromodomain decreases persistent AR signaling and growth of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression.
  • Yang L, Ravindranathan P, Ramanan M, Kapur P, Hammes SR, Hsieh JT, Raj GV. Central role for PELP1 in nonandrogenic activation of the androgen receptor in prostate cancer.Mol Endocrinol. 2012 Apr;26(4):550-61. doi: 10.1210/me.2011-1101. Epub 2012 Mar 8. PubMed PMID: 22403175; PubMed Central PMCID: PMC5417135.

    PELP1 allows for crosstalk between E2 bound to ERβ and AR opening a therapeutic strategy in advanced PCa.
  • Yin Y, Li R, Xu K, Ding S, Li J, Baek G, Ramanand SG, Ding S, Liu Z, Gao Y, Kanchwala MS, Li X, Hutchinson R, Liu X, Woldu SL, Xing C, Desai NB, Feng FY, Burma S, de Bono JS, Dehm SM, Mani RS, Chen BPC, Raj GV.Androgen receptor variants mediate DNA repair after prostate cancer irradiation. Cancer Res. 2017 Jul 28. pii: canres.0164.2017. doi: 10.1158/0008-5472.CAN-17-0164. [Epub ahead of print] PubMed PMID: 28754673.

    Pharmacologic inhibition of DNA-PKc elevated prostate cancer cell death after irradiation.

Breast Cancer

Clinically Relevant Models

  • Centenera MM, Gillis JL, Hanson AR, Jindal S, Taylor RA, Risbridger GP, Sutherland PD, Scher HI, Raj GV, Knudsen KE, Yeadon T; Australian Prostate Cancer BioResource, Tilley WD, Butler LM. Evidence for efficacy of new Hsp90 inhibitors  revealed by ex vivo culture of human prostate tumors.Clin Cancer Res. 2012 Jul 1;18(13):3562-70. doi: 10.1158/1078-0432.CCR-12-0782. Epub 2012 May 9. PubMed PMID: 22573351.

    Ex vivo culture technique has provided information on Hsp90 inhibitor action not previously observed in cell lines or animal models.
  • Centenera MM, Hickey TE, Jindal S, Ryan NK, Ravindranathan P, Mohammed H, Robinson JL, Schiewer MJ, Ma S, Kapur P, Sutherland PD, Hoffmann CE, Roehrborn CG, Gomella LG, Carroll JS, Birrell SN, Knudsen KE, Raj GV, Butler LM, Tilley WD. A patient-derived explant (PDE) model of hormone-dependent cancer.Mol Oncol. 2018 Sep;12(9):1608-1622. doi: 10.1002/1878-0261.12354. Epub 2018 Aug 16. PubMed PMID: 30117261; PubMed Central PMCID: PMC6120230.

    The PDE model provides the ability to rapidly evaluate drug efficacy in patient-derived material has high potential to facilitate implementation of personalized medicine approaches.
  • Centenera MM, Raj GV, Knudsen KE, Tilley WD, Butler LM.Ex vivo culture of human prostate tissue and drug development. Nat Rev Urol. 2013 Aug;10(8):483-7. doi: 10.1038/nrurol.2013.126. Epub 2013 Jun 11. Review. PubMed PMID: 23752995.

    Ex vivo culture poised to accelerate translational "hit rate"  for prostate cancer research.
  • Schiewer MJ, Goodwin JF, Han S, Brenner JC, Augello MA, Dean JL, Liu F, Planck JL, Ravindranathan P, Chinnaiyan AM, McCue P, Gomella LG, Raj GV, Dicker AP, Brody JR, Pascal JM, Centenera MM, Butler LM, Tilley WD, Feng FY, Knudsen KE.Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012 Dec;2(12):1134-49. doi: 10.1158/2159-8290.CD-12-0120. Epub 2012 Sep 19. PubMed PMID: 22993403; PubMed Central PMCID: PMC3519969.

    DNA damage repair and transcription factor regulation offer a paradigm shift in PARP-1 function in human malignancy
  • Shafi AA, Schiewer MJ, de Leeuw R, Dylgjeri E, McCue PA, Shah N, Gomella LG, Lallas CD, Trabulsi EJ, Centenera MM, Hickey TE, Butler LM, Raj G, Tilley WD, Cukierman E, Knudsen KE. Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response. Eur Urol Oncol. 2018 Sep;1(4):325-337. doi: 10.1016/j.euo.2018.04.019. Epub 2018 Jun 6. PubMed PMID: 30467556; PubMed Central PMCID: PMC6241309.

    The PDE model allows for a comprehensive evaluation of individual tumors in their native TME to ultimately develop more effective therapeutic regimens
  • Sivanand S, Peña-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J. A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.Sci Transl Med. 2012 Jun 6;4(137):137ra75. doi: 10.1126/scitranslmed.3003643. PubMed PMID: 22674553; PubMed Central PMCID: PMC3570965.

    Tumorgraft model recapitulates the molecular genetics and drug sensitivities of human tumors 

Therapy Resistance

 

  • Singla N, Ghandour RA, Raj GV. Biomarkers for platinum sensitivity in bladder cancer: are we there yet? Transl Androl Urol. 2019 Jul;8(Suppl 3):S236-S239. doi:10.21037/tau.2019.01.10. PubMed PMID: 31392132Current prognostic biomarkers for the use of neoadjuvant chemotherapy in muscle-invasive bladder cancer are encouraging but need further investigation for wide use in the clininc.
  • Thoreson GR, Gayed BA, Chung PH, Raj GV. Emerging therapies in castration resistant prostate cancer. Can J Urol. 2014 Apr;21(2 Supp 1):98-105. Review. PubMed PMID: 24775731.

    Emerging therapies need time to be fully integrated into clinical practice in order to impact the survival for patients with metastatic prostate cancer.
  • Yin Y, Li R, Xu K, Ding S, Li J, Baek G, Ramanand SG, Ding S, Liu Z, Gao Y, Kanchwala MS, Li X, Hutchinson R, Liu X, Woldu SL, Xing C, Desai NB, Feng FY, Burma S, de Bono JS, Dehm SM, Mani RS, Chen BPC, Raj GV.Androgen receptor variants mediate DNA repair after prostate cancer irradiation. Cancer Res. 2017 Jul 28. pii: canres.0164.2017. doi: 10.1158/0008-5472.CAN-17-0164. [Epub ahead of print] PubMed PMID: 28754673.

    Pharmacologic inhibition of DNA-PKc elevated prostate cancer cell death after irradiation.

Novel Therapeutics

 

Nuclear Receptors

 

          Inhibitor 14d exerts its anticancer activity by inhibiting the AR–PELP1 interaction and AR transactivation.

  • Miao L, Yang L, Li R, Rodrigues DN, Crespo M, Hsieh JT, Tilley WD, de Bono J,  Selth LA, Raj GV. Disrupting Androgen Receptor Signaling Induces Snail-Mediated Epithelial-Mesenchymal Plasticity in Prostate Cancer.Cancer Res. 2017 Jun 1;77(11):3101-3112. doi: 10.1158/0008-5472.CAN-16-2169. Epub 2017 Mar 16. PubMed  PMID: 28302679.

    De-repression of Snail and induction of EMP is an adaptive response to enzalutamide with implications for therapy resistance.
  • Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, Serandour AA, Birrell SN, Bruna A, Saadi A, Menon S, Hadfield J, Pugh M, Raj GV, Brown GD,  D'Santos C, Robinson JL, Silva G, Launchbury R, Perou CM, Stingl J, Caldas C, Tilley WD, Carroll JS. Progesterone receptor modulates ERα action in breast cancer. 2015 Jul 16;523(7560):313-7. doi: 10.1038/nature14583. Epub 2015 Jul 8. Erratum in: Nature. 2015 Oct 1;526(7571):144.  Serandour, Aurelien A A[Corrected to Serandour, Aurelien A]. PubMed PMID: 26153859; PubMed Central PMCID: PMC4650274.

    PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.
  • Regan Anderson TM, Ma SH, Raj GV, Cidlowski JA, Helle TM, Knutson TP, Krutilina RI, Seagroves TN, Lange CA. Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer.Cancer Res. 2016 Mar 15;76(6):1653-63. doi:10.1158/0008-5472.CAN-15-2510. Epub 2016 Jan 29. PubMed PMID: 26825173; PubMed Central PMCID: PMC4794366.

    Phospho-GR/HIF/PELP1 complex is a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients.

 

  • Schiewer MJ, Mandigo AC, Gordon N, Huang F, Gaur S, de Leeuw R, Zhao SG, Evans J, Han S, Parsons T, Birbe R, McCue P, McNair C, Chand SN, Cendon-Florez Y, Gallagher P, McCann JJ, Poudel Neupane N, Shafi AA, Dylgjeri E, Brand LJ, Visakorpi T, Raj GV, Lallas CD, Trabulsi EJ, Gomella LG, Dicker AP, Kelly WK, Leiby BE, Knudsen B, Feng FY, Knudsen KE. PARP-1 regulates DNA repair factor availability. EMBO Mol Med. 2018 Dec;10(12):e8816. doi: 10.15252/emmm.201708816. PMID: 30467127; PMCID: PMC6284389.PARP‐1 activity is increased as a function of disease progression and is associated with poor outcomes.
  • Singhal H, Greene ME, Tarulli G, Zarnke AL, Bourgo RJ, Laine M, Chang YF, Ma S, Dembo AG, Raj GV, Hickey TE, Tilley WD, Greene GL. Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.Sci Adv. 2016 Jun 24;2(6):e1501924. doi: 10.1126/sciadv.1501924. eCollection 2016 Jun. PubMed PMID: 27386569; PubMed Central PMCID: PMC4928895.

    PR redirects ER chromatin binding to antagonize estrogen signaling suggesting that cotargeting of ER and PR in ER(+)/PR(+) breast cancers should be explored.
  • Toocheck C, Clister T, Shupe J, Crum C, Ravindranathan P, Lee TK, Ahn JM, Raj GV, Sukhwani M, Orwig KE, Walker WH.Mouse Spermatogenesis Requires Classical and Nonclassical Testosterone Signaling. Biol Reprod. 2016 Jan;94(1):11. doi: 10.1095/biolreprod.115.132068. Epub 2015 Nov 25. PubMed PMID: 26607719; PubMedCentral PMCID: PMC4809556.

    Classical and nonclassical testosterone signaling regulate overlapping and distinct functions that are required for the maintenance of spermatogenesis and male fertility.
  • Yang L, Ravindranathan P, Ramanan M, Kapur P, Hammes SR, Hsieh JT, Raj GV. Central role for PELP1 in nonandrogenic activation of the androgen receptor in prostate cancer.Mol Endocrinol. 2012 Apr;26(4):550-61. doi: 10.1210/me.2011-1101. Epub 2012 Mar 8. PubMed PMID: 22403175; PubMed Central PMCID: PMC5417135.

    PELP1 allows for crosstalk between E2 bound to ERβ and AR opening a therapeutic strategy in advanced PCa.
  • Zhang B, Kwon OJ, Henry G, Malewska A, Wei X, Zhang L, Brinkley W, Zhang Y, Castro PD, Titus M, Chen R, Sayeeduddin M, Raj GV, Mauck R, Roehrborn C, Creighton CJ, Strand DW, Ittmann MM, Xin L. Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor.Mol Cell. 2016 Sep 15;63(6):976-89. doi: 10.1016/j.molcel.2016.07.025. Epub 2016 Sep 1. PubMed PMID: 27594448; PubMed Central PMCID: PMC5026614.

    Disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases.

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