Mechanisms of prostate cancer initiation and progression
Our group has developed and characterized many laboratory models to study prostate cancer initiation and progression. We have established new patient-derived xenograft models and organoid lines as well as genetically engineered mouse (GEM) prostate cancer models for driver oncogenes such as MYC and ERG. Our recent work combines GEM models, primary prostate organoid culture, and single cell analysis technologies to characterize the oncogenicity of ERG, ERF and FOXA1, and to study prostate cancer tumor-host signals during metastasis.
- Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, Thomas GV, Sawyers CL. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell. 2003 Sep;4(3):223-38. doi: 10.1016/s1535-6108(03)00197-1. Erratum in: Cancer Cell. 2005 Dec;8(6):485.
- Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, Gao D, Sirota I, Carver BS, Wongvipat J, Scher HI, Zheng D, Sawyers CL. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nature Med. 2013;19(8):1023-9. Epub 2013/07/03. PMCID: PMC3737318
- Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R, Wongvipat J, Dowling CM, Gao D, Begthel H, Sachs N, Vries RG, Cuppen E, Chen Y, Sawyers CL, Clevers HC. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 2014;159:163–175. PMCID: PMC4772677.
- Bose R, Karthaus WR, Armenia J, Abida W, Iaquinta PJ, Zhang Z, Wongvipat J, Wasmuth EV, Shah N, Sullivan PS, Doran MG, Wang P, Patruno A, Zhao Y; International SU2C/PCF Prostate Cancer Dream Team, Zheng D, Schultz N, Sawyers CL. ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis. Nature 2017 546(7660):671-675. PMID: 28614298.Adams EJ, Karthaus WR, Hoover E, Liu D, Gruet A, Zhang Z, Cho H, DiLoreto R, Chhangawala S, Liu Y, Watson PA, Davicioni E, Sboner A, Barbieri CE, Bose R, Leslie CS, Sawyers CL. FOXA1 mutations alter pioneering activity, differentiation, and prostate cancer phenotypes. Nature. 2019 571(7765):408-412. doi: 10.1038/s41586-019-1318-9. Epub 2019 Jun 26. PMCID: PMC6661172.
- Adams EJ, Karthaus WR, Hoover E, Liu D, Gruet A, Zhang Z, Cho H, DiLoreto R, Chhangawala S, Liu Y, Watson PA, Davicioni E, Sboner A, Barbieri CE, Bose R, Leslie CS, Sawyers CL. FOXA1 mutations alter pioneering activity, differentiation, and prostate cancer phenotypes. Nature. 2019 571(7765):408-412. doi: 10.1038/s41586-019-1318-9. Epub 2019 Jun 26. PMCID: PMC6661172.
- Karthaus, WR, Hofree, M, Choi, D, Linton, EL, Turkekul, M, Bejnood, A, Carver, B, Gopalan, A, Abida, W, Pe’er D, Regev A, Sawyers CL. (2020). Regenerative potential of prostate luminal cells revealed by single cell analysis. Science. 2020 May 1;368(6490):497-505. doi: 10.1126/science.aay0267. PMCID: PMC7313621.
- Leibold J, Ruscetti M, Cao Z, Ho YJ, Baslan T, Zou M, Abida W, Feucht J, Han T, Barriga FM, Tsanov KM, Zamechek L, Kulick A, Amor C, Tian S, Rybczyk K, Salgado NR, Sánchez-Rivera FJ, Watson PA, de Stanchina E, Wilkinson JE, Dow LE, Abate-Shen C, Sawyers CL, Lowe SW. Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis. Cancer Discov. 2020 Jul;10(7):1038-1057. doi: 10.1158/2159-8290.CD-19-1242. Epub 2020 May 6. PMCID: PMC7334089.
I have co-led several comprehensive genomic landscape studies of castration resistant metastatic prostate cancer and founded AACR Project Genomics Neoplasia Information Exchange (GENIE), on open-access clinical genomic data sharing registry for precision oncology.
- Robinson D, Van Allen EM, Wu YM, Schultz N, ….de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-28. PMCID: PMC4484602.
- Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, Cieslik M, Benelli M, Robinson D, Van Allen EM, Sboner A, Fedrizzi T, Mosquera JM, Robinson BD, De Sarkar N, Kunju LP, Tomlins S, Wu YM, Nava Rodrigues D, Loda M, Gopalan A, Reuter VE, Pritchard CC, Mateo J, Bianchini D, Miranda S, Carreira S, Rescigno P, Filipenko J, Vinson J, Montgomery RB, Beltran H, Heath EI, Scher HI, Kantoff PW, Taplin ME, Schultz N, deBono JS, Demichelis F, Nelson PS, Rubin MA, Chinnaiyan AM, Sawyers CL. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11428-11436. doi: 10.1073/pnas.1902651116. Epub 2019 May 6. PubMed Central PMCID: PMC6561293.
- Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, Reznik E, Chatila WK, Chakravarty D, Han GC, Coleman I, Montgomery B, Pritchard C, Morrissey C, Barbieri CE, Beltran H, Sboner A, Zafeiriou Z, Miranda S, Bielski CM, Penson AV, Tolonen C, Huang FW, Robinson D, Wu YM, Lonigro R, Garraway LA, Demichelis F, Kantoff PW, Taplin ME, Abida W, Taylor BS, Scher HI, Nelson PS, de Bono JS, Rubin MA, Sawyers CL, Chinnaiyan AM, Schultz N, Van Allen EM. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2. PubMed Central PMCID: PMC6107367.
- AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 2017 Aug;7(8):818-831. doi: 10.1158/2159-8290.CD-17-0151. Epub 2017 Jun 1. PMCID: PMC5611790.
Mechanisms of resistance to antiandrogen therapy
Although enzalutamide improves survival of men with metastatic prostate cancer, resistance eventually develops. To date, we have reported four distinct mechanisms of resistance to enzalutamide: mutations in the gene encoding AR, bypass of AR receptor signaling via upregulation of the glucocorticoid receptor, SOX2-dependent lineage plasticity (involving TP53 and RB1), and mesenchymal-derived paracrine signaling via NRG1.
- Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, Zheng D, Sawyers CL. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013;155:1309–1322. PMCID: PMC3932525.
- Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, Rockowitz S, Drier Y, Bernstein BE, Long HW, Freedman ML, Arora VK, Zheng D, Sawyers CL. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. eLife, 2017.
- Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, Wongvipat J, Ku SY, Gao D, Cao Z, Shah N, Adams EJ, Abida W, Watson PA, Prandi D, Huang CH, de Stanchina E, Lowe SW, Ellis L, Beltran H, Rubin MA, Goodrich DW, Demichelis F, Sawyers CL. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017 Jan 6;355(6320):84-88. PubMed Central PMCID: PMC5247742.
- Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, Goodrich MM, Labbé DP, Gomez EC, Wang J, Long HW, Xu B, Brown M, Loda M, Sawyers CL, Ellis L, Goodrich DW. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017 Jan 6;355(6320):78-83. PMCID: PMC5367887.
- Zhang Z, Karthaus WR, Lee YS, Gao VR, Wu C, Russo JW, Liu M, Mota JM, Abida W, Linton E, Lee E, Barnes SD, Chen HA, Mao N, Wongvipat J, Choi D, Chen X, Zhao H, Manova-Todorova K, de Stanchina E, Taplin ME, Balk SP, Rathkopf DE, Gopalan A, Carver BS, Mu P, Jiang X, Watson PA, Sawyers CL. Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer. Cancer Cell. 2020 Aug 10;38(2):279-296.e9. doi: 10.1016/j.ccell.2020.06.005. Epub 2020 Jul 16. PMCID: PMC7472556.
Antiandrogen therapy for prostate cancer
In 2004, we reported that increased expression of the androgen receptor (AR) conferred resistance to existing antiandrogen therapies by converting the cellular response from antagonism to agonism. This observation led us to search for new antiandrogens that could overcome this resistance, resulting in the discovery of enzalutamide with our collaborator, Michael Jung at UCLA. Enzalutamide was approved for treatment of advanced prostate cancer in 2012. We also developed apalutamide, which was approved in 2018 for use in men with castration-resistant prostate cancer who are at risk for metastasis to delay disease progression. Apalutamide inhibits the androgen receptor through a mechanism of action similar to enzalutamide.
- Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33–39.
- Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen C, Higano CS, Beer TM, Hung DT, Scher HI, Jung M Sawyers CL. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324:787–790. PMCID: PMC2981508.
- Scher HI, Beer TM, Higano C, Anand A, Taplin M-E, Efstathiou E, Rathkopf D, Shelkey J, Yu E, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL. Antitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant Prostate Cancer. Lancet, 2010, 375:1437-46. Epub 2010 Apr 14. PMCID: PMC5013546
- Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, Hager JH. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-503. doi: 10.1158/0008-5472.CAN-11-3948. Epub 2012 Jan 20. PMCID: PMC3306502.
- Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, Rix PJ, Chow Maneval E, Chen I, Gönen M, Fleisher M, Larson SM, Sawyers CL, Scher HI. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2013 Oct 1;31(28):3525-30. doi: 10.1200/JCO.2013.50.1684. Epub 2013 Sep 3. PMCID: PMC3782148.
PI3-kinase signaling in prostate cancer
The high frequency of PTEN loss in prostate cancer led us to study PI3-kinase signaling. We discovered reciprocal negative feedback between PI3-kinase and androgen receptor signaling in prostate cancers with PTEN loss and, with Neal Rosen, therapeutic strategies with combinations of alpha- and beta-specific inhibitors that delay drug resistance. In addition, we discovered an oncogenic role for the vesicular trafficking protein RAB35 in a screen for novel regulators of PI3-kinase activation.
- Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H, Scardino PT, Rosen N, Sawyers CL. Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer. Cancer Cell. 2011 May 17;19(5):575-86. PMCID: PMC3142785.
- Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V, Will M, Yellen P, de Stanchina E, Baselga J, Scher HI, Barry ST, Sawyers CL, Chandarlapaty S, Rosen N. Feedback suppression of PI3Kalpha signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kbeta. Cancer Cell. 2015;27(1):109-22. PMCID: PMC4293347.
- Wheeler DB, Zoncu R, Root DE, Sabatini DM, Sawyers CL. Identification of an oncogenic RAB protein. Science. 2015 Oct 9;350(6257):211-7. PMCID: PMC4600465.
Kinase inhibitors for chronic myeloid leukemia
Our laboratory approach is rooted in our history of expertise in BCR-ABL kinase signal transduction. As a clinician investigator in chronic myeloid leukemia (CML), I co-led the phase I and phase II clinical trials of imatinib (with Brian Druker and Moshe Talpaz) culminating in its FDA approval in 2001. My laboratory discovered mutations in the BCR-ABL kinase domain as the primary mechanism of resistance to imatinib, and then collaborated with John Kuriyan to show that these mutations impaired drug binding through steric hindrance (in some cases) or through altered conformation of the kinase domain (more commonly). Based on predictions from the “altered conformation” hypothesis, we identified dasatinib as a second generation ABL inhibitor that can overcome nearly all forms of imatinib resistance. I co-led the phase I and phase II clinical trials of dasatinib that resulted in its approval by the FDA in 2006.
- Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. NEJM 2001; 344:1031–1037.
- Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293:876–880.
- Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2: 117–125.
- Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305: 399–401.