Prostatic adenocarcinoma (PCa) is the most frequently diagnosed malignancy and 2nd leading cause of cancer death in American men. PCa is resistant to standard chemotherapy, but is exquisitely dependent on the activity of the androgen receptor (AR, a ligand-dependent transcription factor) for growth, survival, and progression. As such, AR is the first line therapeutic target for all patients with disseminated disease. AR- directed therapies entail the use of androgen deprivation therapy (ADT), which suppresses testicular androgen synthesis;these modalities prevent AR from binding chromatin and inducing gene expression, and are often used in combination with direct AR antagonists. While initially effective, recurrent tumors arise within 2-3 years wherein the AR has been inappropriately reactivated. This stage of disease, termed """"""""castration-resistant prostate cancer"""""""" (CRPC) is the incurable phase, and underpins the significant morbidity associated with PCa. Thus, there is an urgent need to identify the diverse mechanisms utilized by tumors to reactivate AR, and to develop mechanisms of thwarting this process. Examination of human CRPC revealed that the major mechanism leading to therapy-resistance is upregulation of AR. Consonantly, preclinical modeling of even modest AR upregulation showed that this event alone is sufficient to drive progression to incurable CRPC. The mechanisms by which AR upregulation occurs during disease progression remained incompletely defined - while amplification of the AR locus accounts for a fraction of these observations, a significant proportion of CRPCs show upregulation of AR without gene amplification. Strikingly, our recently reported findings identify perturbation of the RB tumor suppressor as a major mechanism by which AR deregulation occurs and induces CRPC formation, independent of AR amplification. Our collective data have potentially dramatic clinical implications, and strongly support the hypothesis that perturbations of the RB/E2F1/AR axis play a major role in the transition to CRPC, and that RB status can be developed as a metric to direct personalized therapeutic intervention in prostate cancer.
Three aims are proposed to challenge this hypothesis:
Three aims are proposed will: 1) Define the molecular mechanisms and clinical consequence of RB dysfunction in CRPC;2) Delineate the impact of RB loss on aberrant AR signaling;and 3) Examine targeting the RB/E2F1/AR axis to suppress PCa progression.
There is a significant need to understand the mechanisms that lead to prostate cancer growth and progression. Our data show RB is a major effector of AR expression and activity, and strongly suggest RB status can be developed as a molecular tool for precision medicine. The studies here will challenge this concept, provide molecular insight into the cellular and clinical consequence of RB dysfunction, and have the potential for rapidly translatable outcomes to improve prostate cancer management.
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| de Leeuw, Renée; McNair, Christopher; Schiewer, Matthew J et al. (2018) MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer. Clin Cancer Res 24:4201-4214 |
| McNair, Christopher; Xu, Kexin; Mandigo, Amy C et al. (2018) Differential impact of RB status on E2F1 reprogramming in human cancer. J Clin Invest 128:341-358 |
| Thangavel, Chellappagounder; Boopathi, Ettickan; Liu, Yi et al. (2017) RB Loss Promotes Prostate Cancer Metastasis. Cancer Res 77:982-995 |
| Schiewer, Matthew J; Knudsen, Karen E (2017) Not So Fast: Cultivating miRs as Kinks in the Chain of the Cell Cycle. Cancer Cell 31:471-473 |
| Thomas, Jeffrey D; Longen, Charles G; Oyer, Halley M et al. (2017) Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer. Cancer Res 77:2439-2452 |
| McNair, C; Urbanucci, A; Comstock, C E S et al. (2017) Cell cycle-coupled expansion of AR activity promotes cancer progression. Oncogene 36:1655-1668 |
| Schiewer, Matthew J; Knudsen, Karen E (2016) Linking DNA Damage and Hormone Signaling Pathways in Cancer. Trends Endocrinol Metab 27:216-225 |
| de Leeuw, Renée; Berman-Booty, Lisa D; Schiewer, Matthew J et al. (2015) Novel actions of next-generation taxanes benefit advanced stages of prostate cancer. Clin Cancer Res 21:795-807 |
| Augello, Michael A; Berman-Booty, Lisa D; Carr 3rd, Richard et al. (2015) Consequence of the tumor-associated conversion to cyclin D1b. EMBO Mol Med 7:628-47 |
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