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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA176401-01A1
Application #
8642989
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Jhappan, Chamelli
Project Start
2014-01-14
Project End
2018-12-31
Budget Start
2014-01-14
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$431,269
Indirect Cost
$153,031
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Thangavel, Chellappagounder; Boopathi, Ettickan; Ciment, Steve et al. (2014) The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness. Clin Cancer Res 20:5468-82
Knudsen, Karen E (2014) Hormone whodunit: clues for solving the case of intratumor androgen production. Clin Cancer Res 20:5343-5