This is a revised competitive renewal application for our P01 entitled ?Androgen Receptor Action In Castration Resistant Prostate Cancer?. The past several years have seen a paradigm shift in prostate cancer (PCa) therapy, as it is now clear that the androgen receptor (AR) remains active and is a therapeutic target in PCa that relapses after surgical or medical castration (castration-resistant prostate cancer, CRPC). Previous basic, translational and clinical research conducted by investigators in this P01 proposal made major contributions to this paradigm shift by elucidating fundamental mechanisms of AR action and mechanisms of castration- resistance in patients. The CYP17A1 inhibitor abiraterone, and the AR antagonist enzalutamide, are now standard second line hormonal therapies for men who relapse after castration. Unfortunately, most men who respond to these therapies will relapse within 1-2 years. Significantly, while a subset of abiraterone or enzalutamide-resistant PCa may become AR independent, recent results from investigators in this P01 and others indicate that most continue to express high levels of AR that appears to be transcriptionally active. Therefore, a major hypothesis in this proposal is that AR activity still persists and is contributing to tumor growth in abiraterone and enzalutamide-resistant PCa. Moreover, we hypothesize that adaptations made by PCa cells in response to AR targeted therapies create vulnerabilities that can be exploited therapeutically. Hence, overall program goals are to elucidate clinically relevant mechanisms that contribute to CRPC and abiraterone/enzalutamide-resistance, to identify therapeutic approaches that can overcome these resistance mechanisms and/or exploit new vulnerabilities, and to assess these therapeutic approaches in preclinical models that can form foundations for clinical trials. The Projects are as follows: 1) Determining and Exploiting Mechanisms of AR-Mediated Suppression of Cell, 2) Mechanisms Driving AR Full Length and Splice Variant Activities and Antagonist Resistance, 3) Protein Kinases Influencing Androgen Receptor in Castrate Resistant Prostate Cancer, 4) Identification of Essential Genes Underlying AR Activity in Antagonist-Resistant CRPC.

Public Health Relevance

This is a revised renewal application for our P01 entitled ?Androgen Receptor Action In Castration Resistant Prostate Cancer?. It is focused on the hypothesis that androgen receptor (AR) activity persists in prostate cancer (PCa) that relapses after abiraterone and enzalutamide treatment, and that tumor cell adaptations to these AR-targeted therapies create new vulnerabilities that can be therapeutically exploited. Hence, overall program goals are to elucidate clinically relevant resistance mechanisms and assess therapies targeting these mechanisms in preclinical models that can form foundations for clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163227-08
Application #
10112185
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2013-05-24
Project End
2024-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
8
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Beshiri, Michael L; Tice, Caitlin M; Tran, Crystal et al. (2018) A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening. Clin Cancer Res 24:4332-4345
Russo, Joshua W; Liu, Xiaming; Ye, Huihui et al. (2018) Phosphorylation of androgen receptor serine 81 is associated with its reactivation in castration-resistant prostate cancer. Cancer Lett 438:97-104
Mostaghel, Elahe A (2018) Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer. Clin Cancer Res :
Uo, Takuma; Plymate, Stephen R; Sprenger, Cynthia C (2018) The potential of AR-V7 as a therapeutic target. Expert Opin Ther Targets 22:201-216
Arai, Seiji; Jonas, Oliver; Whitman, Matthew A et al. (2018) Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis. Clin Cancer Res 24:5458-5470
Viswanathan, Srinivas R; Ha, Gavin; Hoff, Andreas M et al. (2018) Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing. Cell 174:433-447.e19
Russo, Joshua W; Gao, Ce; Bhasin, Swati S et al. (2018) Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res 78:6354-6362
Sowalsky, Adam G; Ye, Huihui; Bhasin, Manoj et al. (2018) Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations. Cancer Res 78:4716-4730
Zhu, Yezi; Sharp, Adam; Anderson, Courtney M et al. (2018) Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol 73:727-735
Penning, Trevor M (2018) Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer. Vitam Horm 108:309-331

Showing the most recent 10 out of 90 publications