The recent FDA approvals of abiraterone and enzalutamide, two new agents targeting the androgen receptor (AR) signaling axis, have expanded the treatment options and improved outcomes for patients with castration-resistant prostate cancer (CRPC). These drugs have dramatically changed the therapeutic landscape of CRPC even though a significant proportion of patients do not derive any clinical benefit from them. Thus, there has emerged a critically unmet need to address the mechanisms of resistance to these agents. The overall objective of this application is to dissect molecular drivers of therapeutic resistance to abiraterone and enzalutamide. The main hypothesis of this application is that aberrant AR signaling, mediated by the constitutively active AR splice variants, underlies primary and acquired resistance to abiraterone and enzalutamide. The proposed studies will be conducted in a translational setting, involving prospective collection of clinically annotated specimens from patients with metastatic CRPC undergoing standard-of-care treatment with abiraterone or enzalutamide.
Three Specific Aims are proposed:
(Aim 1) to determine whether blood-based detection of a key AR splice variant, AR-V7, indicates primary or acquired resistance to abiraterone or enzalutamide;
(Aim 2) to define the transcriptional landscape of the aberrant AR in a comprehensive fashion, with the goal of determining the relative importance and clinical significance of AR-Vs in drug response and resistance, in the context of other putative competing resistance mechanisms;
and (Aim 3) to determine the role of AR dimers in mediating aberrant AR signaling. If successful, this project will determine the potential clinical utility of a non-invasive assay for AR-V7, will define the relative importance ad clinical significance of a number of competing resistance mechanisms, and will establish AR-Vs as drivers of resistance to AR-targeting agents. Overall, the proposed studies have the potential to transform the clinical management of metastatic CRPC and will help to drive the development of the next wave of approaches targeting the aberrant AR signaling axis.

Public Health Relevance

The recent FDA approvals of abiraterone and enzalutamide have expanded the treatment options and improved outcome for patients with castration-resistant prostate cancer, although resistance to these drugs remains a significant problem. This application will dissect molecular drivers of therapeutic resistance to these two new agents by focusing on abnormal androgen receptor signaling. The research findings have the potential to transform the clinical management of patients with metastatic castration-resistant prostate cancer and may fuel the discovery of novel agents that target abnormal androgen signaling from a new angle.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA185297-02
Application #
9060907
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Kondapaka, Sudhir B
Project Start
2015-05-01
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Urology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Antonarakis, Emmanuel S; Lu, Changxue; Luber, Brandon et al. (2017) Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide. J Clin Oncol 35:2149-2156
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Markowski, Mark C; Silberstein, John L; Eshleman, James R et al. (2017) Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer. JCO Precis Oncol 2017:

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