This application is in response to RFA-CA-12-021: Research Answers to NCI's Provocative Questions-Group D (R01) and addresses PQD1: How does the selective pressure imposed by the use of different types and doses of targeted therapies modify the evolution of drug resistance? The overall objective of this application is to investigate differences in mechanisms of resistance to subsequent therapy caused by variations in androgen deprivation therapy (ADT), the standard-of-care treatment for recurrent prostate cancer (CaP). We hypothesize that different types of ADT in men of different genetic background result in tumors of varied response to additional therapy and may directly affect survival. This application represents a team effort involving investigators with cancer biology, genetics, biostatistics, bioinformatics and clinical experience and therefore provides a unique opportunity to test this hypothesis. Our preliminary data indicate that these differences may arise due to differential expression of the AR co-regulator Filamin A (FlnA) which affects the transcriptional program regulated by the AR and result in differential expression of certain genes, such as the novel AR target Nrdp1, but not that of others, such as the well-known AR target PSA. Using patient derived xenografts (PDX) treated with various forms of ADT, we propose to investigate by rapid high throughput parallel sequencing, in conjunction with ChIP-Seq to identify AR targets and RNA-Seq to look at overall molecular profiles, the targets that are differentially regulated and the molecular mechanisms by which these differences arise. We will determine whether the molecular profile of the PDX is affected by the treatment and whether the resulting molecular constituency determines the response of these tumors to additional treatment (e.g. chemotherapy followed by AR antagonists vs chemo-na?ve AR antagonists). Additionally, we will determine how AR co-regulators including FlnA affect AR transcriptional programs and why certain genes are affected by this program while others are not. Finally, we will investigate whether the differential molecular profile, in particular, the expression of the novel AR transcriptional target Nrdp1 and its downstream effector ErbB3, may be used to predict response of patients to AR inhibitors. We intend to demonstrate that levels of the Nrdp1 or its target ErbB3, but not PSA levels, in the serum of CRPC patients correlate to the aggressiveness of the disease. Expected overall impact: This proposal will utilize a newly identified AR target gene (Nrdp1) to address a significant problem in current management of CRPC where physicians often have to blindly assign one treatment vs. another for patients with CRPC. Prediction of response to AR antagonists' vs chemotherapeutic agents, and the sequence of events to be used to maximize patient response, will significantly improve survival in this group of patients. The results of this study, if validated in human patients, has the potential of being translated to a Phase III trial to determine whether molecular predictors of patient response may differentiate between patients who would benefit from immediate AR inhibitors and those who should get chemotherapy.
This proposal addresses a significant problem in current management of castration resistant prostate cancer (CRPC) where physicians often have to blindly assign one treatment vs. another for patients with CRPC. Here we propose to investigate whether it is possible to predict which patients would benefit most from androgen receptor (AR) antagonists. Prediction of response to AR antagonists vs. chemotherapeutic agents, and the sequence of events to be used to maximize patient response, will significantly improve survival in this group of patients. The results of this study, if validated in human patients, has the potential of being translated to a Phase III trial to determine whether molecular predictors of patient response may differentiate between patients who would benefit from immediate AR inhibitors and those who should get chemotherapy.
