Therapeutic targeting of master regulators in non-canonical AR driven advanced lethal prostate cancers

PROJECT SUMMARY (ABSTRACT)

Androgen receptor (AR) targeted therapies such as abiraterone, enzalutamide, apalutamide, and darolutamide are effective treatments for patients with advanced castrate-resistant prostate cancer (CRPC). However, resistance to these therapies

represents a significant hurdle in the clinical management of advanced CRPC. Despite initial clinical benefit, most patients

relapse with acquired resistance within a year. An emerging mechanism of acquired resistance to AR-targeted therapy is the

ability of tumor cells to adapt a non-canonical AR activity for survival. Preliminary suggests that increased expression of a master regulatory transcription factor (TF) cluster (ELF3, JDP2, PBX1, RARA) is associated with the non-canonical AR activity observed with acquired enzalutamide resistance. Interestingly, expression levels of known AR partners, FOXA1

and HOXB13, were either unaffected or slightly decreased following exposure to enzalutamide in resistant models. AR

chromatin profiling showed a unique binding pattern of AR to novel master regulatory TFs at promoter and enhancer regions that were absent in the presence of DHT. Preliminary data also suggests a decrease in these master TFs suppresses non-

canonical AR activity and reverses acquired resistance to enzalutamide in preclinical models. The overall objective of this application is to determine the role of identified master regulatory TFs on non-canonical AR activity associated with

acquired enzalutamide resistance in CRPC and develop optimal therapeutic options that shift cells back to a phenotype that is clinically manageable and re-sensitized to enzalutamide. Our central hypothesis is that non-canonical AR cistrome

associated with resistance is driven by the recruitment of novel master regulatory transcription factors. Targeting their vulnerability can re-sensitize resistant cells to enzalutamide. The rationale is that through multimodal molecular

characterization, we can explore therapeutic options that can push back these cancer cells to a canonical AR state sensitive to enzalutamide. We will test our central hypothesis and accomplish the objective of this application by pursuing the

following specific aims: (i) Multimodal characterization of non-canonical AR activity in patient-derived xenograft models

of advanced disease. (ii) Assess the functional role of identified master regulatory TF on non-canonical AR activity. (iii) Assess the antitumor activity of candidate combination therapies in multiple PDX models and gather pharmacological and

Toxicology information. Impact: Results from this project will significantly expand our knowledge of the biology of lethal prostate cancer (PCa) and provide optimal treatment strategies that improve outcomes for men with lethal PCa, reducing

the unequal burden of cancer. Our immediate goal is to leverage information from molecular studies to recognize the subset

of patients where resistance is driven by non-canonical AR activity using multi-omic-based markers. Furthermore, our study

will provide the mechanisms and vulnerabilities of the altered AR cistrome drivers and the implications for drug discovery

and developing optimal therapeutic options for this subset of patients. Our long-term goal is to translate our preclinical findings into the clinic in the setting of phase I & II clinical trials.