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

非经典 AR 驱动的晚期致命性前列腺癌中主调节因子的治疗靶向

基本信息

批准号：
10737204
负责人：
Remi Adelaiye-Ogala
金额：
$ 58.92万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737204
关键词：
Abate Address Androgen Receptor Animals Architecture Automobile Driving Back Binding Biological Assay Biology Cancer Burden Cells ChIP-seq Chromatin Clinic Clinical Clinical Management Combined Modality Therapy DNA Data Disease ELF3 gene Enhancers Exposure to Gene Expression Genetic Transcription Goals Knowledge Malignant neoplasm of prostate Mediating Modeling Molecular Neighborhoods Organoids Pathway interactions Patients Pattern Phase I Clinical Trials Phase II Clinical Trials Phenotype Physicians Play Population Pre-Clinical Model Proteins Proteomics RARA gene Reporting Resistance Resistance development Resolution Role Scientist Signal Transduction Systemic Therapy Testing Therapeutic Toxicology Translating abiraterone addiction advanced disease advanced prostate cancer antagonist cancer cell castration resistant prostate cancer drug discovery effective therapy enzalutamide high risk improved improved outcome interest men multimodality multiple omics neoplastic cell novel optimal treatments patient derived xenograft model patient subsets pharmacologic pre-clinical preclinical trial promoter protein expression receptor expression recruit relapse patients targeted treatment therapeutic target therapy resistant transcription factor transcriptome sequencing transcriptomics treatment strategy tumor tumor heterogeneity

项目摘要

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.