Evaluating the Impact of FOXA1 Mutations on the AR Transcriptional Program in Castration-Resistant Prostate Cancer
Abstract
Background and Research Plan: Prostate cancer (PCa) is the most commonly diagnosed cancer in North American men. It is also the second leading cause of cancer-related deaths in this population, claiming over 27,000 lives in 2015 alone. This disease originates in the prostate gland and is acutely dependent on the activity of a critical gene called androgen receptor (AR) for its growth and survival. AR, in turn, requires binding with a steroid molecule called androgen to perform its functions. When diagnosed in the early organ-localized stages, PCa is largely curable by surgical resection. However, in about 20%-30% of the cases, PCa recurs and spreads to secondary sites in the body such as pelvic bones and organs. This stage is called metastatic PCa. Notably, this recurrent PCa retains its acute reliance on AR activity and thus androgen for its growth and survival. Consequently, patients with this disease are mainly treated by starving the cancer cells of androgen either by surgical removal of the entire testis or chemical inactivation of the androgen-producing cells. Though this androgen-deprivation therapy results in initial remission of the tumors, in almost all of the patients disease eventually relapses. This stage is clinically defined as metastatic castration-resistant PCa (mCRPC), and it still remains "addicted" to AR activity, which is abnormally restored without androgen binding. Despite new anti-AR therapies, mCRPC still remains incurable, with half of the patients succumbing to their disease within 16-18 months. This raises a pertinent biological question: What promotes the progression of early/localized PCa to lethal mCRPC? In this project, we comprehensively address this question using the most modern sequencing technologies. As part of a multi-institutional consortium, our lab has gathered over 150 mCRPC patient tumors from multiple secondary sites. We have sequenced the DNA from these tumors to obtain a profile of the distinct genetic errors (aka mutations) that are found in this disease. Here we found new mutations in an important gene called FOXA1 in over 12% of the cases. Notably, FOXA1 mutations were more frequently found in mCRPC (>three-fold) than in localized PCa, suggesting of its involvement in promoting growth in the absence of androgen. Interestingly, FOXA1 has been extensively studied in PCa and has been described to directly interact with and regulate AR activity. In fact, removal of FOXA1 in patient-derived PCa cell lines attenuates AR activity and results in reduced growth -- much like the removal of androgen. Together, these insights allow us to hypothesize that the FOXA1 mutants are functional in mCRPC and, through differential regulation of oncogenic AR activity, enable PCa regrowth despite the reduction in androgen levels. Our project will investigate the functional roles of 12 representative FOXA1 mutants in re-activating androgen-independent pro-tumor AR signaling despite lowered androgen levels. To this end, we will endogenously express the FOXA1 mutants in commonly used AR-positive PCa lines, namely LNCaP and VCaP, and assess the ensuing changes their aggressiveness and molecular profiles using standard assays and innovative sequencing techniques. Career Goals: Alongside my undergraduate training, I gained over 2 years of practical research experience in PCa biology in Dr. Yuzhuo Wang s lab at the BC Cancer Research Centre in Vancouver. There, I studied the role of novel non-coding genes in mediating the progression of PCa to evolve resistance against anti-androgen therapies. This experience helped to ascertain my career goal of becoming a PCa investigator and has led to nine publications till date, including a first-author paper. Encouraged by this background, for my PhD training I have joined Dr. Chinnaiyan s lab, who is a world-renowned leader in cancer genomics and PCa biology. He has made several pioneering discoveries including validation of biomarke
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710130
Entities
People
- Abhijit Parolia
Organizations
- United States Army
- University of Michigan