The RET Kinase Signaling Axis in Neuroendocrine Prostate Cancer Plasticity
Abstract
Prostate cancer is the most common non-cutaneous cancer among men in the United States, with more than 160,000 new cases each year. For most men, the prognosis is good, with a 5-year survival >98%. However, survival for men that progress to metastatic disease is poor, and the 5-year survival rate plummets to <30%. Prostate cancer cells require androgens for growth, and androgen deprivation therapy (ADT) is employed as a first-line therapy. ADT is initially successful in causing tumor regression, but ultimately fails as the tumor returns, resulting in castration-resistant prostate cancer (CRPC). A highly aggressive subtype of CRPC, termed aggressive variant prostate cancer (AVPC), is extremely lethal, causing death within 1 to 2 years. Currently, there are no effective therapies to combat this aggressive subtype, necessitating alternative approaches to identify new treatment strategies to prolong survival and prevent death. We recently identified RET kinase as a potential driver of AVPC and an actionable drug target. RET is highly upregulated in AVPC, and dysregulation of RET has been implicated in several cancers that share neuroendocrine features with AVPC. EZH2 is also highly upregulated in AVPC and a putative target of RET kinase activation. Therefore, we hypothesize that activation of the RET kinase signaling axis is a key event driving progression from prostate adenocarcinoma to AVPC and co-inhibition of EZH2, and RET will resensitize tumors to ADT. Applicability of the Research: AVPC is an emerging subtype of CRPC for which there are no effective therapeutic strategies. The success of this project will impact our understanding of this highly lethal variant, with the potential to immediately impact the current clinical approach to treatment. Importantly, elucidation and successful targeting of AVPC resistance mechanisms have broader applicability to disease management strategies. Combination therapy specifically tailored to target alterations driving tumor progression is an important next step in personalized medicine for prostate cancer patients. Goals of the Principal Investigator: Dr. Zachary Richards is a postdoctoral scholar and budding prostate cancer researcher. His proposal serves to fulfill his long-term goal of preventing death from prostate cancer. He was previously awarded a pre-doctoral fellowship for his work exploring racial disparities in prostate cancer and has contributed to the broader prostate cancer field through publications and invited oral presentations. This proposal serves to expand his breadth of knowledge by contributing to a different aspect and subtype of prostate cancer. His mentor, Dr. Leigh Ellis, is an established prostate cancer researcher with the expertise and acumen to guide Dr. Richards to a successful career. The project is specifically designed to provide Dr. Richards with essential training in specific prostate modeling techniques and technical analyses, while simultaneously contributing new knowledge and insights on AVPC to the broader field. Through completion of this project, Dr. Richards will have taken a crucial next step in expanding his toolbox and expertise to achieve his goal of future discovery as an independent prostate cancer researcher.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910300
Entities
People
- Yuzhen Zhou
Organizations
- Dana–Farber Cancer Institute
- United States Army