Origin of a mesenchymal and stem-like subtype of metastatic castration-resistant prostate cancer

Describe the Scientific Objective and Rationale for the Proposed Project:

We propose a new molecular classification system of metastatic castration-resistant prostate cancer (M-CRPC). Using 2,400 cancer cell intrinsic genes expressions, we identified three subtypes of M-CRPC: AR-active PC (ARPC), Neuronal Progenitor-like PC (NEPC), and Mesenchymal/Stem-like PC (MSPC). Examining multiple patient datasets, we found that MSPC cases have dramatically increased in the recent era. While ARPC and NEPC characteristics mostly match to current knowledge on prostate cancer, the biology of MSPC is largely unknown. In this project, we will characterize the MSPC subtype, focusing on two basic questions: (1) how to identify MSPC and (2) how to treat MSPC.

Describe the Ultimate Applicability of the Research:

What are the likely contributions of this study to the FY19 PCRP Overarching Challenges?

M-CRPC is the lethal form of disease. This study is to establish a new subtyping system of M-CRPC and develop a new mouse model that represents an emerging but uncharacterized subtype. This fits with the Overarching Challenge to 'Define the biology of lethal prostate cancer to reduce death.' We will perform drug screening to identify subtype-specific drug candidates that will aid the Overarching Challenge to 'Develop treatments that improve outcomes for men with lethal prostate cancer.'

What types of patients will it help and how will it help them?

This study will help understand the biology of a defined subset of M-CRPC patients who do not respond to anti-androgen therapies (enzalutamide, abiraterone) and identify specific candidates among existing anti-cancer agents.

What are the potential clinical applications, benefits, and risks?

This study will help identify patients who will respond to existing prostate cancer drugs targeting androgen signaling and who will not. For those (predicted) non-responders, this study will help identify alternative candidate drugs tailored to their biology. Potential risks include deviation from standard-of-care therapy that might have worked in the (predicted) non-responders.

What is the projected time it may take to achieve a patient-related outcome? If the research is too basic for near-term clinical applicability, describe the interim outcomes.

It will take around 2 years to establish this new classification system of M-CRPC and validate subtype-specific biomarkers. Potential interim outcomes include (1) better understanding of M-CRPC biology and (2) preclinical evidences supporting subtype-specific drug treatment.

Describe the Principal Investigator's (PI's) career goals in prostate cancer research. How does the research plan support the PI in achieving career goals?

My career goal is to become a PI who can coordinate both clinical and basic science fields of prostate cancer research. Successful completion of this project will generate a model system, candidate drugs, and target patient groups for me to develop this into an independent project of translational relevance. Eventually, it will yield enough merit for me to become an independent prostate cancer researcher.

How does the mentorship and researcher development plan support the PI in achieving these goals?

I am supported by a unique environment where basic science and clinical science are ideally joined together. In particular, my mentor provided all experimental resources to acquire preliminary data. My co-mentors provided patient-derived data to produce the rationale for the central hypothesis.