SPORE in Prostate Cancer

PROJECT SUMMARY/ABSTRACT
Over the past 20 years, the SPORE in Prostate Cancer at Memorial Sloan Kettering Cancer Center has made
significant advances in prostate cancer research and treatment, using the evolving mechanistic understanding
of the drivers of tumor growth to improve patient management across the clinical spectrum of the disease.
Applying a biomarker- based, risk-adapted approach, our work has led to the development of new diagnostic
blood tests and prognostic models to distinguish indolent from clinically significant cancers, the discovery of
new therapeutic targets, their validation in preclinical models, and the successful development of drugs
directed to them in trials designed according to the recommendations of the Prostate Cancer Working Group 3.
Our efforts have impacted clinical practice worldwide.
The overall objectives of our SPORE are: 1) to interrogate the genomics and molecular pathways relevant to
prostate cancer progression, 2) to identify and validate clinically relevant biomarkers, and 3) to develop novel
agents and therapeutic strategies. In the next 5 years, we propose 3 research projects to address new clinical
challenges that have emerged in the context of the evolving landscape of prostate cancer. For localized
disease, the challenges are to identify patients at high risk for metastasis and death and to determine optimal
upfront treatment to improve cure. To address this, RP-1 will determine germline and somatic genomic
features associated with disease progression in high-risk localized disease and RP-2 will determine the role of
signaling from the prostate microenvironment in resistance to androgen-deprivation therapy and determine the
efficacy of targeting these signals. For patients with metastatic disease, the widespread adoption of potent
next-generation androgen receptor (AR) signaling inhibitors has changed the landscape of prostate cancer,
highlighting the need for therapeutic strategies for cancers that develop AR independence. Previously our
SPORE characterized the AR-independent “lineage plasticity” disease state as driven by TP53 and RB1 loss.
RP-3 now seeks to better define the genomic heterogeneity inherent in this disease state and evaluate novel
therapeutic strategies. PARP inhibitors were recently approved for metastatic cancers with DNA damage repair
mutations, but the response rate is only ~50%. RP-1 will define the genomic context that predicts for PARP
inhibitor response.

Grant Number: 5P50CA092629-24
NIH Institute/Center: NIH
Principal Investigator: Yu Chen