Drivers and Downstream Effectors of WNT Signaling in Lethal Prostate Cancer
Abstract
Rationale: The WNT pathway plays a critical role in development, and activation of this pathway contributes to many cancers, including prostate cancer (PCa). In this pathway, cells produce a group of proteins (WNTs) that can bind to a family of receptor proteins on other cells (FZD receptors). The WNT/FZD complex can then act to increase the levels of a protein called ß-catenin, which can then stimulate the expression of multiple genes that can drive tumor growth. This pathway is termed the canonical WNT pathway. The WNT/FZD complex can also interact with other proteins to activate another pathway termed the noncanonical WNT pathway. This noncanonical pathway is not well-understood in PCa, but may contribute to tumor growth and invasion. Significantly, there are drugs being tested in patients that can block the synthesis of WNTs (inhibitor s of the enzyme PORCN), and thus potentially shut down WNT signaling. However, these drugs have toxicities and may be effective only in a subset of patients whose tumors are strongly dependent on WNT synthesis. Therefore, a major goal of this study is to characterize canonical and noncanonical WNT signaling in PCa so that we can identify the subset of tumors that are most likely to respond to drugs that block WNT production. Moreover, we may identify key proteins that are increased by WNT signaling that would be new candidate therapeutic targets. Objective: Our objective is to comprehensively characterize WNT signaling in PCa and particularly in advanced metastatic castration-resistant prostate cancer (mCRPC). We anticipate that this will lead to identification of proteins or other features that we can examine in tumor biopsies that will tell us whether the patient’s tumor is strongly dependent on WNT and, hence, whether they are likely to respond to a WNT synthesis inhibitor or possibly other agents targeting this pathway. These proteins or other features that can predict who will respond are termed predictive biomarkers, and they are used in clinical trials to select appropriate patients for particular drug treatments. Aims: Our Specific Aims are to (1) identify and validate downstream effectors of noncanonical versus canonical WNT signaling in PCa, (2) assess WNT pathway genes as potential predictive biomarkers for responses to WNT synthesis inhibitors or as therapeutic targets, and (3) identify WNT/ß-catenin independent pathways activated by APC alterations in PCa and corresponding vulnerabilities that may be exploited therapeutically. Applicability of Research: This work will have both short- and long-term impacts. The short-term impact will be enhancement of our understanding of canonical and noncanonical WNT signaling in PCa that will allow us to assess these pathways in clinical samples. This will provide biomarkers that will allow us to identify patients whose tumors are strongly WNT-driven and likely to respond to WNT synthesis inhibitors, and we are optimistic that this will lead to a biomarker-driven phase II trial of a clinically available PORCN inhibitor in mCRPC. This addresses the FY19 PCRP Overarching Challenges to (1) develop treatments that improve outcomes for men with lethal PCa and (2) define the biology of lethal PCa to reduce death. In the long term, we hope to build on results from initial trials to develop more effective combination therapies that may target downstream effectors of WNT. We are also optimistic that our studies of APC in PCa will reveal vulnerabilities conferred by APC mutation or downregulation that can be targeted therapeutically. Moreover, given the apparent major role of WNT pathway activation in resistance to androgen receptor (AR)-targeted therapies (such as abiraterone or enzalutamide), we anticipate that these WNT-targeted therapies may be highly effective when used early in combination with AR-targeted agents. Therefore, we anticipate that a long-term impact will be the development of combination therapies tar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010925
Entities
People
- Steven P Balk
Organizations
- Beth Israel Deaconess Medical Center
- United States Army