Investigating a Novel Approach for Targeting WNT-Driven Prostate Cancers
Abstract
The Problem of Advanced Disease: Metastatic castration-resistant prostate cancer (mCRPC) is the third leading cause of cancer-related deaths in men in the United States and the sixth most common cause of cancer-related deaths in the world. While prostate tumors respond initially to androgen deprivation therapy (ADT), the majority of them develop resistance to ADT, progress to more advanced stages, and respond poorly to even the second or third generation of anti-androgen therapies. Clearly, hormonal therapies are insufficient at stopping disease progression permanently, as tumor cells utilize a variety of mechanisms to evade such therapies, including the activation of compensatory pathways. Thus, it is critical to identify, characterize, and therapeutically target the drivers of such pathways to stop disease progression and improve clinical outcomes. Rationale of the Study: To identify drivers of disease progression, we studied gene expression data from prostate cancer (PCa) samples from 545 high-risk patients with long-term clinical outcomes. We focused on kinases, which are a class of proteins that are readily targetable with drugs. Our analysis demonstrated that a protein called DNA-dependent protein kinase (DNAPK) was more strongly associated with metastatic progression compared to every other kinase. Our clinical data also showed that high expression of DNAPK is associated with increased recurrence and poor survival, and laboratory studies show that inhibition of DNAPK effectively suppresses the aggressive properties of PCa cells. These observations led us to explore the mechanisms by which DNAPK promotes prostate cancer progression. Combined, our clinical data and laboratory studies demonstrated that DNAPK regulates the Wnt signaling pathway, one of the most common cancer-promoting pathways involved in metastasis of many types of malignancies, including PCa. Genetic alterations in the Wnt pathway in mCRPC patients are emerging rapidly, and yet there are no clinical means to turn off Wnt signaling to date, mainly due to the extreme toxicity of Wnt inhibitors. Our preliminary studies show that DNAPK inhibition effectively blocks Wnt-driven aggressive properties in PCa cells. Thus, inhibition of DNAPK may serve as a novel and effective strategy to stop Wnt-driven PCa, especially since the clinical-grade DNAPK inhibitor, CC-115, has passed safety/toxicity studies in phase I clinical trials in other disease sites. Hence, the goals of our grant are to: (1) understand the precise mechanisms by which DNAPK regulates Wnt signaling and subsequent metastasis; (2) explore DNAPK inhibition as a therapeutic strategy in Wnt-driven PCa, either as a monotherapy or in combination with existing standard of care anti-AR therapies; and (3) credential DNAPK as a biomarker of aggressive disease and establish its correlation with Wnt signaling in mCRPC. Clinical Applicability of the Proposed Research: Understanding the mechanism by which the DNAPK-Wnt pathway promotes metastatic progression will help us eventually design drugs that specifically block this pathway. Determining the impact of DNAPK inhibition in aggressive Wnt-driven prostate cancers will provide a strong rationale for starting clinical trials for prostate cancer patients based on DNAPK inhibition. Establishing DNAPK as a biomarker of aggressive disease will help in clinical decision-making by identifying patients with aggressive forms of PCa that may need treatment intensification. The long-term goal of this project is to translate our scientific findings into clinical treatments and prognostic tools. We believe that the contributions made from this project will be clinically significant and will eventually benefit patients with aggressive metastatic disease refractory to the current standard-of-care therapies. Impact on the Field: Characterization of mechanisms of treatment resistance and development of effective treatments are critically required to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810599
Entities
People
- Felix Y. Feng
Organizations
- United States Army
- University of California, San Francisco