Dual Targeting of Cooperating Drivers of Prostate Cancer
Abstract
This project is focused on developing better therapies for patients with metastatic disease. Recently, our biological understanding revealed the fact that different pathways act in concert or compensate for each other to make prostate cancers more aggressive in terms of spreading from the prostate gland to other parts of the body or becoming resistant to therapy. Most projects study one pathway at a time and target drugs to one pathway or focus on pathways that are not amenable to any of our current drugs. More recently, we are learning combination therapies in the right setting, such as docetaxel plus testosterone suppression and abiraterone plus testosterone suppression in metastatic hormone-sensitive disease lead to major prolongation in overall survival. In this application, we focus on studying two independent and parallel pathways controlled by two separate “brakes” that are lost with increasing frequency in advanced prostate cancer. The two pathways are PI3Kinase/AKT controlled by PTEN and Nuclear factor-kappaB controlled by tristetraprolin (TTP). We have some preclinical and clinical data that AKT inhibition enhances androgen receptor (AR) inhibition and preclinical data showing NF-kappaB inhibition enhances AR inhibition. Moreover, we have early preclinical evidence that triplet data (NF-kappaB plus AKT plus AR inhibition) may be more effective than the doublets. The potential clinical application of this work is that it may provide information on patients who have the highest risk of relapse after a prostatectomy and have poor response to androgen deprivation therapy. Moreover, it will help identify the right combination therapy to prevent relapse after a prostatectomy and/or augment the effectiveness of androgen deprivation therapy. We will complete this work over the 3 years of the proposed project. Likely longer-term contributions of this study to advancing the field of prostate cancer care include identifying prognostic markers that can be used in the clinic and development of more effective therapies to increase the cure rate at time of radiation or surgical removal of the prostate by preventing micro-metastatic disease emerging. Moreover, the new therapies could increase the effectiveness of hormonal therapy and prolong the longevity of men with metastatic disease. The facts that AR-directed therapies such as abiraterone and enzalutamide prolong the survival of men with metastatic disease; AKT inhibitors are in advanced phase 3 trials; and the NF-kappaB inhibitor is in early-stage clinical trials make it possible that this work (e.g., development of highly effective triplet therapy targeting AR, AKT, and NF-kappaB) can be translated into patient benefit in the next 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910564
Entities
People
- Christopher Sweeney
Organizations
- Dana–Farber Cancer Institute
- United States Army