Targeting the Mechanisms Driving Double-Negative Basal-Like Prostate Cancer
Abstract
The androgen receptor (AR) has served as a focus for developing life-extending therapeutics for men with advanced prostate cancer. Though very effective initially, the vast majority of patients develop resistance and relapse with castration-resistant prostate cancer (CRPC) that continues to exhibit AR activity. While chemotherapeutic strategies show some promise, there is no effective therapy that substantially prolongs survival for patients with CRPC. However, our recent clinical observations have identified in increasing number of men with CRPC exhibiting an AR-null phenotype following treatment with potent AR pathway antagonists. We refer to these AR-null metastases that do not express the AR and do not have a neuroendocrine phenotype as double-negative prostate cancer (DNPC). This is a paradigm shift, and as such our application centers on understanding the mechanisms driving DNPC and targeting this newly emerging tumor phenotype. Investigations in this field are restricted by a lack of patient tissues and patient-derived xenograft (PDX) models mirroring the heterogeneity of CRPC metastases. However, we have a long-standing rapid autopsy program and PDX development program. To understand the mechanisms driving DNPC and identify targets for therapy, we will interrogate metastatic tissues obtained through our rapid autopsy program and novel DNPC PDX models. We have already identified and need to verify possible molecular mechanisms that promote the conversion from adenocarcinoma with an active AR to the DNPC phenotype. Our application focuses on therapy and mechanisms resistance. The DNPC patient tissues and DNPC PDX models will be used to identify additional novel targets for therapy. We have already identified possible targets for therapy including but not limited to the fibroblast growth factor (FGF) and Glial Derived Neurotrophic Factor (GDNF) pathways and Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6 (CEACAM6) that we will target in our cell lines and PDX models to determine if they have the potential for rapid clinical translation to the clinic. Therefore, we will test the hypothesis that DNPC is driven by a limited number of molecular programs that promote survival and proliferation, a subset of which subsume the role of the androgen receptor in conventional androgen receptor-driven CRPC. Identifying these programs will provide key therapeutic targets capable of suppressing tumor progression. The experiments in this application will (1) identify survival and growth programs operative in DNPC though deep molecular profiling of metastatic tumors and PDX models, (2) utilize engineered cell lines and PDX models to determine whether specific molecular alterations observed in the human DNPC tumors cause androgen receptor-bypass and promote a DNPC phenotype, and (3) target key survival pathways in DNPC to confirm inhibition of these pathways will attenuate the growth of DNPC tumors and support further evaluation in the clinic. In conclusion, interrogating the DNPC phenotype in CRPC metastases, PDX models, and cell lines could identify (i) new therapies with drugs already available in the clinic, (ii) mechanisms of resistance, and (iii) patients who will respond to therapy preventing overtreatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710414
Entities
People
- Colm Morrissey
Organizations
- United States Army
- University of Washington