Defining the Potential of Early Molecular Subtypes of Prostate Cancer to Progress to AR-Indifferent Disease
Abstract
Prostate cancer is a highly clinically variable disease—some patients do very well, and some patients do very poorly—and this variability occurs across all stages and phases of the disease, from clinically localized prostate cancer to advanced, castration-resistant prostate cancer (CRPC). Molecular characterization has revealed a great deal of variability at the molecular level as well, and distinct subtypes of prostate cancer have been recognized in both early untreated prostate cancer and treatment-resistant CRPC. Resistance to therapy is the major cause of death in prostate cancer, and prostate cancers can become resistant using multiple pathways. Some of these remain dependent on the androgen receptor (AR), making additional therapies targeting AR the best choice. However, others will be AR-indifferent, such as a lethal, advanced form known as neuroendocrine prostate cancer (NEPC), and other therapeutic strategies (such as DNA damaging agents) will be necessary. However, which cancers will become AR-indifferent and which will remain AR-dependent is still not clear. This is a critically important question for the treatment of men with advanced prostate cancer; cancers that remain dependent on AR activity can be successfully treated with next-generation agents targeting the AR, such as enzalutamide or abiraterone, while AR-indifferent cancers will not respond to these therapies and require different approaches. Therefore, understanding which prostate cancers have a propensity to transition to AR-indifferent disease will allow clinicians to get patients on the right course of therapy earlier. Our collaborative group has been among the leaders in defining and characterizing molecular subtypes of prostate cancer in both early untreated prostate cancer and advanced CRPC. We hypothesize that specific subtypes of early prostate cancer are more susceptible or resistant to conversion to AR-indifferent NEPC. We will define characteristics in the DNA and RNA of prostate cancers making them resistant or susceptible to conversion to NEPC and use model systems of prostate cancer progression and treatment resistance to test the ability of specific changes to inhibit this transition. We will define the molecular mechanisms that are responsible for this phenomenon and, in doing so, expose new drug targets to prevent conversion to NEPC. These studies will directly benefit patients with advanced CRPC in both the short and long term. In the short term, there will be immediate clinical utility by delivering biomarkers that guide management choices for men with lethal CRPC—deciding on more AR-targeting therapy or alternative strategies. In the long term, this project will provide a better understanding of the underlying biology of treatment resistance and why different prostate cancers follow different evolutionary paths, which will lead to novel biomarkers, novel therapeutic targets, and benefit for men with both advanced and early prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910403
Entities
People
- Christopher E. Barbieri
Organizations
- United States Army
- Weill Cornell Medicine