Developing and Translating Innovative Strategies to Therapeutically Target Prostate Cancer Lineage Plasticity

Principal Investigators: David Goodrich, PhD (Roswell Park Comprehensive Cancer Center), Gurkamal Chatta, MD (Roswell Park Comprehensive Cancer Center), Dean Tang, PhD (Roswell Park Comprehensive Cancer Center), Dominic Smiraglia, PhD (Roswell Park Comprehensive Cancer Center)

Co-Investigators: Mark Long, PhD (Roswell Park Comprehensive Cancer Center), Himisha Beltran, MD (Dana-Farber Cancer Institute)

Description:

• Androgen receptor (AR)-targeted therapy is standard of care for advanced prostate cancer, yet virtually every patient eventually develops treatment resistance and progresses to castration resistant prostate cancer (CRPC).  CRPC can take on various forms in the same patient, including forms driven by AR pathway alterations and forms that no longer rely on AR (AR-independent), such as neuroendocrine prostate cancer (NEPC).
• Lineage plasticity, the ability of cancer cells to alter their phenotype and take on characteristics of alternate cell types, is known to be a key contributor to treatment resistance and progression to NEPC.
• While prior studies have focused on the role of lineage plasticity in NEPC and other forms of AR-independent CRPC, Dr. Goodrich and team hypothesize that lineage plasticity actually drives all forms of CRPC, and that a subset of cancer cells can develop this potential early and persist through therapy. Thus, therapeutic approaches that target lineage plasticity may prevent CRPC.
• In this project, the team will investigate three treatment strategies to target lineage plasticity in prostate cancer and prevent progression to CRPC: 1) targeting a gene that appears essential in AR-independent prostate cancer cells (BCL2), and 2) targeting epigenetic mechanisms that enable lineage plasticity (DNA methylation).  Both of these strategies will be tested in combination with a third strategy, which uses supraphysiologic androgens (bipolar androgen therapy) to suppress prostate cancer cell reprogramming from an AR-dependent to an AR-independent state.
• These studies will use a combined approach of experimental models and samples from clinical trials testing these treatments in patients, to determine the potential therapeutic utility and mechanisms of action of these treatment strategies for preventing CRPC and prolonging the efficacy of AR-targeted therapy.
• If successful, this project will identify new therapeutic strategies to prevent lineage plasticity and progression to CRPC.

What this means to patients:  Lineage plasticity is a biological process important in early organism development, that is hijacked by cancer cells to adapt to cancer therapies and progress. This project will test the ability of several therapeutic approaches to prevent lineage plasticity and the development of CRPC.  This may lead to innovative new combination approaches that improve patient outcomes by extending the clinical benefit of AR-targeted therapies.