Turn the New Enemy to the Old Foe: Neuroendocrine-to-Luminal Redifferentiation
Abstract
This project addresses the FY22 PCRP Overarching Challenge, Develop treatments that improve outcomes for men with lethal prostate cancer. The goal of our research is to develop treatments for the most aggressive and lethal form of prostate cancer, so-called neuroendocrine prostate cancer (NEPC). What is NEPC? Most of prostate cancer at diagnosis is characterized with a pathology feature called luminal adenocarcinoma, which expresses androgen-receptor (AR) and prostate-specific antigen (PSA) at high levels. Luminal prostate cancer can be treated with drugs that inhibit AR (for example, enzalutamide, apalutamide, and darolutamide, all approved by the FDA) because AR is required for luminal prostate cancer cells to survive and proliferate. However, about 2% of prostate cancers at diagnosis do not express AR or PSA; instead, they express molecular markers associated with neuroendocrine cells (cells that receive neuronal input and release various hormones), defining them as NEPC (i.e., de novo NEPC). What is more concerning for those patients with luminal prostate cancer and treated with AR-targeting drugs, 10-17% of their tumors shut down AR and PSA expression and start to express NEPC markers (i.e., treatment-induced NEPC). Because NEPC does not express AR, AR-targeting inhibitors show no activity on them. Currently, the only therapy option for NEPC is platinum-based chemotherapy, which is nonspecific, toxic, and easy to develop drug resistance. How should we develop effective strategies to treat NEPC? Because NEPC can derive from luminal prostate cancer as an escaping mechanism from AR-targeted therapy, we argue that it is plausible to reverse this process and convert NEPC back to luminal prostate cancer by treating NEPC with certain drugs. This is an innovative and potentially high-gain idea that has not been explored previously. The objective of this project is to test this bold idea and find the drugs that revert NEPC back to luminal prostate cancer, at least the re-expression of AR so that the tumors are rendered sensitive to AR-targeting inhibitors again. To achieve this objective, we propose to accomplish two specific aims. In Aim 1, we will perform high-throughput screening with a robotic system of a large-size drug library on a human NEPC cell line for drugs that can turn back on the AR expression and the AR signaling. In Aim 2, we will combine each of the top-ranked drugs that passed the screen in Aim 1 with the most widely used AR-targeting inhibitor enzalutamide to treat the human NEPC cell line so that we can determine whether NEPC cells can be killed by the combination treatment. Because each treatment alone is not expected to affect the survival of NEPC cells, if the combination treatment kills NEPC cells, that will prove our idea that NEPC cells can be sensitized to AR-targeting inhibitors. Our project is highly relevant to the FY22 PCRP mission of eliminating death from prostate cancer and enhancing the well-being of men experiencing the impact of prostate cancer because treatment-induced NEPC has become a growing clinical threat due to the increasing use of AR- targeting inhibitors in the clinic to treat advanced prostate cancer. By taking a previously unexplored approach, our research may identify new drugs that turn NEPC back to the more tractable AR-dependent prostate cancer. Subsequent translational studies may develop the combination treatment strategy discovered in this study into a new paradigm to treat both de novo and treatment-induced NEPC. We envision that the ultimate clinical application of the findings from our research will significantly prolong the survival and improve the well-being of most of the patients with NEPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310010
Entities
People
- Xin Lu
Organizations
- United States Army
- University of Notre Dame