Targeting LSD1 in Neuroendocrine Prostate Cancer
Abstract
Nearly all prostate cancers start off as adenocarcinomas driven by the androgen receptor (AR) and express glandular genes. However, some adenocarcinomas switch to become neuroendocrine prostate cancers (NEPC) in which the AR and glandular genes are turned off but nerve or brain genes are turned on. NEPC is the most lethal form of prostate cancer, and there are several reasons why patients with NEPC do worse. First, adenocarcinomas can be treated with drugs that block the AR such as abiraterone or enzalutamide. However, these drugs do not work in NEPC because the AR is commonly turned off when tumors switch to NEPC. Very little is known about how AR gets turned off or what else allows NEPC tumors to survive. As a consequence, there are no effective treatments for NEPC patients, and patients with NEPC are often excluded from clinical trials due to NEPC’s aggressiveness. This demonstrates an urgent need to improve our understanding of how adenocarcinomas switch to NEPC so that we can block that process and treat NEPC tumors more effectively. In studies from our laboratory, we determined the protein lysine specific demethylase 1 (LSD1) promotes the switch to NEPC and that blocking LSD1 is a promising approach to treat NEPC tumors. Understanding how LSD1 causes tumors to switch to NEPC and testing drugs that block LSD1 so that we may develop a new treatment strategy for NEPC patients is the focus of this application. LSD1 works by turning genes on and off in cells, including cancer. Previously, we determined LSD1 primarily turns genes on in prostate adenocarcinoma cells and does so by cooperating with specific partner proteins. Importantly, we determined that LSD1 is even more highly expressed (abundant) in NEPC patient tumors, but LSD1 turns off genes, including glandular adenocarcinoma genes, making these tumors more brain- or nerve-like. Moreover, we determined that NEPC tumors are exquisitely sensitive to an LSD1 inhibitor called SP2509, and SP2509’s effects in NEPC are explained in part by turning back on the AR and glandular genes. This, in turn, makes NEPC tumors susceptible to AR-targeting treatments again. These results demonstrate that LSD1 is important for NEPC cell survival and blocking LSD1 is a promising approach for patients with NEPC. Importantly, SP2509 phase I clinical trials in sarcoma patients have recently begun, but there is currently insufficient laboratory data to justify clinical trials in men with NEPC tumors, tumors that we predict will be particularly susceptible to LSD1 inhibition. In Aim 1, we will determine how LSD1 cooperates with specific protein partners to turn glandular genes off and shift adenocarcinoma tumors to NEPC. We will first treat a large panel of NEPC cell lines with the LSD1 inhibitor SP2509 and measure gene changes that indicate SP2509 has hit the target. Doing so will identify biomarkers that indicate LSD1 has been blocked that may be used in future SP2509 phase I clinical trials to define an effective dose. We will also determine how LSD1 cooperates with protein partners to turn off glandular genes. Doing so will further clarify biomarkers and possible combination treatment strategies to kill NEPC cells even more effectively (i.e., targeting the protein partner + LSD1). Finally, understanding how SP2509 works in NEPC will enable us to anticipate how tumors become resistant to treatment. We demonstrated that NEPC tumors are exquisitely sensitive to SP2509 when grown in culture. Importantly, SP2509 by itself works well in NEPC tumors in which the AR is completely absent, but SP2509 + the AR inhibitor enzalutamide works even better than SP2509 alone in NEPC tumors that still express the AR. In Aim 2, we will test the safety and anti-tumor activity of LSD1 inhibition in NEPC patient tumors implanted in mice. Doing so will allow us to confirm the value of markers of response identified in Aim 1 and provide the rationale for clinical trials of LSD1 inhibiti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010405
Entities
People
- Joshi J Alumkal
Organizations
- United States Army
- University of Michigan