Targeting N-Cadherin for Inhibition of Enzalutamide Resistance and Emergence of Neuroendocrine Prostate Cancer
Abstract
Background: Neuroendocrine prostate carcinoma (NEPC) is a highly lethal disease that can emerge during treatment with potent anti-androgens such as enzalutamide and abiraterone, which are used to treat castration resistant prostate cancer (CRPC). There is currently no effective cure for NEPC. There is an urgent need to find a new therapeutic strategy to prevent the emergence of NEPC. N-cadherin is a cell adhesion protein associated with the progression of prostate cancer to castration resistance, metastasis, and treatment resistance. We have previously shown that N-cadherin overexpression can cause CRPC. N-cadherin activates an inflammatory signaling pathway and induces stem cell-like properties in cancer cells. Cancer stem cells are primitive cells with unlimited proliferative potential and ability to change their characteristics to adapt and survive during metastasis and/or drug treatment. Recent characterization of NEPC samples suggests that NEPC shares features with normal and cancer-associated stem cells. Studying biopsy samples from the metastases of men who failed abiraterone or enzalutamide therapy, we found that N-cadherin expression is a marker of NEPC. Strikingly, N- cadherin, which is a transmembrane protein, was found located in the nuclei of NEPC, raising the hypothesis that this change in cellular localization could underlie the emergence of NEPC. Using biochemical methods, we further discovered that nuclear N-cadherin is bound to beta-catenin protein that regulates stem cells and cell fate. The mechanisms by which N-cadherin affects cellular functions are diverse. For example, N-cadherin affects the stability and activity of cell surface receptors whose function is to receive signals from the extracellular environment and to activate a number of signaling cascades in the cell. Hypothesis/Objectives: We hypothesize that N-cadherin plays a critical role in the development of NEPC during treatment with enzalutamide. We further hypothesize that N-cadherin directly regulates the expression of genes that allow changes in cellular lineage to NEPC. The objective of the proposed study is to identify potential new therapy strategies through understanding the fundamental molecular mechanisms whereby N-cadherin promotes aggressive prostate cancer. In Specific Aim 1, we study the mechanism by which N-cadherin accelerates the emergence of the NEPC phenotype. In specific Aim 2, we test whether enzalutamide-resistance and NEPC develop when N-cadherin is completely eliminated by gene deletion. The goal of Specific Aim 3 is to test whether newly developed human antibodies against N-cadherin can delay development of resistance to enzalutamide, and NEPC by inhibiting Wnt/beta-catenin signaling pathway and N-cadherin translocation to nucleus. Contributions to the Field of Prostate Cancer Research: The proposed research will elucidate the mechanisms through which N-cadherin promotes prostate cancer progression to NEPC, and will facilitate new understanding of the disease. This is the first study that investigates how adherent junction proteins can affect cellular plasticity by directly regulating gene expression in the nucleus, leading to more advanced disease. Potential Clinical Application: Finding new targets and signaling pathways that regulate NEPC will potentially lead to new treatment strategies for NEPC. The proposed study directly addresses the FY21 PCRP Overarching Challenges to define the biology of lethal prostate cancer to reduce death, and potentially leads to development of treatments that improve outcomes for men with lethal prostate cancer. Through the proposed research, we expect to discover the molecular mechanisms by which adherens junction proteins promote therapy-resistant advanced prostate cancer. The study will explore therapeutic strategies for NEPC, including (1) human N-cadherin antibodies which inhibits cellular signaling pathways activated in enzalutamide-resistant t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210570
Entities
People
- Robert Reiter
Organizations
- United States Army
- University of California, Los Angeles