Targeting a Key Tumor Plasticity Driver in Lethal Prostate Cancer
Abstract
Most patients with prostate cancer disease are treated with androgen deprivation therapy or drugs targeting the androgen receptor such as Xtandi (enzalutamide) or Casodex (bicalutamide). Patients with the disease progressing further can also be treated with chemotherapy drugs such as Taxotere (docetaxel) or Jevtana (cabazitaxel). Recent clinical and preclinical studies clearly indicate that cells, even in the same tumor mass, can be different in their morphology and molecular makeups, something referred to as tumor heterogeneity. It is also clear now that, after prolonged treatments with the aforementioned drugs, tumor cells evolve or change from an initially luminal cell type in the treatment-naïve tumors to other types such as cancer stem-like cells (CSCs) or neuroendocrine (NE) cells, something referred to as tumor plasticity. Studies also have strongly suggested that such tumor cell heterogeneity or plasticity is the main reason why tumors become resistant to the different therapeutics. However, although recent studies started tackling the question what changes in the tumor promotes the tumor plasticity or heterogeneity, they yielded few factors or mechanisms that are therapeutically easily actionable. Our recent study identified a nuclear receptor protein as a strong candidate driving factor for promoting tumor plasticity or heterogeneity. As a receptor protein, it binds to small molecule with distinct chemical structures. We found that, in a small cohort of tumors examined, this receptor protein is over-produced in subsets of tumor cells in over 50% of the cases and that its overexpression appears to associate with tumor metastasis. In line with its pro-tumorigenic role, we found that its small molecule inhibitors/antagonists developed by us and others displayed high efficacy in inhibition of growth of several metastatic, castration-resistant prostate cancer (mCRPC) models, including a patient-derived xenograft (PDX) tumor, without overt toxicity in the tumor host mice. Using other methods, we also demonstrated that Rev-erb-alpha can make CRPC cells more resistant to the drugs and that it promotes tumor cell features of cancer stem-like cell (CSC) and neuroendocrine (NE). This receptor protein has not been studied in prostate cancer. For this initial study, our objectives are (1) to firmly determine its role in driving tumor plasticity through its activity in promoting open chromatin structure; (2) to demonstrate that its small molecule inhibitor, either alone or in combination with Xtandi or the chemo drugs, is highly efficacious and safe in blocking tumor growth and plasticity of clinically relevant CRPC models, including therapy-resistant, lethal forms of the disease, such as NEPC or small cell neuroendocrine prostate cancer (SCNC); and (3) to address for clinical relevance and help identify suitable cohorts of patients for the future treatment, we will examine whether its overexpression is associated with metastasis and/or biochemical recurrence and with high tumor plasticity. Our study will offer a unique therapeutic opportunity in selectively targeting the abnormal function of this receptor without perturbing its normal functions. Findings from our study will establish that targeting its aberrant function with small molecule inhibitors is a highly efficacious and safe. These findings will provide new therapeutic strategy and possibly novel therapeutics that will help find a solution to the PCRP Overarching Challenge, “Develop treatments that improve outcomes for men with lethal prostate cancer.” Our study will also provide mechanistic information on the receptor as a new driver factor of tumor plasticity and therapy resistance. Therefore, our study will also directly address the Overarching Challenge, “Define the biology of lethal prostate cancer to reduce death.” Therefore, findings from our study will help patients with metastatic diseases that are relapsed after treatment(s) with d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110603
Entities
People
- Hongwu Chen
Organizations
- United States Army
- University of California, Davis