Therapeutic Targeting of a Novel Tumor-Intrinsic Signaling Pathway for Lethal Prostate Cancer
Abstract
Most patients with prostate cancer disease are treated with androgen deprivation therapy or so-called androgen receptor signaling inhibitors (ARSIs) such as Xytiga (abiraterone), Xtandi (enzalutamide), or Casodex (bicalutamide). It is now known that, after prolonged treatments with the aforementioned drugs, tumor cells evolve or change from initially one cell type (called luminal) in the treatment-naïve tumors to other cell 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 plasticity is the main reason why tumors become resistant to the different therapeutics. However, although recent studies revealed several important protein factors that mediate the plasticity and resistance, they yielded few opportunities for effective therapeutic targeting, as most of the factors or mechanisms that are therapeutically untargetable. Our recent study identified a membrane receptor ADR protein as a strong candidate driver for promoting tumor plasticity and ARSI resistance. As a receptor protein, it binds to small molecule with distinct chemical structures and is thus highly attractive for drug development. Indeed, drug candidates targeting this ADR are at clinical trials for Alzheimer’s and other neurological diseases. We found that small molecule inhibitors of this ADR developed by us and others displayed high efficacy in inhibition of growth of several metastatic, castration-resistant prostate cancer (mCRPC) and ARSI-resistant cell and tumor models, including a patient-derived xenograft (PDX) tumor. Our objectives are (1) to firmly determine its role in driving tumor plasticity and therapy resistance; (2) to demonstrate that its small molecule inhibitors, either alone or in combination with the current ARSIs, are highly efficacious and safe in blocking tumor growth and metastasis and thus effectively delaying the emergence of lethal form; and (3) to address for clinical relevance and help identify suitable cohorts of patients for future treatment, we will develop markers and assays. One short-term applicability of this study (once this study is completed) is nomination of an adrenergic receptor (ADR) inhibitor/drug candidates such as the ORM compound for clinical trials for treatment of androgen receptor signaling inhibitor (ARSI)-resistant prostate cancer patients and patients with high risk of developing resistance. Our results from prostate cancer cells showed that the ORM drug candidate, which is currently at phase II trial for Alzheimer’s disease, is highly effective in killing ARSI-resistant cells in cell culture. We are confident that the ORM drug candidate will be highly effective in treating ARSI-resistant tumors in our preclinical models including ones derived from patients’ tumors (PDXs). With the ORM drug candidate at a phase II trial with a favorable safety profile, it can be quickly moved by us or others to phase 1/2 trials for prostate cancer patients when our study establishes the safety and efficacy of the drug candidates. Another short-term applicability of this study is that the markers (i.e., the ADR and its controlled genes and proteins in the prostate cancer tumors) and assays developed by this study will be highly valuable for selection of patients for the clinical trial with drug candidates targeting the ADR. One long-term applicability (hopefully in the next 5-8 years) is to develop highly effective and safe drugs that selectively target the ADR hyper-signaling in lethal prostate cancer. The candidate compound we developed has much improved potency than the ones from pharma in killing advanced prostate cells and tumors in a limited number of preclinical models. This candidate drug compound is identified using the prostate cancer cells where the ADR functions in a unique way that is different from its normal function and is thus more selective in targeting the ADR in prostate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310302
Entities
People
- Hongwu Chen
Organizations
- United States Army
- University of California, Davis