Ceramide Nanoliposomes as a Novel Therapeutic Option for Lethal Prostate Cancer: Exploiting De Novo Sphingolipid Synthesis
Abstract
Prostate cancer is one of the biggest health burdens for men in the military and for men worldwide. Current therapies for patients that are not suitable for surgery or radiation therapy, such as in the case of recurrent prostate cancer, are extremely limited in long-term effectiveness. Thus, new therapeutic approaches are urgently needed. Our data shows that delivery of a pro-death lipid, ceramide, in the form of a ceramide nanoliposome (CNL), is effective in cell models of prostate cancer. Specifically, when administered in combination with anti-androgen drugs that are already being used in prostate cancer patients with limited prolonged efficacy, the combinatorial approach exerts an even better therapeutic response. Importantly, it is also extremely efficacious as a monotherapy against highly aggressive castration-resistant prostate cancer, for which effective drugs are lacking. Our proposal examines a mechanism behind this surprising efficacy and seeks to validate this efficacy in mouse models of prostate cancer. We have uncovered a hormonally regulated protein that controls the synthesis of endogenous pro-death ceramides induced by CNL. This proposal seeks to understand how this protein is regulated by androgens in prostate cancer and how it may contribute to lethal prostate cancer. Deciphering how ceramide metabolism is altered in prostate cancer models has the potential to enable ceramide-based therapeutics and identify new therapeutic biomarkers. The biochemical and pharmacological data generated through this grant will guide a Phase 2 clinical trial with CNL in prostate cancer patients, leveraging a successfully completed FDA-approved Phase 1 trial that showed no dose-limiting toxicities with demonstrated evidence of efficacy in solid tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210696
Entities
People
- Todd Fox
Organizations
- United States Army
- University of Virginia