Abstract 2079: Ceramide nanoliposomes a novel therapeutic option for androgen receptor negative prostate cancer

Abstract

Prostate cancer (PCa) is estimated to account for 20% of newly diagnosed cancers and 10% of cancer-related deaths in US men during 2019. Prostate is a hormone-responsive gland that depends on male hormones, such as testosterone, for its normal growth and development. These hormones also play a role on the onset and progression of PCa. The androgen receptor (AR) is the main nuclear receptor activated by these hormones and regulates several key cellular pathways that contribute to worsening of the disease. Several antagonists for AR have been developed, as well as drugs that block the conversion of precursor steroids to testosterone. These drugs are extremely efficacious in patients, however within 24 months virtually all tumors recur and progress to castration resistant PCa (CRPC), a stage of disease that ultimately leads to death from PCa. To address this lack of efficacy and lack of therapeutics for CRPC, we decided to investigate the potential of ceramide nanoliposomes (CNL) as a new modality for PCa in preclinical models. Ceramide is a sphingolipid, a class of bioactive lipids that serve to keep membrane structure intact but also have the ability to trigger signaling cascades. CNL have been shown to be efficacious as a treatment in several tumor models including a successful phase 1 clinical trial in solid tumors. Strikingly, we observed that in vitro CNL is very efficacious against AR-negative PCa cells, which represent the later stages of the disease. However, in AR-positive this efficacy was reduced, but improved upon combination treatment with AR inhibitors. By combining CNL with Enzalutamide (AR antagonist) or Abiraterone acetate (testosterone synthesis inhibitor) we observed enhanced efficacy and synergistic effects. We then sought to understand the molecular mechanism underlying this synergistic effect. We observed that by blocking AR, cells were able to synthesize sphingolipids de novo and adding CNL further magnified this effect. We then looked at the expression of the key enzymes in this synthesis pathway and determined that AR negatively regulates an important subunit (SPTSSB) and this negative regulation hinders the efficacy of CNL. In conclusion, we have not only found a promising therapeutic for patients that currently have no treatment options, but also a novel molecular pathway regulated by AR in prostate cells. Citation Format: Pedro Costa-Pinheiro, Abigail Heher, Michael Raymond, Kasey Jividen, Todd Fox, Mark Kester. Ceramide nanoliposomes a novel therapeutic option for androgen receptor negative prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2079.