SAT021 Development Of Niclosamide Analogs For Treatment Of Androgen Receptor Positive Hepatocellular Carcinoma

Abstract

Abstract Disclosure: E.J. Montgomery: None. E. Xing: None. A. Dauki: None. H. Radomska: None. S.K. Kulp: None. L. Granchie: None. P. Li: None. C.C. Coss: None. Introduction: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of cancer death worldwide. HCC is also highly sexually dimorphic with males having a 2-4 times higher risk of HCC occurrence than females regardless of the disease etiology. Based upon the discrepancy in HCC incidence between the sexes, the role of sex hormone receptors, such as the androgen receptor (AR), in HCC progression has been investigated. Despite the evidence behind AR’s role in HCC lethality, clinical trials of anti-androgen therapy in HCC showed no significant clinical benefit. We recently reported the presence of abundant ligand-independent AR splice variants (AR-SVs) in HCC. Niclosamide is an anthelmintic drug that was identified in drugs screens for AR-V7 degrading and anti-HCC properties making it well-positioned as a potential therapeutic for AR/AR-SV positive HCC. Despite these features, niclosamide suffers from poor bioavailability by design resulting in dose limiting toxicities. Objective: 1) Identify and understand key functional groups of niclosamide for development of niclosamide analogs. 2) Develop niclosamide analogs towards improving bioavailability and limiting first pass metabolism. Methods: HCC cell lines were treated with niclosamide to determine impacts on AR expression, cell proliferation, and cell invasion. Mouse pharmacokinetics studies to evaluate drug parameters were conducted through Charles River Laboratories. Toxicity studies on a valine conjugate of niclosamide were carried out in mice over a two-week span using a range of drug concentrations. Results: Numerous niclosamide analogs were evaluated resulting in a valine conjugated niclosamide with improved bioavailability, a niclosamide analog with improved first pass metabolism, and its valine conjugate. Valine conjugated niclosamide showed improved oral exposure without resulting in toxicities. Conclusions: Niclosamide is a drug showing key activity against AR and HCC that lends itself to treatment of AR/AR-SV positive HCC. Niclosamide analogs improve upon the parental drug by overcoming its limited bioavailability and its dose limiting GI toxicity while shedding light on additional pathways for further improvement. Presentation: Saturday, June 17, 2023