# Valine–Niclosamide for Treatment of Androgen Receptor Splice Variant-Positive Hepatocellular Carcinoma

## TL;DR

Researchers repurposed niclosamide, an anti-tapeworm drug, as a potential treatment for a specific type of liver cancer by improving its oral availability using valine.

## Contribution

The study introduces valine–niclosamide as a novel pro-drug with improved bioavailability for targeting androgen receptor splice variant-positive hepatocellular carcinoma.

## Key findings

- Valine-conjugated niclosamide showed improved oral exposure compared to niclosamide.
- Niclosamide analogs retained anti-androgen receptor activity in hepatocellular carcinoma cell lines.
- The drug demonstrated potential as a broad anti-cancer therapeutic in preclinical models.

## Abstract

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of global cancer-related mortality. At present, the current front-line systemic therapies for advanced hepatocellular carcinoma offer limited improvements to overall survival. In this study, we repurposed niclosamide, an anti-tapeworm therapeutic, for use in HCC by utilizing an amino acid conjugate, valine–niclosamide. This study provides further evidence of the role of the androgen receptor (AR) and its truncated splice variants (SVs) in HCC and offers valine–niclosamide as a candidate therapeutic that addresses not only AR signaling in HCC but also other known pro-cancer signaling pathways. We believe that these data provide a rationale for the further study of valine-conjugated niclosamide as a broad anti-cancer therapeutic that addresses, in part, niclosamide’s poor oral bioavailability and describe AR-SV-positive advanced HCC as a potential use case for valine–niclosamide.

Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted.