All ETDs from UAB

Advisory Committee Chair

Donald J Buchsbaum

Advisory Committee Members

Rajeev Samant

Andra Frost

Fred Bertrand

Yonghe Li

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Ovarian and triple-negative breast cancers (TNBC) are aggressive due to their dependence on Wnt/β-catenin signaling. Niclosamide, a strong inhibitor of Wnt/β-catenin signaling, is an efficacious cytotoxic agent for various cancers in vitro, including ovarian and breast cancers. However, it has cross-reactivity with mTOR, STAT3, and Notch pathways. A limitation of using the agent in animal studies involves its poor water solubility and bioavailability. This study investigates novel compounds based on the structure of niclosamide to improve specificity for the Wnt/β-catenin signaling pathway. The investigation evaluates three questions: 1) whether WNT974 inhibits Wnt/β-catenin signaling in ovarian cancer; 2) whether novel analogs of niclosamide retain capacity to inhibit Wnt/β-catenin and mTOR signaling activities comparable to that of niclosamide in ovarian cancer; 3) and whether novel benzimidazole inhibitors developed at Southern Research are selective for Wnt/β-catenin signaling in TNBC over noncancerous cells. Porcupine inhibitor WNT974 obtained from Novartis was evaluated as an agent with therapeutic efficacy against ovarian cancer. The agent inhibited Wnt/β-catenin signaling and promoted cell cycle arrest. Combination treatment of human ovarian cancer ascites cells with WNT974 and carboplatin yielded greater reduction in ATP levels than either drug alone. While Wnt/β-catenin-activating RSPO fusions were not present in the samples, porcupine expression correlated with sensitivity to WNT974. Analogs 11 and 32 were developed by Dr. Pui-Kai Li at Ohio State University to improve on capacity of niclosamide to treat ovarian cancer. Analogs 11 and 32 inhibited proliferation of ovarian cancer cell lines and mouse patient-derived xenograft cells. Analogs 11 and 32 also inhibited Wnt/β-catenin and mTOR signaling pathways comparable to niclosamide. The property of niclosamide to target multiple pathways, such as mTOR, STAT3, and Notch, is believed to confer toxicity in normal tissues and mitigate anti-tumor efficacy. To limit normal tissue toxicity and enhance efficacy in cancers, novel benzimidazole compounds developed at Southern Research were evaluated for their potency and Wnt/β-catenin-inhibiting efficacy in TNBC cell lines. Compounds SRI33576 and SRI35889 show specificity for Wnt/β-catenin signaling with limited effects on other pathways. These compounds exhibited a greater decrease in cell viability in TNBC cell lines than in nontumorigenic MCF10A cells in vitro.

Share

COinS