Evaluating Synthetic Actin Targeting Compounds for Use in a HER2 Targeted Cancer Therapeutic

Abstract

Human Epidermal Growth Factor Receptor-2 (HER2) is a driver and clinical target in a subset of breast and ovarian cancers with high rates of metastasis. Metastatic cancer cells require rapid actin polymerization and remodeling. This vulnerability can be exploited with marine macrolide toxins targeting actin; however, to achieve clinical benefits, we must overcome the limited availability and delivery mechanisms for these actin toxins. The goal of this thesis is to test the vulnerability of metastatic HER2-positive (HER2+) cancer cells to the marine macrolide toxin Mycalolide B (Myc B) and a series of novel synthetic analogs. The effects of Myc B and analogs on HER2+ breast and ovarian cancer cell lines (HCC1954, SKOV3) were measured in cell viability, motility and invasion assays. Myc B showed potent growth suppressive and cytotoxic effects on HER2+ cancer cells. At sub-lethal doses, Myc B caused rapid loss of leading edge protrusions, and sustained defects in HER2+ cancer cell motility and invasion. Myc B treatment was compatible with killing of HER2+ cancer cells by the clinically used HER2 inhibitor Trastuzumab-emtansine (T-DM1). In a HER2+ tumor xenograft model, intratumoral injections of Myc B reduced tumor growth and metastasis, and was most effective when combined with Trastuzumab. To address the limited availability of Myc B, we screened a panel of synthetic analogs of Myc B, and identified several capable of promoting the collapse of the actin cytoskeleton in HER2+ cancer cells, leading to increased cytotoxicity, growth suppression and impaired cell motility. With further optimization of Myc B analogs, we can develop delivery systems, including novel antibody-drug conjugates that limit metastasis in HER2+ cancers.