A HIGH-THROUGHPUT SCREEN TO IDENTIFY SMALL MOLECULES THAT SELECTIVELY TARGET TUMOR-INITIATING CELLS IN A MOUSE MODEL OF HER2-INDUCED BREAST CANCER

Abstract

<p><strong>A growing body of evidence suggests that most human tumors, including those of the breast, are organized as cellular hierarchies. Positioned at the apex of these hierarchies are tumor-initiating cells (TICs), which are capable of limitless self-renewal and also differentiate, to give rise to various populations of non-tumorigenic cells that make up the bulk of the tumor. Importantly, recent findings have demonstrated that TICs are refractory to current best practice therapies, and thus likely account for high rates of tumor recurrence following remission. Therefore, it will likely be important to identify novel means of targeting TICs in order to achieve durable cancer cures.</strong></p> <p><strong>Using a highly sensitive transplantation assay, our laboratory previously showed that mammary tumors arising in various strains of transgenic mice comprise a very high fraction of TICs, and that when cells from these tumors are propagated in serum-free medium as tumorspheres, the high frequency of TICs is maintained. We therefore sought to use mouse mammary tumorspheres as an <em>in vitro</em> system with which to identify TIC-targeted agents and carried out a high-throughput screen of nearly 32,000 small molecules. To eliminate compounds showing general toxicity, we employed mouse mammospheres, which primarily comprise normal mammary epithelial stem and progenitor cells, in a secondary screen. Using this platform, we identified a small molecule that selectively targeted tumorsphere-derived cells <em>in vitro</em> and led to tumor growth arrest and tumor cell death <em>in vivo</em>. This study illustrates the utility of mouse models and high throughput screening to identify compounds which may target TICs but spare untransformed stem cells.</strong></p>