Developing Improved Models of Basal Cell Carcinoma to Evaluate Tumor-Drug Response

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Project Summary / Abstract Basal cell carcinoma (BCC) is the most common cancer in North America. Driven by constitutive activation of the Hedgehog (Hh) signaling pathway, these tumors are typically removed by surgery; however, a subset of patients with locally advanced or inherited BCCs require treatment with Hh pathway inhibitors such as vismodegib. Although these inhibitors are often effective at regressing BCC, these drugs typically do not eradicate all tumors cells, and resistance can develop over time. These outcomes underscore the need to identify and evaluate additional therapeutic approaches. A major hindrance to developing novel therapies against BCC has been the relative lack of adequate, diverse and convenient model systems for studying this cancer. Current models of BCC all possess major shortcomings that have limited their widespread use. Taking advantage of our extensive experience studying BCC, as well as recent technical advances in our lab, we seek to generate and characterize improved models of this most common cancer. In Aim 1, we will focus on developing a technique to serially biopsy macroscopic BCCs in mice. As an initial proof of concept, we will treat tumor-bearing mice with vismodegib, and collect pre- and post-treatment tumor material for pathological, genetic and molecular analyses. In Aim 2, we will generate and characterize cell lines from these macroscopic tumors and test their responses to vismodegib and JQ1, an inhibitor of downstream Hh signaling. We will also develop methods to culture these cells as organoids to better mimic the in vivo 3-dimensional architecture of these tumors. Finally, we will attempt to culture human BCC cell lines. Altogether, these studies will lead to the development of improved models of BCC for future use in evaluating novel treatment approaches.