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

项目摘要/摘要 基底细胞癌是北美最常见的癌症。由构造性激活驱动 Hedgehog(HH)信号通路，这些肿瘤通常通过手术切除；然而， 患有局部晚期或遗传性基底细胞癌的患者需要使用HH途径抑制剂进行治疗，如 Vismodegib。虽然这些抑制剂通常在消退基底细胞癌方面有效，但这些药物通常不起作用。 消灭所有的肿瘤细胞，随着时间的推移，耐药性可能会发展。这些结果强调了有必要 确定和评估其他治疗方法。 开发针对基底细胞癌的新疗法的一个主要障碍是相对缺乏足够的、多样化的 和方便的模型系统来研究这种癌症。目前的密件抄送模型都具有主要的 限制了它们广泛使用的缺点。利用我们丰富的学习经验 BCC，以及我们实验室的最新技术进步，我们寻求生成并表征改进的模型 这种最常见的癌症。在目标1中，我们将重点开发一种连续宏观活检的技术 小鼠体内的BCCs。作为概念的初步验证，我们将用vismodegib治疗荷瘤小鼠，并收集前 以及用于病理学、遗传学和分子分析的治疗后肿瘤材料。在目标2中，我们将生成 并鉴定这些肉眼肿瘤的细胞系，并测试它们对vismodegib和JQ1，以及 下游HH信号的抑制物。我们还将开发将这些细胞培养成类器官的方法 更好地模拟这些肿瘤的体内三维结构。最后，我们将尝试培养人类 BCC细胞系。综上所述，这些研究将有助于今后改进的BCC模型的发展。 用于评估新的治疗方法。

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.