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

开发改进的基底细胞癌模型以评估肿瘤药物反应

• 批准号: 10518702
• 负责人: Sunny Y Wong
• 金额: $ 40.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10518702
• 关键词: 3-Dimensional; Aftercare; Animal Model; Applications Grants; Architecture; Area; Basal Cell Nevus Syndrome; Basal cell carcinoma; Biological Models; Biology; Biopsy; Bromodomain; Cell Culture Techniques; Cell Line; Cells; Cilia; Development; Diagnosis; Disease; Drug resistance; Erinaceidae; Future; Genetic; Genetic Predisposition to Disease; Goals; Grant; Harvest; Histopathology; Human; Inherited; Lesion; Life; Malignant Neoplasms; Methods; Microscopic; Modeling; Molecular; Molecular Analysis; Mus; Neoplasm Metastasis; North America; Operative Surgical Procedures; Organoids; Outcome; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Proto-Oncogenes; Protocols documentation; Reporting; Research; Resistance; Sampling; Skin; Somatic Mutation; Study models; System; Techniques; Testing; Therapeutic; Time; Tumor Suppressor Proteins; afferent nerve; driver mutation; exome sequencing; experience; gain of function mutation; genetic analysis; improved; in vitro Model; in vitro testing; in vivo; in vivo Model; inhibitor; mouse model; neoplastic cell; novel; novel therapeutics; patient subsets; pre-clinical; response; smoothened signaling pathway; stem cells; transcriptome sequencing; treatment strategy; tumor; wound

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.

项目总结/摘要 基底细胞癌（BCC）是北美最常见的癌症。由组成性激活驱动， 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BCC的患者需要用Hh通路抑制剂治疗， 维莫德吉虽然这些抑制剂通常对BCC的消退有效，但这些药物通常不会 消灭所有的肿瘤细胞，耐药性可以随着时间的推移而发展。这些成果突出表明， 确定和评估其他治疗方法。 开发针对BCC的新疗法的一个主要障碍是相对缺乏足够的、多样的、有效的治疗方法。 和方便的模型系统来研究这种癌症。目前的BCC模型都具有主要的 这些缺点限制了它们的广泛使用。利用我们丰富的学习经验 BCC，以及我们实验室最近的技术进步，我们寻求生成和表征改进的模型 这种最常见的癌症。在目标1中，我们将专注于开发一种技术， 小鼠中的BCC。作为概念的初步证明，我们将用维莫德吉治疗荷瘤小鼠，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 并表征来自这些肉眼可见肿瘤的细胞系，并测试它们对维莫德吉和JQ 1的反应， 下游Hh信号传导的抑制剂。我们还将开发将这些细胞培养为类器官的方法， 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。总之，这些研究将导致未来的BCC改进模型的发展 用于评估新的治疗方法。