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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要基底细胞癌（BCC）是北美最常见的癌症。由本构激活驱动 Hedgehog (Hh) 信号通路，这些肿瘤通常通过手术切除；然而，一个子集患有局部晚期或遗传性 BCC 的患者需要使用 Hh 通路抑制剂治疗，例如维斯莫德吉布。尽管这些抑制剂通常可以有效消退 BCC，但这些药物通常不能根除所有肿瘤细胞，并且随着时间的推移会产生耐药性。这些结果强调需要确定并评估其他治疗方法。开发针对 BCC 的新疗法的一个主要障碍是相对缺乏足够、多样化的药物以及用于研究这种癌症的方便的模型系统。 BCC现有型号均具备主要缺点限制了其广泛使用。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，我们寻求生成和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活检宏观的技术小鼠的 BCC。作为初步的概念证明，我们将用 vismodegib 治疗荷瘤小鼠，并收集预以及用于病理、遗传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宏观肿瘤的细胞系，并测试它们对 vismodegib 和 JQ1（一种下游 Hh 信号传导抑制剂。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 3 维结构。最后，我们将尝试培养人类 BCC 细胞系。总而言之，这些研究将导致未来 BCC 改进模型的开发用于评估新的治疗方法。