Optimizing Syngeneic Mouse Models to Target Mutant p53

优化靶向突变型p53的同基因小鼠模型 项目摘要 抑癌基因p53是人类基因组的守护者。p53是一种转录因子， 在不同的压力下，包括环境致癌物，反式激活细胞中的一系列靶基因 和癌基因激活。p53编码序列中的遗传突变发生在约80%的所有Li家族中。 Fraumeni综合征（LFS）是一种罕见的常染色体显性遗传性疾病， 易患多种癌症。p53编码序列的体细胞突变发生在大约一半的 所有的癌症。大多数p53编码序列的改变，无论是LFS患者的生殖细胞还是LFS患者的体细胞， 癌组织中的突变是DNA结合结构域中的错义突变，其导致致癌蛋白。由于 突变型p53基因突变频率高，在癌症发生和发展中起关键作用， 抗癌疗法开发的优先目标。已经开发了几种小分子 为了将突变型p53转化为表现出某些野生型特性的形式（即，p53再活化）。等 这些化合物正在进行临床试验，但没有一种得到FDA的批准。有几大 用于癌症研究的小鼠模型的类型，每种都有弱点和优势：同基因的，人类细胞系- 来源的异种移植物、患者来源的异种移植物、基因工程的和致癌物诱导的。大多数治疗性 针对突变型p53的程序使用免疫缺陷的人细胞系来源的异种移植物。同基因 小鼠模型，也称为同种异体移植肿瘤系统，由来自相同基因的肿瘤组织组成。 背景作为给定的小鼠品系。具有功能性免疫系统的同基因小鼠模型具有上级优势 用于免疫发育的人细胞系来源的异种移植物。同基因小鼠模型是 有助于开发新的抗肿瘤免疫疗法，但没有相应的模型，大多数 人类癌症中发现的p53热点突变在本项目中，我们将研究 使用优化的同基因小鼠模型的顶级体细胞人p53热点突变体。具体来说，我们将 将前十位的人p53热点突变敲入代表性的同基因小鼠肿瘤细胞系。我们将 在具有功能性免疫系统的小鼠中测试靶向p53突变体的单克隆抗体和疫苗。 这项工作将定义同基因小鼠细胞系的新用途，并测试验证和认证的方法。 优化的p53实验模型系统。我们的研究结果将具有广泛和深远的翻译 通过解决针对突变型p53的精确药物的未满足的临床需求，具有重要意义。

Optimizing Syngeneic Mouse Models to Target Mutant p53 Project Abstract The tumor suppressor gene p53 is the guardian of the human genome. p53 is a transcription factor that transactivates a battery of target genes in cells upon diverse stressors, including environmental carcinogens and oncogene activation. Inherited mutations in the p53 coding sequence occur in ~80% of all families with Li- Fraumeni syndrome (LFS), a rare autosomal dominant hereditary disorder characterized by a high-penetrance predisposition to multiple types of cancers. Somatic mutation of the p53 coding sequence occurs in about half of all cancers. Most alterations in the p53 coding sequence, either germline in LFS patients or somatic in cancer tissues, are missense mutations in the DNA-binding domain that result in an oncogenic protein. Due to its high mutation frequency and critical role in cancer initiation and progression, mutant p53 is a high- priority target for the development of anticancer therapies. Several small molecules have been developed to convert mutant p53 to a form that exhibits some wild-type properties (i.e., p53 reactivation). Such compounds are in clinical trials, yet none of them have been approved by the FDA. There are several major types of mouse models for cancer research, each with weaknesses and strengths: syngeneic, human cell line- derived xenograft, patient-derived xenograft, genetically engineered, and carcinogen-induced. Most therapeutic programs against mutant p53 use human cell line-derived xenograft, which is immunodeficient. Syngeneic mouse models, also known as allograft tumor systems, consist of tumor tissues derived from the same genetic background as a given mouse strain. Syngeneic mouse models with a functional immune system are superior to human cell line-derived xenografts for immunotherapeutic development. Syngeneic mouse models are instrumental in developing novel antitumor immunotherapies, yet there are no corresponding models to most p53 hotspot mutations found in human cancers. In this project, we will study the potential vulnerability of top somatic human p53 hotspot mutants using optimized syngeneic mouse models. Specifically, we will knock the top ten human p53 hotspot mutations into representative syngeneic mouse tumor cell lines. We will test monoclonal antibodies and vaccines targeting the p53 mutants in mice with a functional immune system. This work will define new uses of syngeneic mouse cell lines and test approaches to validate and credential the optimized p53 experimental model systems. Our findings will have broad and far-reaching translational significance by addressing the unmet clinical need for precision medicine against mutant p53.