Optimizing Syngeneic Mouse Models to Target Mutant p53

优化靶向突变p53的同基因小鼠模型

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.