Optimizing Syngeneic Mouse Models to Target Mutant p53

优化同基因小鼠模型以靶向突变 p53

基本信息

批准号：
10677353
负责人：
Yong Li
金额：
$ 59.68万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-17 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677353
关键词：
Address Allografting Amino Acids Antibodies Antigen Presentation Antigens Arsenic B-Lymphocytes Basic Science Biological Models Bispecific Antibodies Bispecific Monoclonal Antibodies Cancer Patient Carcinogens Cell surface Cells Clinical Clinical Trials Code Credentialing Cultured Tumor Cells DNA Binding Domain DNA Vaccines Data Development Drug Targeting Engraftment Environment Environmental Carcinogens Exhibits Experimental Models Family Frequencies Genes Genetic Genetic Engineering Hereditary Disease Human Human Cell Line Human Genome Immune response Immune system Immunocompetent Immunologic Deficiency Syndromes Immunotherapeutic agent Immunotherapy Infiltration Inherited Li-Fraumeni Syndrome Major Histocompatibility Complex Malignant Neoplasms Mediating Missense Mutation Modeling Monoclonal Antibodies Mouse Cell Line Mouse Strains Mus Mutate Mutation Natural Immunity Oncogene Activation Oncogenic Patients Penetrance Performance Phosphoric Monoester Hydrolases Physiologic pulse Plasma Cells Predisposition Prognosis Property Proteins Research Role Serum Somatic Mutation Supporting Cell System T cell response T-Cell Receptor T-Lymphocyte TP53 gene Targeted Research Testing Therapeutic Tissues Traction Translational Research Tumor Antigens Tumor Cell Line Tumor Suppression Tumor Suppressor Genes Tumor Tissue United States Food and Drug Administration Vaccines Work Xenograft Model Xenograft procedure anticancer research antigen-specific T cells autosome cancer care cancer initiation cancer therapy cancer type cellular targeting drug development immune checkpoint blockade improved inhibiting antibody mouse model mutant neoantigens neoplasm immunotherapy neoplastic cell novel novel strategies patient derived xenograft model precision medicine precision oncology prevent programs research and development response small molecule stressor targeted agent therapeutic development transcription factor tumor tumor progression tumorigenesis vector

项目摘要

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.

优化同基因小鼠模型以靶向突变 p53 项目摘要抑癌基因p53是人类基因组的守护者。 p53 是一种转录因子在多种压力源（包括环境致癌物）下反式激活细胞中的一系列靶基因和癌基因激活。 p53 编码序列的遗传性突变发生在大约 80% 的 Li- 家族中。 Fraumeni 综合征 (LFS)，一种罕见的常染色体显性遗传性疾病，其特征是高外显率易患多种癌症。 p53编码序列的体细胞突变发生在大约一半的人中所有癌症。 p53 编码序列的大多数改变，无论是 LFS 患者的种系还是 LFS 患者的体细胞癌症组织是 DNA 结合域中的错义突变，导致致癌蛋白。由于其高突变频率以及在癌症发生和进展中的关键作用，突变体 p53 是一种高突变率开发抗癌疗法的优先目标。已开发出多种小分子将突变型 p53 转化为表现出某些野生型特性的形式（即 p53 重新激活）。这样的化合物正在进行临床试验，但尚未获得 FDA 批准。主要有几个用于癌症研究的小鼠模型类型，每种模型都有弱点和优点：同基因、人类细胞系- 衍生的异种移植物、患者衍生的异种移植物、基因工程和致癌物诱导的。最有治疗作用针对突变 p53 的计划使用源自人类细胞系的异种移植物，这种移植物具有免疫缺陷。同系小鼠模型，也称为同种异体移植肿瘤系统，由源自相同遗传基因的肿瘤组织组成背景为给定的小鼠品系。具有功能性免疫系统的同基因小鼠模型更优越人类细胞系衍生的异种移植物用于免疫治疗开发。同基因小鼠模型是有助于开发新型抗肿瘤免疫疗法，但大多数都没有相应的模型在人类癌症中发现 p53 热点突变。在这个项目中，我们将研究潜在的脆弱性使用优化的同基因小鼠模型研究顶级体细胞人类 p53 热点突变体。具体来说，我们将将前十个人类 p53 热点突变敲入代表性的同基因小鼠肿瘤细胞系中。我们将在具有功能性免疫系统的小鼠中测试针对 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以及验证和认证的测试方法优化的p53实验模型系统。我们的研究结果将产生广泛而深远的转化通过解决针对突变 p53 的精准医学未得到满足的临床需求，具有重要意义。