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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.

靶向突变型P53的同基因小鼠模型的优化项目摘要抑癌基因P53是人类基因组的守护神。P53是一种转录因子，在不同的应激源，包括环境致癌物质的作用下，激活细胞中的一组靶基因以及癌基因的激活。P53编码序列的遗传性突变在所有LI-LI家系中发生在~80% Fraumeni综合征(LFS)，一种罕见的常染色体显性遗传性疾病，以高外显性为特征易患多种癌症。P53编码序列的体细胞突变发生在大约一半在所有癌症中。大多数P53编码序列的改变，要么是LFS患者的胚系，要么是体细胞的癌症组织，是DNA结合域中的错义突变，导致致癌蛋白。由于突变型p53是一种高突变频率的基因，在肿瘤的发生发展中起关键作用。抗癌治疗发展的优先目标。已经开发出了几种小分子将突变型p53转化为表现出某些野生型特性的形式(即，P53重新激活)。是这样的化合物正在进行临床试验，但没有一种化合物获得FDA的批准。有几个主要的用于癌症研究的小鼠模型的类型，每种都有弱点和优点：同基因的，人类细胞系- 衍生异种移植、病人衍生异种移植、基因工程异种移植和致癌物诱导。最具治疗作用针对突变型p53的程序使用人类细胞系衍生的异种移植，这是免疫缺陷的。同基因的小鼠模型，也被称为同种异体肿瘤系统，由来自相同基因的肿瘤组织组成背景为给定的老鼠品系。具有功能免疫系统的同基因小鼠模型是优越的人类细胞系来源的异种移植用于免疫治疗的开发。同基因小鼠模型有有助于开发新的抗肿瘤免疫疗法，但大多数还没有相应的模型人类癌症中发现的P53热点突变。在这个项目中，我们将研究潜在的漏洞使用优化的同基因小鼠模型的顶级体细胞人类p53热点突变体。具体来说，我们将将排名前十的人类P53热点突变转化为具有代表性的同基因小鼠肿瘤细胞系。我们会在具有功能免疫系统的小鼠中测试针对P53突变体的单抗和疫苗。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实验模型体系。我们的发现将具有广泛而深远的翻译意义通过解决尚未满足的针对突变型p53的精确药物的临床需求，具有重要意义。