HTLV I Tax1 protein chemosensitization of p53 mutant tumors

HTLV I Tax1 蛋白对 p53 突变肿瘤的化疗增敏

基本信息

批准号：
7872281
负责人：
Gary M. Kupfer
金额：
$ 18万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7872281
关键词：
Adjuvant Adult Adverse effects Affect Antineoplastic Agents Apoptosis Apoptotic Biological Markers Biological Models Biology Breast Lymphoma Cancer Biology Cell Culture System Cell Culture Techniques Cell Death Cell Line Cells Chemosensitization Clinical Clinical Oncology Clinical Trials Collaborations Colon Carcinoma DNA Damage Data Development Drug resistance Exposure to Fanconi&apos s Anemia Genomic Instability Goals Grant Human Human T-lymphotropic virus 1 Hypersensitivity Joints Jurkat Cells Laboratories Length Lung Malignant Neoplasms Mediating Mining Modeling Mouse Cell Line Mus Mutate Mutation N-terminal Normal tissue morphology Null Lymphocytes Oncogene Proteins Pathway interactions Patients Pediatric Neoplasm Pediatric Oncology Peptides Physicians Protein p53 Proteins Publications Qualifying Research Research Personnel Resistance Scientist Solid T-Cell Leukemia TP53 gene Taxes Technology Testing Therapeutic Therapeutic Index Tissues Toxic effect Translational Research Virginia Work anticancer research base cancer care cancer therapy cell type chemotherapy effective therapy experience human cancer mouse model improved in vivo interest killings medical schools model development mutant oncology pre-clinical protein expression public health relevance research study response tax Gene Products therapy resistant tool tumor ultraviolet damage

项目摘要

DESCRIPTION (provided by applicant): Our work on human T cell leukemia virus I (HTLV I) has revealed that the oncoprotein Tax, when introduced into p53 null cells, causes apoptosis upon exposure to UV damage, resulting in increased cell death. Tax-induced sensitization to DNA damage reveals an approach to abrogate p53 mutant tumor resistance. p53 mutant tumors remain among the most difficult to treat in human cancer because of their inherent resistance to therapy-induced apoptosis. p53 is mutated in a majority of all human cancer, including many pediatric tumors. Development of strategies to treat resistant p53 mutant tumors is one of the most important problems in clinical oncology. The long-term goal of our team is to study genomic instability in order to understand both basic mechanisms of cellular response as well as its importance to clinical problems. Dr. Kupfer is a physician-scientist whose laboratory has focused on genomic instability and DNA damage hypersensitivity utilizing the Fanconi anemia model. A major focus in Dr. Semmes' research is HTLV-1 biology and he was instrumental in demonstrating Tax-induced genomic instability as a model for development of ATL. The common interest in genomic instability has facilitated this collaboration. The objective of this application is to understand how Tax functions in chemosensitization. This will be explored by testing for the Tax effect upon sensitization in model systems with functionally distinct p53 backgrounds, probing for the mechanism of Tax- induced apoptosis in a p53 independent fashion, and defining the minimal domain necessary for such an effect. The central hypothesis for the proposed research is that Tax activates a pro- apoptotic pathway in p53 mutant cells, while promoting resistance in p53 wild type cells. The rationale for this proposal is that by uncovering the mechanism by which Tax accomplishes these functions we will reveal target molecules for the development of more effective cancer therapy. Together, we have extensive experience in translational research and a solid appreciation for moving bench observation to clinical utilization. In Aim 1, we will determine the spectrum of DNA damage sensitivity induced by Tax in p53 mutant cells. These studies will define which types of DNA damage delineate the Tax effect. In addition we will identify which p53 mutants are susceptible to this approach as well as narrow down the specific domain of Tax responsible for its effect. Next, we will test the use of a synthesized peptide corresponding to the domain of Tax that contains the chemosensitization effect. Next, in Aim 2, we will demonstrate the use of Tax in mouse models of human cancer. First we will use Jurkat cells that inducibly express Tax as a tumor explant model to test the Tax effect in vivo. Next we will use the peptides validated in Aim 1 for use against spontaneous tumors arising in p53 -/- mice. Our work has the potential to dramatically improve the approach to treating resistant cancer. PUBLIC HEALTH RELEVANCE: p53 mutations are commonly found in tumors and are a major cause of resistance to standard chemotherapy. Thus, p53 mediated chemoresistance is a major clinical oncology problem. In our work on HTLV I Tax protein, we have observed that expression of Tax in a p53 mutant resistant cell lines results in increased sensitivity to DNA damage. In our proposed work, we hypothesize that Tax could serve as a clinical tool to use as a chemosensitization agent in order to make standard chemotherapy more effective in resistant tumors. We will demonstrate the use of Tax in cell line and mouse tumor explant models as preclinical proof of principle in anticipation of working toward an eventual clinical trial.

描述（由申请人提供）：我们对人类 T 细胞白血病病毒 I (HTLV I) 的研究表明，当将癌蛋白 Tax 引入 p53 缺失细胞时，在暴露于紫外线损伤时会引起细胞凋亡，从而导致细胞死亡增加。 Tax 诱导的 DNA 损伤敏感性揭示了一种消除 p53 突变体肿瘤抗性的方法。 p53 突变肿瘤仍然是人类癌症中最难治疗的肿瘤之一，因为它们对治疗诱导的细胞凋亡具有固有的抵抗力。 p53 在大多数人类癌症中都会发生突变，包括许多儿童肿瘤。开发治疗耐药性p53突变肿瘤的策略是临床肿瘤学中最重要的问题之一。我们团队的长期目标是研究基因组不稳定性，以了解细胞反应的基本机制及其对临床问题的重要性。 Kupfer 博士是一位医师兼科学家，他的实验室致力于利用 Fanconi 贫血模型研究基因组不稳定性和 DNA 损伤超敏反应。 Semmes 博士的研究重点是 HTLV-1 生物学，他在证明 Tax 诱导的基因组不稳定性作为 ATL 开发模型方面发挥了重要作用。对基因组不稳定性的共同兴趣促进了这种合作。此应用的目的是了解 Tax 在化学增敏中的作用。这将通过在具有功能不同的p53背景的模型系统中测试Tax对敏化的影响、以独立于p53的方式探索Tax诱导细胞凋亡的机制以及定义这种效应所需的最小域来探索。本研究的中心假设是，Tax 激活 p53 突变细胞中的促凋亡途径，同时促进 p53 野生型细胞的抵抗力。该提案的基本原理是，通过揭示 Tax 实现这些功能的机制，我们将揭示用于开发更有效的癌症治疗的目标分子。我们在转化研究方面拥有丰富的经验，并且非常重视将实验室观察转化为临床应用。在目标 1 中，我们将确定 p53 突变细胞中 Tax 诱导的 DNA 损伤敏感性谱。这些研究将确定哪种类型的 DNA 损伤能够描述税收效应。此外，我们将确定哪些 p53 突变体对这种方法敏感，并缩小负责其影响的 Tax 的特定范围。接下来，我们将测试使用与具有化学增敏作用的Tax域相对应的合成肽。接下来，在目标 2 中，我们将演示 Tax 在人类癌症小鼠模型中的应用。首先我们将使用诱导表达Tax的Jurkat细胞作为肿瘤外植体模型来测试Tax的体内效果。接下来，我们将使用目标 1 中验证的肽来对抗 p53 -/- 小鼠中产生的自发性肿瘤。我们的工作有可能显着改善治疗耐药性癌症的方法。公共卫生相关性：p53 突变常见于肿瘤中，是对标准化疗产生耐药性的主要原因。因此，p53介导的化疗耐药性是一个主要的临床肿瘤学问题。在我们对 HTLV I Tax 蛋白的研究中，我们观察到在 p53 突变抗性细胞系中表达 Tax 会导致对 DNA 损伤的敏感性增加。在我们提出的工作中，我们假设 Tax 可以作为一种临床工具，用作化疗增敏剂，以使标准化疗在耐药肿瘤中更有效。我们将展示 Tax 在细胞系和小鼠肿瘤外植体模型中的使用，作为临床前原理证明，以期开展最终的临床试验。