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

• 批准号: 8053781
• 负责人: Gary M. Kupfer
• 金额: $ 20.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/8053781
• 关键词: Adjuvant; Adult; Adverse effects; Affect; Antineoplastic Agents; Apoptosis; Apoptotic; Biological Markers; Biological Models; Biology; 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' s Anemia; Genomic Instability; Goals; Grant; Human; Human T-lymphotropic virus 1; Hypersensitivity; Joints; Jurkat Cells; Laboratories; Length; Lymphoma; Malignant Neoplasms; Malignant neoplasm of lung; 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; 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; malignant breast neoplasm; 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

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无效细胞时，暴露在紫外线损伤下会导致细胞凋亡，导致细胞死亡增加。税收诱导的DNA损伤致敏揭示了一种消除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抗性。P53在大多数人类癌症中发生突变，包括许多儿童肿瘤。开发治疗耐药p53突变肿瘤的策略是临床肿瘤学的重要问题之一。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博士是一名内科科学家，他的实验室专注于利用范可尼贫血模型研究基因组不稳定性和DNA损伤超敏反应。Semmes博士的主要研究重点是HTLV-1生物学，他在证明税收诱导的基因组不稳定性作为ATL发展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一合作。本应用程序的目的是了解在化学致敏中Tax是如何起作用的。这将通过在具有功能不同的p53背景的模型系统中测试税收对致敏的影响，以p53独立的方式探索税收诱导细胞凋亡的机制，并定义这种影响所需的最小结构域来探索。本研究的中心假设是，在p53突变细胞中，Tax激活了促凋亡通路，同时促进了p53野生型细胞的抗性。这项提议的基本原理是，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，并对将实验台观察转化为临床应用有着深刻的认识。在Aim 1中，我们将确定Tax在p53突变细胞中诱导的DNA损伤敏感性谱。这些研究将确定哪些类型的DNA损伤描述了税收效应。此外，我们将确定哪些p53突变体易受这种方法的影响，并缩小对其影响负责的特定Tax域。接下来，我们将测试使用与含有化学致敏作用的Tax结构域对应的合成肽。接下来，在目标2中，我们将演示在人类癌症小鼠模型中使用Tax。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，在体内测试Tax的效果。接下来，我们将使用在Aim 1中验证的肽用于对抗p53 -/-小鼠中产生的自发性肿瘤。我们的工作有可能极大地改善治疗耐药癌症的方法。