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: 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
• 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' 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

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）：我们关于人类T细胞白血病病毒I（HTLV I）的工作表明，当将癌蛋白税引入p53空细胞中时，会导致暴露于紫外线损伤后凋亡，从而导致细胞死亡增加。税收引起的对DNA损伤的敏化揭示了一种消除p53突变肿瘤耐药性的方法。 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凋亡具有固有的抗性。 p53在所有人类癌症的大多数中都突变，包括许多小儿肿瘤。制定治疗抗性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博士是一位医师科学家，他的实验室专注于利用Fanconi贫血模型的基因组不稳定性和DNA损伤超敏反应。 Semmes博士研究的主要重点是HTLV-1生物学，他在证明税收诱导的基因组不稳定性作为ATL开发模型方面发挥了作用。基因组不稳定性的共同兴趣促进了这一合作。该应用的目的是了解化学敏化中的税收功能。这将通过测试具有功能不同的p53背景的模型系统中对敏化的税收效应来探讨这一点，并以p53独立的方式探测了税收诱导的凋亡的机制，并定义了这种效果所需的最小域。拟议研究的中心假设是，税收激活了p53突变细胞中的凋亡途径，同时促进了p53野生型细胞的耐药性。该提案的理由是，通过揭示税收实现这些功能的机制，我们将揭示目标分子以开发更有效的癌症治疗。共同，我们在翻译研究方面拥有丰富的经验，并对将基准观察转移到临床利用方面有着良好的欣赏。在AIM 1中，我们将确定p53突变细胞中税收引起的DNA损伤敏感性的光谱。这些研究将定义哪种类型的DNA损害描述税收效应。此外，我们将确定哪些p53突变体容易受到这种方法的影响，并缩小负责其作用的特定税收领域。接下来，我们将测试与包含化学敏化作用的税收域相对应的合成肽的使用。接下来，在AIM 2中，我们将证明在人类癌症的小鼠模型中使用税收。首先，我们将使用诱导税作为肿瘤外植体模型的Jurkat细胞在体内测试税收效应。接下来，我们将使用AIM 1中验证的肽用于对p53 - / - 小鼠产生的自发肿瘤的使用。我们的工作有可能显着改善治疗抗性癌症的方法。 公共卫生相关性：p53突变通常在肿瘤中发现，是对标准化疗的抵抗力的主要原因。因此，p53介导的化学抗性是主要的临床肿瘤学问题。在我们关于HTLV I税收蛋白的工作中，我们观察到p53突变体抗性细胞系中的税收表达会导致对DNA损伤的敏感性。在我们提出的工作中，我们假设税收可以用作化学敏化剂的临床工具，以使标准化学疗法在耐药性肿瘤中更有效。我们将证明在细胞系和小鼠肿瘤外植体模型中使用税收作为临床前的原理证明，以期为最终的临床试验而努力。