Predicting and overcoming chemoradioresistance in p53-mutant head and neck cancer

预测和克服 p53 突变头颈癌的放化疗耐药性

基本信息

批准号：
8893048
负责人：
Jeffrey Nicholas Myers
金额：
$ 49.12万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-20 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893048
关键词：
Affect Algorithms Automobile Driving Biological Markers Cancer Etiology Cell Line Cessation of life Cisplatin Clinical Clinical Trials Complex DNA Damage DNA Repair Data Disease Future Genes Genomics Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Health Heterogeneity In Vitro Knowledge Lead Malignant Epithelial Cell Malignant Neoplasms Mediating Molecular Mucositis Mucous Membrane Mutate Mutation Oral mucous membrane structure Outcome Pathway interactions Patients Phosphotransferases Pre-Clinical Model Predictive Factor Prognostic Factor Publishing Radiation Radiation therapy Radiosensitization Resistance Risk Survival Rate System TP53 gene Testing Therapeutic Treatment Failure Work Xenograft Model base cancer therapy chemoradiation chemotherapy clinically significant cohort high risk improved in vitro Model in vivo in vivo Model kinase inhibitor mouse model mutant neoplastic cell novel personalized medicine response senescence treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Head and Neck Squamous Cell Carcinoma (HNSCC) is a leading cause of cancer deaths worldwide and recent unbiased comprehensive genomic characterizations of HNSCC revealed that TP53 is the most common somatically mutated gene in this tumor type. The main objective of this project is to explore novel ways to improve the outcome of HNSCC patients who harbor deleterious TP53 mutations. While it has been established that HNSCC patients harboring TP53 mutations tend to have poor therapeutic response, efforts to utilize p53 mutational status as a clinical biomarker to guide therapy have been unsuccessful thus far due to the complex heterogeneity of TP53 mutations. We have developed a novel TP53 scoring algorithm based upon evolutionary action (EAp53) that can accurately stratify patients as high or low risk subtypes, which we hypothesize will predict survival, therapeutic response and treatment failure in HNSCC patients. In this application, we first propose to validate this EAp53 scoring system in several HNSCC patient cohorts and in preclinical models. Moreover, we propose to demonstrate that the promising Wee-1 kinase inhibitor currently being used in clinical trials, MK-1775, in combination with cisplatin and/or radiation can overcome the high risk mutant p53-mediated resistance to chemotherapy or radiation in HNSCC using in vitro and in vivo models. We shall also examine the cellular and molecular mechanisms by which Wee-1 kinase inhibition sensitizes HNSCC to cisplatin and/or radiation treatment. Our work may have far reaching clinical significance by enabling identification of patients least likely to benefit from contemporary treatment strategies. In addition, we will overcome resistance to chemotherapy and radiation through synthetic lethal strategies targeting DNA repair and discover mechanisms driving the response of tumor cells to DNA damaging agents in the presence of Wee 1 kinase inhibition which could improve future cancer treatment.

描述（由申请人提供）：头部和颈部鳞状细胞癌（HNSCC）是全球癌症死亡的主要原因，最近对HNSCC的无偏见的全面基因组特征表明，TP53是该肿瘤类型中最常见的体形突变基因。该项目的主要目的是探索新的方法来改善具有有害TP53突变的HNSCC患者的结果。虽然已经确定，具有TP53突变的HNSCC患者的治疗反应往往较差，但由于TP53突变的复杂异质性，迄今为止，将p53突变状态作为临床生物标志物进行指导治疗的努力尚未成功。我们基于进化作用（EAP53）开发了一种新型的TP53评分算法，该算法可以准确地将患者分类为高风险亚型或低风险亚型，我们假设这将预测HNSCC患者的生存，治疗反应和治疗失败。在此应用程序中，我们首先建议在几个HNSCC患者队列和临床前模型中验证此EAP53评分系统。此外，我们建议证明，当前在临床试验中使用的有希望的WEE-1激酶抑制剂MK-1775与顺铂和/或辐射结合使用，可以利用Intro and InviVO模型来克服高风险突变体对化学疗法或辐射的高风险突变介导的抗性。我们还将检查WEE-1激酶抑制作用将HNSCC敏感到顺铂和/或辐射处理的细胞和分子机制。我们的工作可能通过鉴定患者从当代治疗策略中受益最小的患者，可能具有临床意义。此外，我们将通过针对DNA修复的合成致命策略来克服对化学疗法和放射线的抵抗力，并发现在存在WEE 1激酶抑制的情况下，促进肿瘤细胞对DNA破坏剂的反应的机制，这可以改善未来的癌症治疗。