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：
9067264
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/9067264
关键词：
Affect Algorithms Automobile Driving Cancer Etiology Cell Line Cessation of life Cisplatin 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 Treatment Failure Work Xenograft Model base cancer therapy chemoradiation chemotherapy clinical biomarkers clinically significant cohort high risk improved improved outcome in vitro Model in vivo in vivo Model kinase inhibitor mouse model mutant mutational status neoplastic cell novel patient stratification personalized medicine response senescence survival prediction treatment response 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）：头颈鳞状细胞癌（HNSCC）是全世界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显示，TP53 是该肿瘤类型中最常见的体细胞突变基因。该项目的主要目标是探索改善携带有害 TP53 突变的 HNSCC 患者预后的新方法。虽然已经确定携带 TP53 突变的 HNSCC 患者往往治疗反应较差，但由于 TP53 突变的复杂异质性，利用 p53 突变状态作为临床生物标志物来指导治疗的努力迄今尚未成功。我们开发了一种基于进化作用（EAp53）的新型 TP53 评分算法，可以准确地将患者分层为高风险或低风险亚型，我们假设这将预测 HNSCC 患者的生存率、治疗反应和治疗失败。在此应用中，我们首先建议在几个 HNSCC 患者队列和临床前模型中验证该 EAp53 评分系统。此外，我们建议证明目前在临床试验中使用的有前景的 Wee-1 激酶抑制剂 MK-1775 与顺铂和/或放疗联合使用可以克服 HNSCC 中高风险突变体 p53 介导的化疗或放疗耐药性体外和体内模型。我们还将研究 Wee-1 激酶抑制使 HNSCC 对顺铂和/或放射治疗敏感的细胞和分子机制。我们的工作可能具有深远的临床意义，能够识别出最不可能从当代治疗策略中受益的患者。此外，我们将通过针对 DNA 修复的合成致死策略克服对化疗和放疗的耐药性，并发现在 Wee 1 激酶抑制存在的情况下驱动肿瘤细胞对 DNA 损伤剂做出反应的机制，这可以改善未来的癌症治疗。