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

• 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
• 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

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(申请人提供)：头颈部鳞状细胞癌(HNSCC)是全球癌症死亡的主要原因，最近对HNSCC进行的无偏见综合基因组特征显示，TP53是该肿瘤类型中最常见的体细胞突变基因。这个项目的主要目标是探索新的方法来改善携带有害的TP53突变的HNSCC患者的预后。虽然已经证实携带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，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。我们开发了一种新的基于进化行为的TP53评分算法(EAp53)，该算法可以准确地将患者分为高风险亚型或低风险亚型，我们假设这些亚型将预测HNSCC患者的生存、治疗反应和治疗失败。在这项应用中，我们首先建议在几个HNSCC患者队列和临床前模型中验证EAp53评分系统。此外，我们建议通过体外和体内模型证明，目前用于临床试验的有前景的WeE-1激酶抑制剂MK-1775与顺铂和/或放射联合使用可以克服HNSCC中高危突变型p53介导的化疗或放射耐药。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，因为我们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修复的合成致命策略来克服对化疗和辐射的抵抗力，并发现在存在Wee 1激酶抑制的情况下驱动肿瘤细胞对DNA损伤剂的反应的机制，这可能会改善未来的癌症治疗。