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

描述（申请人提供）：头颈部鳞状细胞癌（HNSCC）是世界范围内癌症死亡的主要原因，最近对HNSCC的无偏见综合基因组特征显示TP53是这种肿瘤类型中最常见的体细胞突变基因。该项目的主要目的是探索新的方法来改善携带有害TP53突变的HNSCC患者的预后。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，迄今为止利用p53突变状态作为临床生物标志物指导治疗的努力尚未成功。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为高风险或低风险亚型，我们假设这将预测HNSCC患者的生存、治疗反应和治疗失败。在本应用中，我们首先提出在几个HNSCC患者队列和临床前模型中验证EAp53评分系统。此外，我们建议在体外和体内模型中证明，目前在临床试验中使用的有前途的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p53介导的高风险突变体对化疗或放疗的耐药。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，能够识别最不可能从当代治疗策略中受益的患者。此外，我们将通过合成靶向DNA修复的致命策略来克服化疗和放疗的耐药性，并发现在抑制Wee 1激酶存在的情况下驱动肿瘤细胞对DNA损伤剂反应的机制，这可能会改善未来的癌症治疗。

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.