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

描述（由申请人提供）：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的无偏倚综合基因组表征显示，TP 53是该肿瘤类型中最常见的体细胞突变基因。该项目的主要目的是探索新的方法来改善HNSCC患者的结果，这些患者携带有害的TP 53突变。虽然已经确定携带TP 53突变的HNSCC患者倾向于具有差的治疗反应，但是由于TP 53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为止尚未成功。我们开发了一种基于进化作用（EAp 53）的新型TP 53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患者的生存率，治疗反应和治疗失败。在本申请中，我们首先提出在几个HNSCC患者队列和临床前模型中验证EAp 53评分系统。此外，我们建议证明，有前途的Wee-1激酶抑制剂，目前正在使用的临床试验，MK-1775，与顺铂和/或放射治疗相结合，可以克服高风险突变p53介导的耐药性化疗或放射治疗HNSCC使用在体外和体内模型。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，使识别患者最不可能受益于当代治疗策略。此外，我们将通过靶向DNA修复的合成致死策略克服对化疗和放疗的抗性，并发现在Wee 1激酶抑制剂存在下驱动肿瘤细胞对DNA损伤剂的反应的机制，这可能会改善未来的癌症治疗。

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.