Synthetic Lethal Therapy for HPV-Negative Head and Neck Cancer

项目摘要/摘要 头颈部鳞状细胞癌（HNSCC）每年影响全世界超过890，000个个体， 并导致超过45万人死亡尽管治疗HNSCC取得了重大进展， 免疫检查点阻断（ICB）、内在和适应性抗性对改善免疫系统的免疫功能提出了巨大挑战。 患者结局。在这些癌症中，最主要的遗传改变是肿瘤抑制基因的突变。 TP 53，占患者的85%以上。耶鲁大学头颈部孢子旨在解决关键 由于对免疫、DNA损伤和靶向治疗的抵抗，HNSCC的治疗存在障碍。我们以前的 工作确定了抑制极光激酶A（AURKA）和WEE 1，一种G2/M检查点激酶， 导致体外HNSCC细胞系和体内异种移植物和患者来源的异种移植物的细胞死亡的诱导。 vivo.这些创新的激酶抑制剂组合代表了一种全新的治疗TP 53的方法。 变异的癌症本研究将有助于临床对HPV阴性的HNSCC进行联合治疗， 特别是在合成致死性和靶向细胞周期的TP 53 mut介导的药物应答的背景下 监管部门拟议的工作将确定不同的TP 53突变如何影响对AURKA的药物反应 抑制剂与WEE 1抑制剂组合治疗HNSCC。目的1：探讨TP 53与细胞凋亡的关系。 HPV阴性HNSCC细胞中突变基因型和对AURKA和WEE 1抑制剂的药物应答。我们将 对具有不同TP 53基因型的等基因细胞系进行治疗组合，包括强烈突变 破坏型、弱破坏型、功能获得型、功能丧失型和野生型。目标2将在临床前评估 联合治疗产生应答生物标志物的疗效和潜在试验设计的模型， 使用由Tp 53和Cdkn 2a突变驱动的HNSCC的新的基因工程小鼠模型。这 多样性补充将为Barrantes先生提供学习和发展技术， 沟通和批判性思维的研究技能在癌症治疗领域。该补充还将 支持额外的先决条件课程，并有机会让他证明他的能力，完成 耶鲁大学癌症生物学T32癌症生物学导论课程的研究生水平课程。我们预计 他的研究成功，包括至少一个科学出版物产生的这个项目。委员会共 我预计，这一研究经验将提供巴兰特斯先生的发展机会，作为一个 富有成效的研究人员和更有竞争力的申请医学或研究生院。

Project Abstract / Summary Head and neck squamous cell carcinomas (HNSCC) affect more than 890,000 individuals annually worldwide, and lead to over 450,000 deaths. Although significant progress has been made treating HNSCC including immune checkpoint blockade (ICB), intrinsic and adaptive resistance present great challenges to improving patient outcomes. In these cancers, the most dominant genetic alteration is mutation of the tumor suppressor TP53, which accounts for over 85% of patients. The Yale Head and Neck SPORE seeks to address critical barriers to cure of HNSCC due to resistance to immune, DNA damaging and targeted therapy. Our previous work identified synthetic lethality of inhibition of Aurora Kinase A (AURKA) and WEE1, a G2/M checkpoint kinase, leading to induction of cell death for HNSCC cell lines in vitro and xenografts and patient-derived xenografts in vivo. These innovative combinations of kinase inhibitors represent a completely new approach to treating TP53- mutated cancer. This study will help us to combination therapies to the clinic of HPV-negative HNSCC, particularly in the context of synthetic lethality and TP53mut-mediated drug response targeting cell cycle regulators. The proposed work will determine how different TP53 mutations affect drug response to AURKA inhibitor in combination with WEE1 inhibitor in HNSCC. Aim 1 will explore the relationship between TP53 mutation genotype and drug response to AURKA and WEE1 inhibitors in HPV-negative HNSCC cells. We will perform treatment combinations on isogenic cell lines with different TP53 genotypes including mutations strongly disruptive, weakly disruption, gain of function, loss of function and wild type. Aim 2 will preclinically assess the efficacy of the combinational treatment to generate response biomarkers and model potential trial design by using a new genetically engineered mouse model of HNSCC driven both by Tp53 and Cdkn2a mutations. This Diversity Supplement will provide Mr. Barrantes with an opportunity to learn and develop technical, communicative, and critical thinking research skills in the realm of cancer therapeutics. This supplement will also support additional pre-requisite coursework, and the opportunity for him to demonstrate his ability to complete graduate level coursework in the Yale Cancer Biology T32 Introduction to Cancer Biology Course. We expect his research success to include at least one scientific publication resulting from this project. Altogether, we anticipate that this research experience will provide Mr. Barrantes with opportunities for development as a productive researcher and more competitive application for medical or graduate school.