Project 2: Synthetic Lethal Therapy for HPV-Negative Head and Neck Cancer

项目 2：HPV 阴性头颈癌的合成致死疗法

基本信息

批准号：
10441510
负责人：
BARBARA BURTNESS
金额：
$ 50.64万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441510
关键词：
Affect Aneuploidy Apoptosis Biological Markers CASP3 gene CDC2 gene CDKN2A gene CHEK1 gene Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Line Cell Survival Cells Characteristics Cisplatin Clinic Clinical Clinical Trials Complement Cyclin-Dependent Kinases DNA Damage DNA Repair DNA Sequence Alteration Data Defect Dependence Doctor of Philosophy Dose Drug Combinations Drug Targeting Effectiveness Enrollment Evaluation Exhibits Freezing Future G1/S Checkpoint Pathway G2 Phase Generations Genes Genomics Goals HPV-negative head and neck cancer Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Human Human Papillomavirus Inflammatory Lead Malignant Epithelial Cell Malignant Neoplasms Measures Mitosis Mitotic Mitotic spindle Modeling Mus Mutate Mutation Normal Cell Normal tissue morphology Operative Surgical Procedures PLK1 gene Patient Selection Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Phenotype Phosphorylation Phosphotransferases Ploidies Population Protein Dephosphorylation Protein-Serine-Threonine Kinases Resectable Resistance Signal Transduction TP53 gene Testing Toxic effect Translating Tumor Suppressor Proteins Work Xenograft Model Xenograft procedure anti-cancer aurora kinase A base cancer cell checkpoint inhibition cohort cytotoxic cytotoxicity effective therapy exome sequencing experimental study gain of function genomic biomarker inhibitor kinase inhibitor neoantigens novel patient biomarkers patient derived xenograft model pre-clinical predictive marker preservation repaired replication stress response response biomarker single cell sequencing synergism targeted agent therapy resistant translational impact tumor

项目摘要

Summary HPV-negative head and neck squamous cell carcinomas (HNSCC) typically lose G1/S cell cycle checkpoints, with most tumors having mutations in TP53, and many also mutating other tumor suppressors such as CDKN2A. Such tumors become dependent on checkpoints associated with G2/M to repair DNA damage arising from replication stress and other genomic insults. This dependency suggests a tumor-selective vulnerability to synthetic lethal strategies controlling progress through G2/M. In extensive preliminary data, we show that AZD1775/adavosertib, an inhibitor of the G2/M checkpoint kinase WEE1, potently sensitizes TP53mut HNSCC cell lines to inhibition of Aurora A kinase (AURKA). WEE1 induces an inhibitory Y15-phosphorylation of CDK1, blocking M-phase entry and thus blunting the cytotoxic effects AURKA inhibition. WEE1 inhibition abrogates this arrest, accelerating mitotic entry for cells bearing highly disruptive spindle abnormalities and other defects arising from AURKA inhibition, resulting in mitotic catastrophe and apoptosis. We found combined AURKA/WEE1 inhibition is potent in HNSCC xenografts, while well-tolerated in normal tissue and cells. We have extended this concept, identifying additional promising drug combinations between WEE1 and other G2/M regulatory kinases (PLK1 and CHK1). Notably, the limited number of cells surviving synthetic lethal treatment are characterized by aneuploidy and other defects suggesting they may have increased tumor mutation burden (TMB), express neoantigens, and upregulated inflammatory signaling associated with sensitivity to immune checkpoint inhibition. This project will take this observation directly to the clinic. We will conduct a pre-operative window phase I and expansion clinical trial of the late generation, high potency selective AURKA inhibitor LY3295668 with adavosertib combination, establishing pharmacodynamic proof of concept, identifying biomarkers for patient selection in future studies, and placing synergistic combinations in context of genomic alteration and treatment resistance. In Aim 1, we will evaluate mechanisms of combination lethality, and use single cell sequencing and Luminex profiling to query TMB, predict neoantigens, and measure inflammatory signaling. Aim 2 will query the effect of classes of common HNSCC TP53 and CDKN2A mutations, and cisplatin resistance, on response to a WEE1-AURKA inhibitor combination, using defined cell line models and patient derived xenografts (PDXs). In Aim 3, we will perform a pre-operative window trial to establish recommended phase 2 doses, determine activity and establish pharmacodynamic proof of concept, and to evaluate putative predictive biomarkers for response to combination WEE1/AURKA inhibition in HNSCC.

概括 HPV阴性头和颈部鳞状细胞癌（HNSCC）通常会丢失G1/S细胞周期检查点，大多数肿瘤在TP53中具有突变，许多肿瘤也突变其他抑制其他肿瘤（例如CDKN2A）。这样的肿瘤取决于与G2/m相关的检查点，以修复由DNA损伤复制应力和其他基因组侮辱。这种依赖性表明肿瘤选择性脆弱性通过G2/m控制进步的合成致命策略。在广泛的初步数据中，我们表明 AZD1775/Adavosertib，G2/M检查点激酶WEE1的抑制剂，有效地使TP53MUT HNSCC敏感细胞系抑制极光A激酶（Aurka）。 WEE1诱导CDK1的抑制性Y15磷酸化阻断M期进入，从而使细胞毒性效应Aurka抑制作用。 WEE1抑制作用消除了逮捕，加速具有高度破坏性纺锤体异常和其他缺陷的细胞的有丝分裂进入来自Aurka抑制作用，导致有丝分裂灾难和凋亡。我们发现了Aurka/wee1的组合抑制作用在HNSCC异种移植物中有效，同时在正常组织和细胞中耐受性良好。我们已经扩展了这个概念，确定WEE1与其他G2/M调节激酶之间的其他有希望的药物组合（PLK1和CHK1）。值得注意的是，幸存的合成致死治疗的细胞数量有限。非整倍性和其他缺陷，表明它们可能增加了肿瘤突变负担（TMB），表达新抗原，并上调与对免疫检查点抑制敏感性相关的炎症信号传导。该项目将直接将该观察结果直接带到诊所。我们将进行术前的窗口阶段和晚期的扩展临床试验，高效力选择性Aurka抑制剂LY3295668 Adavosertib组合，建立药效学概念证明，确定患者的生物标志物在未来的研究中选择，并将协同组合放在基因组改变和治疗的背景下反抗。在AIM 1中，我们将评估组合致死性的机制，并使用单细胞测序和 Luminex分析以查询TMB，预测新抗原并测量炎症信号传导。 AIM 2会查询常见的HNSCC TP53和CDKN2A突变以及顺铂的抗性对响应的影响 WEE1-AURKA抑制剂组合，使用定义的细胞系模型和患者衍生的异种移植物（PDXS）。在 AIM 3，我们将执行术前窗口试验以建立建议的2阶段剂量，确定活动并建立药效学概念证明，并评估推定的预测生物标志物以应对反应在HNSCC中组合WEE1/Aurka抑制作用。