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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：
10668986
负责人：
BARBARA BURTNESS
金额：
$ 48.08万
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/10668986
关键词：
Acceleration 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 Centrosome 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 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 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 Phase Phenotype Phosphorylation Phosphotransferases Ploidies Population Protein Dephosphorylation Protein-Serine-Threonine Kinases Recommendation Resectable Resistance Serine Signal Transduction TP53 gene Testing Toxic effect Translating Tumor Suppressor Proteins Work Xenograft Model Xenograft procedure anti-cancer aurora kinase A biomarker identification 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 pharmacologic 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.

总结 HPV阴性头颈部鳞状细胞癌（HNSCC）通常失去G1/S细胞周期检查点，大多数肿瘤在TP 53中具有突变，并且许多肿瘤还突变其它肿瘤抑制因子如CDKN 2A。这些肿瘤变得依赖于与G2/M相关的检查点来修复由G2/M引起的DNA损伤。复制应激和其他基因组损伤。这种依赖性表明肿瘤选择性易受通过G2/M控制进展的合成致死策略。在大量的初步数据中，我们表明， AZD 1775/adavosertib是一种G2/M检查点激酶WEE 1抑制剂，可有效致敏TP 53 mut HNSCC 细胞系抑制Aurora A激酶（AURKA）。WEE 1诱导CDK 1的抑制性Y15磷酸化，阻断M期进入，从而减弱AURKA抑制的细胞毒性作用。WEE 1抑制消除了这一点阻滞，加速有丝分裂进入具有高度破坏性的纺锤体异常和其他缺陷的细胞，从AURKA抑制，导致有丝分裂灾难和凋亡。我们发现组合AURKA/WEE 1 抑制在HNSCC异种移植物中是有效的，而在正常组织和细胞中耐受良好。我们已经扩展了这个概念，确定WEE 1和其他G2/M调节激酶之间的其他有希望的药物组合 (PLK1 CHK1）。值得注意的是，在合成致死处理中存活的有限数量的细胞的特征在于：非整倍体和其他缺陷表明他们可能增加了肿瘤突变负荷（TMB），表达新抗原，以及与免疫检查点抑制敏感性相关的上调炎症信号传导。该项目将直接将观察结果带到诊所。我们将进行术前窗口期I，新一代高效选择性AURKA抑制剂LY 3295668的扩展临床试验， adavosertib联合用药，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，并在基因组改变和治疗的背景下放置协同组合阻力在目标1中，我们将评估联合致死的机制，并使用单细胞测序和 Luminex分析用于查询TMB、预测新抗原和测量炎症信号传导。目标2将查询常见的HNSCC TP 53和CDKN 2A突变类型以及顺铂耐药对化疗反应的影响 WEE 1-AURKA抑制剂组合，使用确定的细胞系模型和患者来源的异种移植物（PDX）。在目标3，我们将进行术前窗口试验，以确定推荐的II期剂量，并建立药效学概念证明，并评价反应的推定预测生物标志物与HNSCC中WEE 1/AURKA联合抑制有关。