Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer

利用 WEE1/p53 合成致死作用作为头颈癌的新型疗法

• 批准号: 9398810
• 负责人: Bruce E Clurman
• 金额: $ 41.53万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-14 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9398810
• 关键词: Address; Affect; Aftercare; Biology; Biopsy; CDC2 Protein Kinase; CDK2 gene; Cell Culture Techniques; Cell Line; Cells; Cisplatin; Clinic; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; DNA Damage; DNA Repair; DNA replication fork; Data; Development; Engineering; G1 Arrest; G2/M Arrest; G2/M Checkpoint Pathway; Gene Silencing; Genes; Genome; Genome Stability; Genomic Instability; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histologic; Human; Human Papillomavirus; Human papilloma virus infection; Hypersensitivity; In Vitro; Knowledge; Lead; Link; Malignant Epithelial Cell; Mediating; Mitosis; Modeling; Mus; Mutate; Mutation; Nature; Neoadjuvant Therapy; Normal Cell; Oncogenic; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Phosphotransferases; Point Mutation; Pre-Clinical Model; Protein p53; Publishing; Risk; S Phase; Sampling; Small Interfering RNA; Solid; Solid Neoplasm; Specificity; Stress; Suppressor Mutations; Surveys; TP53 gene; Testing; Therapeutic; Time; Translating; Treatment Failure; Treatment Protocols; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; Xenograft procedure; base; bench to bedside; cancer cell; cell killing; chemotherapeutic agent; chemotherapy; clinical efficacy; clinically relevant; combinatorial; cytotoxicity; docetaxel; gene repair; genotoxicity; high risk; improved; in vivo; inhibitor/antagonist; killings; knock-down; malignant phenotype; mutant; neoplastic cell; new therapeutic target; novel; novel therapeutics; outcome forecast; phase I trial; preclinical study; premature; prevent; response; response biomarker; success; targeted cancer therapy; targeted treatment; tumor; tumor growth

This proposal addresses one of the most urgent needs in the clinical management of head and neck squamous cell carcinoma (HNSCC), the development of targeted and less toxic therapies. Recent studies have shown that 50-60% of HNSCC tumors harbor mutations in the TP53 tumor suppressor gene with other studies demonstrating that disruptive mutations in TP53 are associated with worse prognosis and survival. Additional studies have linked HPV infection as a second pathway to p53 inactivation in HNSCC. Despite overwhelming evidence implicating p53 functional derangement in the biology and clinical outcome of HNSCC, there are no targeted therapies that capitalize on this knowledge. Towards this goal, we hypothesized that the driver oncogenic/tumor suppressor mutations (i.e., TP53 loss) that confer dominant malignant phenotypes in cancer cells also engender unique, exploitable vulnerabilities. Since p53 mutant HNSCCs are aggressive tumors incapable of G1 arrest and with higher levels of genomic instability, these tumors rely on a functional G2/M cell cycle checkpoint to repair the DNA damage that might occur as a result of this instability or through genotoxic therapy. In support of this hypothesis, we identified p53 synthetic lethal interactions with several G2/M checkpoint regulators using high throughput arrayed siRNA gene silencing against human kinases in p53-mutated HNSCC. Moreover, treatment with AZD1775, a specific WEE1 inhibitor, blocked tumor growth as a single agent and caused tumor regression when used in combination with cisplatin in p53 mutant HNSCC xenografts. To translate these findings to the clinic, we opened a phase I clinical trial with AZD1775 in combination with neoadjuvant weekly cisplatin and docetaxel in previously untreated, metastatic HNSCC patients. Building on these successes, this proposal will provide needed mechanistic understanding on the biology of p53 alterations and G2/M reliance in HNSCC, while providing translational data to advance WEE1 inhibition with AZD1775 as a novel therapy for HNSCC. Therefore, in Aim 1 we will determine the mechanism(s) of growth arrest upon WEE1 inhibition in HNSCC and determine how p53 inactivation affects this response. In Aim 2 we will identify novel sensitizers to the WEE1 inhibitor AZD1775 to unveil novel synergistic and less toxic partners for combinatorial therapy. Lastly, in Aim 3, we will leverage our ongoing phase I clinical trial to functionally evaluate the effects of AZD1775 on tumor biopsies and relevant preclinical models established from patient biopsies before and after treatment to correlate markers of WEE1 inhibition to p53 status and clinical efficacy for the first time in HNSCC. This new knowledge will help inform which HNSCC might benefit most from this line of therapy and help advance AZD1775 into phase II clinical trials.

这项建议解决了头颈部鳞状细胞癌临床治疗中最迫切的需求之一。 细胞癌(HNSCC)，开发有针对性和毒性较低的治疗方法。最近的研究表明， 50%-60%的HNSCC肿瘤存在TP53抑癌基因突变 表明TP53的破坏性突变与更差的预后和生存相关。其他内容 研究表明，HPV感染是HNSCC中P53失活的第二个途径。尽管压倒性地 有证据表明P53功能紊乱与HNSCC的生物学和临床结局有关，目前尚无 利用这一知识进行有针对性的治疗。为了达到这个目标，我们假设司机 致癌/抑癌基因突变(即TP53缺失)导致癌症中的主要恶性表型 细胞还会产生独特的、可利用的漏洞。由于p53突变的HNSCCs是侵袭性肿瘤 这些肿瘤不能停滞在G1期，而且基因组不稳定，依赖于功能正常的G2/M细胞 循环检查点以修复可能由于这种不稳定或通过遗传毒性而发生的DNA损伤 心理治疗。为了支持这一假设，我们确定了p53与几个G2/M检查点的合成致命性相互作用 在p53突变的HNSCC中使用高通量阵列siRNA基因沉默来对抗人蛋白激酶的调节剂。 此外，用特定的WEE1抑制剂AZD1775治疗，作为单一药物阻止肿瘤生长和 联合顺铂治疗P53基因突变的HNSCC移植瘤时，肿瘤消退。翻译 将这些发现提交给临床，我们开启了AZD1775联合新佐剂的I期临床试验 每周一次的顺铂和多西紫杉醇治疗未经治疗的转移性HNSCC患者。在这些成功的基础上， 这一建议将提供对p53改变和G2/M依赖生物学所需的机械性理解 在HNSCC中，在提供翻译数据以促进WEE1抑制的同时，AZD1775作为一种新的治疗方法 HNSCC。因此，在目标1中，我们将确定WEE1抑制生长抑制的机制(S)。 并确定P53失活如何影响这一反应。在目标2中，我们将确定新型致敏剂 WEE1抑制剂AZD1775推出用于联合治疗的新的协同和低毒合作伙伴。最后， 在目标3中，我们将利用我们正在进行的I期临床试验从功能上评估AZD1775对 从治疗前后的患者活检建立的肿瘤活检和相关临床前模型 首次将WEE1抑制指标与HNSCC的P53状态和临床疗效相关联。这是一项新的 知识将有助于告知哪些HNSCC可能从这一治疗路线中受益最大，并有助于推进AZD1775 进入二期临床试验。