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

基本信息

批准号：
10171805
负责人：
Bruce E Clurman
金额：
$ 16.67万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-14 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171805
关键词：
Address Affect Aftercare Biology Biopsy CDC2 gene 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 Papillomavirus Transforming Protein E6 Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Phosphotransferases Point Mutation Pre-Clinical Model Prognosis Publishing Risk S Phase Sampling Small Interfering RNA Solid Solid Neoplasm Specificity 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 co-clinical trial combinatorial cytotoxicity docetaxel gene repair genotoxicity high risk improved in vivo individualized medicine inhibitor/antagonist knock-down malignant phenotype mutant neoplastic cell new therapeutic target novel novel therapeutics patient derived xenograft model phase I trial preclinical study premature prevent replication stress response response biomarker success targeted cancer therapy targeted treatment treatment optimization tumor tumor growth

项目摘要

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.

该提案解决了头颈部临床管理中最紧迫的需求之一细胞癌（HNSCC），靶向和毒性较小的疗法的发展。最近的研究表明 HNSCC肿瘤中有50-60％的tp53肿瘤抑制基因中的突变与其他研究证明TP53中的破坏性突变与预后较差和生存有关。额外的研究将HPV感染与HNSCC中P53失活的第二个途径联系起来。尽管压倒了在HNSCC的生物学和临床结果中涉及p53功能危险的证据，没有具有利用这一知识的有针对性疗法。为了实现这一目标，我们假设驾驶员致癌/肿瘤抑制突变（即TP53损失），在癌症中赋予主要恶性表型细胞还会产生独特的，可剥削的脆弱性。由于p53突变体HNSCC是侵略性肿瘤这些肿瘤无法阻止G1停滞和较高水平的基因组不稳定性，依赖于功能性G2/M细胞循环检查站以修复由于这种不稳定性或通过遗传毒性而发生的DNA损伤治疗。为了支持这一假设，我们确定了与多个G2/M检查点的p53合成致命相互作用使用高吞吐量的siRNA基因沉默的调节剂对p53突变的HNSCC中的人类激酶。此外，用特定的WEE1抑制剂AZD1775治疗，阻止了肿瘤的生长作为单一药物，并且当在p53突变HNSCC异种移植物中与顺铂结合使用时，引起肿瘤消退。翻译这些发现向诊所的发现，我们与AZD1775与NeoAdjuvant开设了I期临床试验先前未经治疗的转移性HNSCC患者中的每周顺铂和多西他赛。以这些成功为基础该建议将对p53改变和G2/M依赖的生物学提供所需的机械理解在HNSCC中，在提供翻译数据以促进WEE1抑制的同时，用AZD1775作为一种新的疗法 HNSCC。因此，在AIM 1中，我们将在WEE1抑制后确定生长停滞的机制 HNSCC并确定p53失活如何影响这一响应。在AIM 2中，我们将确定新颖的灵敏度 WEE1抑制剂AZD1775揭示了新型的协同作用和毒性较小的合并治疗伴侣。最后，在AIM 3中，我们将利用我们正在进行的I期临床试验来评估AZD1775对治疗前后，由患者活检中建立的肿瘤活检和相关临床前模型 HNSCC首次将WEE1抑制与p53状态和临床功效的标记相关。这个新知识将有助于告知哪些HNSCC可能会从这种治疗方案中受益最大，并帮助促进AZD1775 进入II期临床试验。