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.

该提案解决了头颈鳞状细胞癌临床管理中最紧迫的需求之一细胞癌（HNSCC），开发靶向且毒性较小的疗法。最近的研究表明根据其他研究，50-60% 的 HNSCC 肿瘤存在 TP53 肿瘤抑制基因突变证明 TP53 的破坏性突变与较差的预后和生存相关。额外的研究表明，HPV 感染是 HNSCC 中 p53 失活的第二条途径。尽管势不可挡有证据表明 p53 功能紊乱与 HNSCC 的生物学和临床结果有关，但尚无证据利用这些知识的靶向治疗。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 丢失）赋予癌症显性恶性表型细胞还产生独特的、可利用的漏洞。由于 p53 突变 HNSCC 是侵袭性肿瘤这些肿瘤无法进行 G1 期阻滞且具有较高水平的基因组不稳定性，因此依赖于功能性 G2/M 细胞循环检查点来修复由于这种不稳定性或基因毒性而可能发生的 DNA 损伤治疗。为了支持这一假设，我们鉴定了 p53 与几个 G2/M 检查点的合成致死相互作用使用高通量阵列 siRNA 基因沉默来抑制 p53 突变 HNSCC 中的人激酶。此外，使用 AZD1775（一种特定的 WEE1 抑制剂）作为单一药物治疗可阻止肿瘤生长，并且当与 p53 突变 HNSCC 异种移植物中的顺铂联合使用时，引起肿瘤消退。翻译将这些发现推向临床，我们开启了 AZD1775 联合新辅助治疗的 I 期临床试验对于先前未经治疗的转移性 HNSCC 患者，每周使用顺铂和多西紫杉醇。在这些成功的基础上，该提案将为 p53 改变和 G2/M 依赖的生物学提供所需的机制理解在 HNSCC 中，同时提供转化数据以推进 AZD1775 抑制 WEE1 作为一种新疗法 HNSCC。因此，在目标 1 中，我们将确定 WEE1 抑制后生长停滞的机制 HNSCC 并确定 p53 失活如何影响这种反应。在目标 2 中，我们将鉴定新型敏化剂 WEE1 抑制剂 AZD1775 揭示了用于组合治疗的新型协同且毒性较小的伙伴。最后，在目标 3 中，我们将利用正在进行的 I 期临床试验来功能评估 AZD1775 对肿瘤活检和根据治疗前后患者活检建立的相关临床前模型首次将 WEE1 抑制标志物与 p53 状态和 HNSCC 临床疗效相关联。这个新的知识将有助于了解哪些 HNSCC 可能从该疗法中获益最多，并有助于推进 AZD1775 进入II期临床试验。