Targeting PI3Kalpha beta and the ErbB family of protein-tyrosine kinases in cisplatin-resistant head and neck squamous cell carcinomas (HNSCC)

项目总结： 晚期头颈部鳞状细胞癌(HNSCC)的死亡率仍然很高，原因是 癌症复发和转移。顺铂是治疗肺癌最常用的抗癌药物。 复发和转移的HNSCC，但大多数患者最终会对这种治疗产生耐药性 并在一年内死亡。因此，目前迫切需要改进顺铂的治疗方法，但仍未得到满足。 耐药HNSCC。在过去的20年中，晚期HNSCC治疗的一个主要进展是 FDA批准的EGFR抗体西妥昔单抗的使用。患者对西妥昔单抗的反应良好 联合治疗，但它们只会使总存活率提高2-3个月。异常激活 通过代偿机制的关键生存途径往往导致顺铂和 EGFR抑制剂。在头颈癌中，EGFR最重要的下游靶点是PI3K。EGFR和 其他受体蛋白激活PI3K(PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ)，然后启动Akt和 MTOR可促进肿瘤生长、转移和治疗耐药。事实上，PI3Kα的突变和扩增 在超过30%的患者肿瘤中被发现。因此，PI3K/Akt/mTOR是一种最有吸引力的治疗方法 HNSCC的目标。然而，尽管已经确定了许多PAN和异构体特异性的PI3K抑制剂，但没有一个 由于疗效不佳和无法忍受的毒性，在临床环境中用于治疗是有效的 由PAN-PI3K抑制剂引起。因此，寻找有效的PI3K抑制剂治疗HNSCC已迫在眉睫。我们 最近研究了ErbB家族和PI3K通路的同时阻断。我们使用了PI3Kα/δ抑制剂 最近被FDA批准用于治疗复发性/难治性滤泡性淋巴瘤的Copanlisib和PAN-ErbB 家族抑制剂Afatinib，并发现联合应用完全阻断了PI3K/Akt/mTOR通路和 显著抑制体外细胞的增殖、存活、迁移和侵袭，以及异种移植瘤 在动物中形成的。我们的数据提示了一种针对PI3Kα/δ和ErbB的新的潜在治疗策略 治疗顺铂耐药的HNSCC的家庭。为了检验我们的假设，我们将：(1)确定重要性和 需要PI3K亚型来调节Akt/mTOR通路的激活，以及肿瘤的生长、转移 (2)分析FOXO3a依赖和独立上调HER3 在用不同的PI3K抑制剂治疗和HER3在赋予PI3K抑制剂耐药性方面的作用(S)；以及，(3) 发现ErbB家族和PI3K联合靶向治疗顺铂耐药的HNSCC的潜力 在多个老鼠模型中。该项目的完成将为如何有效地治疗 顺铂耐药的转移性HNSCC。

PROJECT SUMMARY: The mortality rate for advanced head and neck squamous cell carcinoma (HNSCC) remains very high due to cancer recurrence and metastasis. Cisplatin is the most commonly used anti-cancer drug for treatment of recurrent and metastatic HNSCC, but the majority of patients will eventually develop resistance to this treatment and die within one year. Therefore, there is an urgent, yet still unmet, need for improved therapies for cisplatin- resistant HNSCC. A major advancement in the treatment of advanced HNSCC in the past 20 years has been the use of the FDA-approved EGFR antibody, Cetuximab. Patients respond well to the Cetuximab-based combination therapies, but they result in only 2-3 months improvement in overall survival. Abnormal activation of key survival pathways through compensatory mechanisms often leads to therapeutic failure of cisplatin and EGFR inhibitors. A most important downstream target of EGFR in head and neck cancer is PI3K. EGFR and other receptor proteins activate PI3K (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), which then initiate activation of Akt and mTOR to promote tumor growth, metastasis, and therapy resistance. In fact, PI3Kα mutation and amplification was found in more than 30% of tumors in patients. Therefore, PI3K/Akt/mTOR is a most attractive therapeutic target in HNSCC. However, although many pan- and isoform-specific PI3K inhibitors have been identified, none have been effective for therapeutic use in the clinical setting due to poor effective results and intolerable toxicity caused by the pan-PI3K inhibitors. Thus, it is urgent to find effective PI3K inhibitors for HNSCC therapy. We recently explored simultaneous blockage of ErbB family and PI3K pathways. We used PI3Kα/δ inhibitor Copanlisib, recently approved by the FDA for treatment of elapsed/refractory follicular lymphoma, and pan-ErbB family inhibitor Afatinib, and found that the combination completely blocked PI3K/Akt/mTOR pathways and significantly suppressed cell proliferation, survival, migration, and invasion in vitro, as well as xenograft tumor formation in animals. Our data suggest a new potential therapeutic strategy that targets the PI3Kα/δ and ErbB family to treat cisplatin-resistant HNSCC. To test our hypothesis, we will: (1) determine the significance and requirement of PI3K isoforms to regulate activation of the Akt/mTOR pathway, and tumor growth, metastasis, and resistance to EGFR inhibitor; (2) analyze the FOXO3a-dependent and independent up-regulation of HER3 upon treatment with different PI3K inhibitors and the role(s) of HER3 to confer PI3K inhibitor resistance; and, (3) discover the therapeutic potential of the ErbB family and PI3K to co-target cisplatin-resistant HNSCC treatment in multiple mouse models. Completion of this project will provide important insights into how to effectively treat cisplatin-resistant metastatic HNSCC.