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

靶向 PI3Kalpha beta 和 ErbB 蛋白酪氨酸激酶家族治疗顺铂耐药的头颈鳞状细胞癌 (HNSCC)

• 批准号: 10667253
• 负责人: KEVIN J. CULLEN
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667253
• 关键词: Animals; Antineoplastic Agents; Cause of Death; Cell Proliferation; Cetuximab; Cisplatin; Clinical; Clinical Trials; Combined Modality Therapy; Data; ERBB2 gene; ERBB3 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; ErbB4 gene; Erlotinib; FDA approved; FRAP1 gene; Failure; Family; Family member; Fc Receptor; Follicular Lymphoma; Gefitinib; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; In Vitro; Laboratories; Malignant Epithelial Cell; Minority; Mutation; Neoplasm Metastasis; Newly Diagnosed; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Phosphotransferases; Play; Protein Family; Protein Isoforms; Protein Tyrosine Kinase; Recurrence; Refractory; Resistance; Resistance development; Role; Survival Rate; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Treatment Efficacy; Up-Regulation; Work; Xenograft procedure; base; cancer recurrence; improved; in vivo; inhibitor; insight; kinase inhibitor; lapatinib; migration; mortality; mouse model; novel therapeutics; patient derived xenograft model; receptor; response; therapeutic target; therapeutically effective; tumor; tumor growth; tumor xenograft

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.

项目概要： 晚期头颈鳞状细胞癌 (HNSCC) 的死亡率仍然非常高，原因是 顺铂是治疗癌症复发和转移最常用的抗癌药物。 复发性和转移性 HNSCC，但大多数患者最终会对这种治疗产生耐药性 因此，迫切需要改进顺铂疗法，但尚未得到满足。 过去 20 年来，晚期 HNSCC 的治疗取得了重大进展。 使用 FDA 批准的 EGFR 抗体西妥昔单抗 患者对基于西妥昔单抗的反应良好。 联合疗法，但它们只能使异常激活的总生存期延长 2-3 个月。 通过代偿机制的关键生存途径的破坏通常会导致顺铂和 EGFR 抑制剂。EGFR 在头颈癌中最重要的下游靶点是 EGFR 和 EGFR。 其他受体蛋白激活 PI3K（PI3Kα、PI3Kβ、PI3Kγ 和 PI3Kδ），然后启动 Akt 和 mTOR促进肿瘤生长、转移和治疗耐药性实际上是PI3Kα突变和扩增。 在超过 30% 的患者肿瘤中发现，因此 PI3K/Akt/mTOR 是最有吸引力的治疗方法。 然而，尽管已经鉴定出许多泛特异性和亚型特异性 PI3K 抑制剂，但还没有发现。 由于效果不佳和无法耐受的毒性，在临床环境中已有效用于治疗用途 因此，迫切需要寻找有效的 PI3K 抑制剂来治疗 HNSCC。 最近探索了同时阻断 ErbB 家族和 PI3K 通路，我们使用 PI3Kα/δ 抑制剂。 Copanlisib，最近被 FDA 批准用于治疗复发/难治性滤泡性淋巴瘤，以及 pan-ErbB 家族抑制剂阿法替尼，发现该组合完全阻断 PI3K/Akt/mTOR 通路， 显着抑制体外细胞增殖、存活、迁移和侵袭，以及异种移植肿瘤 我们的数据提出了一种针对 PI3Kα/δ 和 ErbB 的新的潜在治疗策略。 家庭治疗顺铂耐药的 HNSCC 为了检验我们的假设，我们将：（1）确定显着性和 PI3K 同种型调节 Akt/mTOR 通路激活以及肿瘤生长、转移、 (2) 分析 HER3 的 FOXO3a 依赖性和独立上调 使用不同 PI3K 抑制剂治疗以及 HER3 赋予 PI3K 抑制剂耐药性的作用； 发现 ErbB 家族和 PI3K 联合靶向顺铂耐药 HNSCC 治疗的治疗潜力 该项目的完成将为如何有效治疗提供重要的见解。 顺铂耐药的转移性 HNSCC。