Targeting BCL-2 family-regulated cell death for HNSCC treatment

靶向 BCL-2 家族调节的细胞死亡治疗 HNSCC

• 批准号: 9812923
• 负责人: Hisashi Harada
• 金额: $ 7.76万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812923
• 关键词: Apoptosis; Apoptotic; BCL1 Oncogene; BCL2 gene; Biochemical; Cell Death; Cell Death Induction; Cell Line; Cetuximab; Chronic Lymphocytic Leukemia; Cisplatin; Clinic; Clinical; Clinical Trials; Data; Development; Drug resistance; Drug usage; Epidermal Growth Factor Receptor; Family; Fenretinide; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Immunocompetent; In Vitro; MCL1 gene; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mitochondria; Modality; Modeling; Molecular; Mouth Carcinoma; Mutate; Nitroquinolines; Outcome; Oxides; Pathway interactions; Patients; Pharmaceutical Preparations; Platinum; Protein Family; Refractory; Regimen; Resistance; Resistance development; Solid Neoplasm; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Work; Xenograft procedure; antitumor effect; base; chemotherapy; cytotoxic; endoplasmic reticulum stress; improved; in vitro activity; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; novel; novel strategies; outcome forecast; overexpression; retinamide; targeted treatment; therapeutic target; treatment choice; treatment strategy

Project Summary The goal of this application is to demonstrate the feasibility of new combination treatments in several mouse models of head and neck squamous cell carcinoma (HNSCC). The long-term prognosis of patients with advanced HNSCC has shown little improvement over the last three decades. Induction chemotherapy with platinum-based compounds (e.g. cisplatin) and epidermal growth factor receptor (EGFR)-targeted therapy with cetuximab are the current chemotherapeutic treatments of choice for HNSCC, but the prolonged use of these drugs is limited by their toxicity and by the development of resistance. Tumor cell death induced by both conventional and targeted chemotherapy is often mediated by the BCL-2 family-dependent mitochondrial apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are frequently mutated or deleted in HNSCC rendering it refractory to treatment. To counter such resistance, direct therapeutic targeting of the BCL-2 family is conceptually appealing. Our long-term goal is to develop novel strategies for HNSCC treatment that directly target this intrinsic apoptotic pathway. We have investigated the cytotoxic effects of cisplatin, which is used as standard therapy for locally advanced HNSCC. As preliminary data, we have demonstrated that (1) The pro-apoptotic BCL-2 family protein Noxa is upregulated by cisplatin and is required for cisplatin-induced apoptosis in a variety of HNSCC cells; (2) Noxa overexpression enhances cell death induced by a pro-survival BCL-2/BCL-XL inhibitor, navitoclax (ABT-263) in HNSCC cells in vitro regardless of p53 status; (3) Noxa can be induced by an endoplasmic reticulum (ER)-stress inducer, fenretinide (N-4- hydroxyphenyl-retinamide). Using fenretinide as an alternative Noxa inducer, combination with fenretinide and navitoclax efficiently induce cell death in HNSCC cells that are resistant to cisplatin. Based on the above results, our central hypothesis is that simultaneous inhibition of MCL-1, BCL-XL, and BCL-2 is crucial for cell death induction during HNSCC treatment. In order to test this hypothesis, we will determine the molecular mechanisms of cisplatin + navitoclax or fenretinide + navitoclax activity in vitro (Aim 1). Furthermore, we will define a new treatment modality by demonstrating the cytotoxic and overall therapeutic effects of cisplatin + navitoclax or fenretinide + navitoclax combination in mouse models of HNSCC (Aim 2). The outcome of this project will lead to development of alternative therapeutic strategies to directly modify the cell death machinery in HNSCC.

项目摘要 该应用的目的是证明几只鼠标新组合治疗的可行性 头颈鳞状细胞癌（HNSCC）的模型。患者的长期预后 在过去的三十年中，Advanced HNSCC几乎没有进步。诱导化学疗法 基于铂的化合物（例如顺铂）和表皮生长因子受体（EGFR）靶向的治疗 西妥昔单抗是当前的HNSCC选择的化学治疗治疗方法，但长期使用这些治疗方法 药物受其毒性和抗药性发展的限制。两者诱导的肿瘤细胞死亡 常规和靶向化疗通常由Bcl-2家族依赖性线粒体介导 凋亡途径。但是，这种凋亡途径的发起人（例如p53）经常被突变或 在HNSCC中删除，使其难以治疗。为了应对这种阻力，直接治疗靶向 在概念上，Bcl-2家族很有吸引力。我们的长期目标是为HNSCC制定新颖的策略 直接针对这种内在凋亡途径的处理。我们已经研究了细胞毒性作用 顺铂，它用作局部晚期HNSCC的标准疗法。作为初步数据，我们有 证明（1）促凋亡的Bcl-2家族蛋白NOXA被顺铂上调，需要 用于顺铂诱导的多种HNSCC细胞中的凋亡； （2）NOXA过表达增强了细胞死亡 由促生存的Bcl-2/bcl-XL抑制剂，HNSCC细胞中的Navitoclax（ABT-263）诱导的体外诱导 p53状态； （3）NOXA可以由内质网（ER）诱导诱导诱导剂，fenretinide（N-4--）诱导 羟基苯基 - 雷宁酰胺）。使用芬肠丁胺作为替代性NOXA诱导剂，与芬雷丁胺的结合和 Navitoclax有效诱导对顺铂抗性的HNSCC细胞中的细胞死亡。基于上述 结果，我们的中心假设是同时抑制MCL-1，BCL-XL和BCL-2对于细胞至关重要 HNSCC治疗期间的死亡诱导。为了检验这一假设，我们将确定分子 顺铂 + Navitoclax或fenretinide + Navitoclax活性在体外的机制（AIM 1）。此外，我们会的 通过证明顺铂 +的细胞毒性和整体治疗作用来定义一种新的治疗方式 HNSCC鼠标模型中的Navitoclax或Fenretinide + Navitoclax组合（AIM 2）。结果的结果 项目将导致开发替代性治疗策略，以直接修改细胞死亡机制 在HNSCC中。