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 本申请的目的是证明新的组合治疗在几种小鼠中的可行性。 头颈部鳞状细胞癌（HNSCC）模型。患者远期预后 在过去的三十年中，晚期HNSCC几乎没有表现出改善。诱导化疗 基于铂的化合物（例如顺铂）和表皮生长因子受体（EGFR）靶向疗法， 西妥昔单抗是目前HNSCC的化疗治疗选择，但长期使用这些 药物受到其毒性和耐药性发展的限制。两者均诱导肿瘤细胞死亡 常规和靶向化疗通常由BCL-2家族依赖性线粒体介导， 凋亡途径然而，这种凋亡途径的启动子，如p53，经常被突变或突变。 在HNSCC中缺失，使其对治疗难治。为了对抗这种耐药性，直接治疗靶向 BCL-2家族在概念上很有吸引力。我们的长期目标是为HNSCC开发新的策略 直接靶向这种内在凋亡途径的治疗。我们研究了 顺铂，其用作局部晚期HNSCC的标准疗法。作为初步数据， 证明（1）促凋亡BCL-2家族蛋白Noxa被顺铂上调， 顺铂诱导的多种HNSCC细胞凋亡;（2）Noxa过表达增强细胞死亡 由促存活BCL-2/BCL-XL抑制剂navitoclax（ABT-263）在体外HNSCC细胞中诱导， p53状态;（3）Noxa可由内质网（ER）应激诱导剂芬维A胺（N-4- 羟苯基-视黄酰胺）。使用芬维A胺作为替代的Noxa诱导剂，与芬维A胺和 navitoclax有效地诱导对顺铂具有抗性的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对细胞增殖至关重要。 HNSCC治疗期间的死亡诱导。为了验证这一假设，我们将确定分子 顺铂+ navitoclax或芬维A胺+ navitoclax体外活性的机制（目的1）。此外，我们将 通过证明顺铂+的细胞毒性和总体治疗效果，定义一种新的治疗方式 navitoclax或芬维A胺+ navitoclax组合在HNSCC小鼠模型中的作用（目的2）。这场 该项目将导致替代治疗策略的发展，直接修改细胞死亡机制 在HNSCC。