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

项目摘要 这项申请的目的是在几只小鼠身上证明新的联合治疗的可行性 头颈部鳞状细胞癌模型。慢性阻塞性肺疾病患者的远期预后 在过去的三十年里，先进的HNSCC几乎没有什么进步。诱导性化疗 铂类化合物(如顺铂)和表皮生长因子受体(EGFR)靶向治疗 西妥昔单抗是目前治疗HNSCC的首选化疗药物，但长期使用这些药物 药物受到其毒性和耐药性发展的限制。两者均可诱导肿瘤细胞死亡 常规和靶向化疗通常由依赖bcl2家族的线粒体介导。 细胞凋亡途径。然而，这种凋亡途径的启动者，如p53，经常发生突变或 在HNSCC中被删除，使其难以治疗。为了对抗这种耐药性，直接治疗靶向 BCL-2家族的基因在概念上很有吸引力。我们的长期目标是为HNSCC开发新的战略 直接针对这一内在的细胞凋亡途径的治疗。我们已经研究了它的细胞毒性效应。 顺铂，用于局部晚期HNSCC的标准治疗。作为初步数据，我们有 结果表明：(1)促凋亡的bcl2家族蛋白noxa被顺铂上调，并且是必需的。 用于顺铂诱导多种HNSCC细胞的凋亡；(2)NoxA过表达促进细胞死亡 促生存型bcl2/bclxl抑制剂Navitoclax(ABT-263)对HNSCC细胞的体外诱导作用 (3)NOXA可被内质网应激诱导剂芬维甲素(N-4-NOXA)诱导。 羟基苯基维甲酰胺)。用非维甲酸作为NOXA的替代诱导剂，与非维甲酸联合使用 Navitoclax可有效诱导对顺铂耐药的HNSCC细胞死亡。基于以上几点 结果，我们的中心假设是同时抑制MCL-1、BCL-XL和BCL-2对细胞至关重要 HNSCC治疗过程中的死亡诱导。为了验证这一假说，我们将确定分子 顺铂+长春花碱或非维甲酸+长春花碱的体外作用机制(目标1)。此外，我们还将 通过展示顺铂+的细胞毒性和整体疗效来定义新的治疗模式 NAVITOCLAX或非维甲酸+NAVITOCLAX联合治疗HNSCC小鼠模型(目标2)。这样做的结果是 该项目将导致开发替代治疗策略，以直接修改细胞死亡机制 在HNSCC。

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.