Molecular Targeting Strategies in HNSCC

描述(申请人提供)：头颈部鳞状细胞癌(HNSCCs)是一种常见的人类恶性肿瘤，五年存活率在过去几十年中没有改善。与人乳头瘤病毒(HPV)相关的HNSCC的发病率正在增加，并代表着一个新的健康问题。目前治疗HNSCC的方法与相当大的毒性有关，大约50%的患者复发。此外，晚期或复发的HNSCC肿瘤通常是化疗耐药的。我们的长期目标是开发新的治疗药物和策略，这些药物和策略可以单独使用，也可以与常规治疗结合使用，以提高HNSCC患者的存活率并减少毒性。在大多数HNSCC中，Bcl2蛋白家族的抗凋亡成员，包括Bclxl和Bcl2的过度表达与HNSCC的化疗耐药有关。在初步研究中，我们已经证明了一种小分子的Bclxl和Bcl2的抑制剂ABT-737，在体外与顺铂协同作用，通过上调促凋亡的Noxa的过程，在体外杀死HNSCC细胞。此外，蛋白酶体抑制剂Bortezomib在体外通过诱导促凋亡的Bik和Bim促进HNSCC细胞死亡，Bik和Bim是Bclxl/Bcl2的天然拮抗剂。Bortezomib还诱导了自噬的分子特征，抑制自噬增强了HNSCC细胞对Bortezomib诱导的细胞死亡的体外抵抗力。硼替佐米联合顺铂在体外表现出协同作用，在体内增强了对HNSCC移植瘤的抗肿瘤作用。HPV阳性的HNSCC细胞对Bortezomib/化疗表现出高度的敏感性，初步研究结果表明，在HPV阳性的细胞中，Bortezomib诱导的自噬水平增加。我们假设HNSCC对靶向蛋白酶体或抗凋亡的Bcl2家族成员的药物的敏感性受自噬、HPV和诱导促凋亡的Bcl2家族成员的调节。我们提出了三个具体目标。具体目标1将通过检测自噬诱导和人乳头瘤病毒的作用，研究体外对基于蛋白酶体抑制剂的方案的敏感性的细胞机制。《特定目标2》将研究小分子抑制剂ABT-737和GX15-070单独和联合化疗靶向抗凋亡的Bcl2家族成员在体外和体内的抗HNSCC作用，以及相应的机制。特异靶向3将在体内研究蛋白酶体靶向、单独靶向和联合靶向抗凋亡的Bcl-2家族成员抗HNSCC肿瘤的作用和机制。我们预计，我们的研究结果将阐明控制HNSCC细胞和肿瘤对靶向蛋白酶体或抗细胞凋亡的Bcl-2家族成员的药物敏感性的独特机制。我们还期望我们的结果将指导新的治疗策略的设计，并为HNSCC协同药物组合的临床评估提供基础。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinomas (HNSCCs) are a common human malignancy with 5-year survival rates that have not improved for the past several decades. The incidence of human papilloma virus (HPV)- associated HNSCC is increasing and represents an emerging health problem. Current therapies for HNSCC are associated with considerable toxicities and roughly 50% of patients suffer recurrence. Moreover, advanced stage or recurring HNSCC tumors are frequently chemoresistant. Our long-term goal is to develop novel therapeutic agents and strategies that can be used alone, or in combination with conventional treatments, to improve survival and reduce toxicities in HNSCC patients. Overexpression of anti-apoptotic members of the Bcl-2 protein family, including Bcl-XL and Bcl-2, is observed in a majority of HNSCC and correlates with chemotherapy resistance in this disease. In preliminary studies we have shown that a small molecule inhibitor of Bcl-XL and Bcl-2, ABT-737, synergized with cisplatin to kill HNSCC cells in vitro, via a process involving upregulation of pro-apoptotic Noxa. Additionally, the proteasome inhibitor bortezomib promoted HNSCC cell death in vitro, via induction of pro-apoptotic Bik and Bim, proteins that act as natural antagonists of Bcl-XL/Bcl-2. Bortezomib also induced molecular features of autophagy, and suppression of autophagy enhanced the in vitro resistance of HNSCC cells to bortezomib- induced cell death. The combination of bortezomib and cisplatin exhibited synergism in vitro and enhanced anti-tumor effects against HNSCC xenografts in vivo. HPV-positive HNSCC cells exhibited heighted sensitivity to bortezomib/chemotherapy, and preliminary findings suggest elevated levels of bortezomib-induced autophagy in HPV-positive cells. We hypothesize that HNSCC sensitivity to treatments that incorporate agents targeting the proteasome or anti-apoptotic Bcl-2 family members is modulated by autophagy, HPV, and induction of pro-apoptotic Bcl-2 family members. We propose three Specific Aims. Specific Aim 1 will investigate cellular mechanisms conferring in vitro sensitivity to proteasome inhibitor-based regimens, by examining the roles of autophagy induction and HPV. Specific Aim 2 will examine in vitro and in vivo anti- HNSCC effects, and corresponding mechanisms, resulting from targeting of anti-apoptotic Bcl-2 family members with the small molecule inhibitors ABT-737 and GX15-070, alone and in combination with chemotherapy. Specific Aim 3 will investigate in vivo anti-HNSCC tumor effects and mechanisms resulting from proteasome targeting, alone and in combination with targeting of anti-apoptotic Bcl-2 family members. We anticipate that results from our studies will elucidate unique mechanisms that control the sensitivities of HNSCC cells and tumors to agents targeting the proteasome or anti-apoptotic Bcl-2 family members. We also expect that our results will guide the design of novel treatment strategies and provide the basis for clinical evaluation of synergistic drug combinations in HNSCC.