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，其5年生存率在过去几十年中没有提高。人乳头状瘤病毒（HPV）相关HNSCC的发病率正在增加，并代表了一个新出现的健康问题。目前治疗HNSCC的方法具有相当大的毒性，大约50%的患者会复发。此外，晚期或复发性鳞状细胞癌通常具有化疗耐药性。我们的长期目标是开发新的治疗药物和策略，可以单独使用，也可以与常规治疗联合使用，以提高HNSCC患者的生存率并减少毒性。Bcl-2蛋白家族的抗凋亡成员，包括Bcl-XL和Bcl-2，在大多数HNSCC中观察到过表达，并与该疾病的化疗耐药相关。在初步研究中，我们发现Bcl-XL和Bcl-2的一种小分子抑制剂ABT-737与顺铂协同作用，通过上调促凋亡的Noxa来体外杀死HNSCC细胞。此外，蛋白酶体抑制剂硼替佐米通过诱导促凋亡的Bik和Bim蛋白（作为Bcl-XL/Bcl-2的天然拮抗剂）在体外促进HNSCC细胞死亡。硼替佐米还诱导了自噬的分子特征，自噬的抑制增强了HNSCC细胞对硼替佐米诱导的细胞死亡的体外抗性。硼替佐米联合顺铂在体外表现出协同作用，并在体内增强了对HNSCC异种移植物的抗肿瘤作用。hpv阳性HNSCC细胞对硼替佐米/化疗表现出高度敏感性，初步研究结果表明，在hpv阳性细胞中，硼替佐米诱导的自噬水平升高。我们假设HNSCC对针对蛋白酶体或抗凋亡Bcl-2家族成员的药物治疗的敏感性是由自噬、HPV和诱导促凋亡Bcl-2家族成员调节的。我们提出三个具体目标。特异性目的1将通过检查自噬诱导和HPV的作用，研究赋予蛋白酶体抑制剂为基础的方案体外敏感性的细胞机制。特异性Aim 2将检测小分子抑制剂ABT-737和GX15-070单独或联合化疗靶向抗凋亡Bcl-2家族成员的体外和体内抗HNSCC作用及其相应机制。特异性目的3将研究蛋白酶体单独或联合靶向抗凋亡Bcl-2家族成员在体内抗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凋亡Bcl-2家族成员的药物敏感性的独特机制。我们也期望我们的研究结果将指导新的治疗策略的设计，并为HNSCC的协同药物组合的临床评价提供基础。

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. PUBLIC HEALTH RELEVANCE: Head and neck squamous cell carcinomas (HNSCC) are highly resistant to chemotherapy and current therapies cause adverse toxicities. The chemoresistance of these cancers stems from defective cell death pathways. Our studies will investigate novel mechanisms that regulate HNSCC cell death following treatment with agents targeting the proteasome or anti-apoptotic Bcl-2 family members. Additionally, we will examine the in vivo efficacies and mechanisms of these agents against HNSCC tumors when used alone, or in combination, seeking to exploit pathways that confer sensitivity to these agents. Our results will provide the basis for new treatment strategies for this disease.