Molecular Targeting Strategies in HNSCC

HNSCC 的分子靶向策略

• 批准号: 8259089
• 负责人: Daniel E Johnson
• 金额: $ 30.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259089
• 关键词: Accounting; Apoptosis; Apoptotic; Autophagocytosis; BH3 Domain; Bortezomib; Cell Death; Cell Death Signaling Process; Cell Line; Cells; Cisplatin; Disease; Drug Combinations; Equilibrium; Exhibits; Failure; Family member; Foundations; Goals; Head and Neck Squamous Cell Carcinoma; Health; Human; Human Papillomavirus; In Vitro; Incidence; Malignant Epithelial Cell; Malignant Neoplasms; Molecular; Molecular Target; Noxae; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pre-Clinical Model; Process; Proteasome Inhibitor; Protein Family; Proteins; Radiosurgery; Recurrence; Regimen; Resistance; Role; Staging; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Toxic effect; United States; Up-Regulation; Virus Activation; Xenograft procedure; base; chemotherapy; conventional therapy; design; improved; in vivo; inhibitor/antagonist; killings; member; multicatalytic endopeptidase complex; neoplastic cell; novel; novel therapeutics; overexpression; pro-apoptotic protein; public health relevance; research clinical testing; small molecule; standard care; stem; success; synergism; treatment strategy; tumor; tumor xenograft

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.

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是一种常见的人类恶性肿瘤，5年生存率在过去几十年中没有改善。人乳头状瘤病毒（HPV）相关的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HNSCC的治疗与相当大的毒性相关，大约50%的患者复发。此外，晚期或复发的HNSCC肿瘤通常具有化学抗性。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，或与常规治疗相结合，以提高HNSCC患者的生存率并降低毒性。 Bcl-2蛋白家族的抗凋亡成员（包括Bcl-XL和Bcl-2）的过表达在大多数HNSCC中观察到，并且与该疾病中的化疗抗性相关。在初步研究中，我们已经表明Bcl-XL和Bcl-2的小分子抑制剂ABT-737与顺铂协同作用，通过涉及促凋亡Noxa上调的过程在体外杀死HNSCC细胞。此外，蛋白酶体抑制剂硼替佐米通过诱导促凋亡Bik和Bim（充当Bcl-XL/Bcl-2的天然拮抗剂的蛋白质）在体外促进HNSCC细胞死亡。硼替佐米还诱导自噬的分子特征，并且自噬的抑制增强了HNSCC细胞对硼替佐米诱导的细胞死亡的体外抗性。硼替佐米和顺铂的组合在体外表现出协同作用，并增强了对HNSCC异种移植物的体内抗肿瘤作用。HPV阳性HNSCC细胞对硼替佐米/化疗的敏感性升高，初步研究结果表明HPV阳性细胞中硼替佐米诱导的自噬水平升高。我们假设HNSCC对包含靶向蛋白酶体或抗凋亡Bcl-2家族成员的药物的治疗的敏感性受到自噬、HPV和促凋亡Bcl-2家族成员的诱导的调节。我们提出三个具体目标。具体目标1将通过检查自噬诱导和HPV的作用，研究赋予蛋白酶体通道为基础的方案体外敏感性的细胞机制。具体目标2将检查体外和体内抗HNSCC作用以及相应的机制，这些作用是由小分子抑制剂ABT-737和GX 15 - 070单独和与化疗联合靶向抗凋亡Bcl-2家族成员引起的。具体目标3将研究蛋白酶体靶向单独和与抗凋亡Bcl-2家族成员靶向组合产生的体内抗HNSCC肿瘤作用和机制。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。我们还希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。 公共卫生关系：头颈部鳞状细胞癌（HNSCC）对化疗具有高度耐药性，目前的治疗会引起不良毒性。这些癌症的化学抗性源于有缺陷的细胞死亡途径。我们的研究将探讨新的机制，调节HNSCC细胞死亡后的治疗药物靶向蛋白酶体或抗凋亡Bcl-2家族成员。此外，我们将研究这些药物单独或联合使用时对HNSCC肿瘤的体内疗效和机制，寻求利用赋予这些药物敏感性的途径。我们的研究结果将为这种疾病的新治疗策略提供基础。