Tumor-based Modulators of Antibody-Dependent Cellular Cytotoxicity (ADCC)

描述（由申请方提供）：基于抗体的特异性和多功能性，单克隆抗体治疗是抗癌药物的重要组成部分。单克隆抗体的抗肿瘤作用源自两种主要作用机制：调节信号转导和存活，以及诱导针对肿瘤细胞的免疫应答。某些单克隆抗体可以通过Fc受体介导的相互作用与免疫效应细胞（主要是自然杀伤（NK）细胞）结合， 依赖性细胞毒性（ADCC）。临床前和临床证据表明，ADCC对于许多治疗性单克隆抗体的抗肿瘤应答是重要的。然而，像大多数癌症治疗剂一样，肿瘤对单克隆抗体疗法产生抗性。已经在致癌信号网络中鉴定了遗传抗性决定簇-例如，在EGFR信号网络中-其调节可以增强治疗反应-例如，EGFR靶向小分子或单克隆抗体-基于增殖减少和细胞死亡增强。然而，似乎耐药决定因素也可以调节肿瘤对ADCC的反应。这些决定因素尚未确定。该项目旨在阐明ADCC的新的基于肿瘤的分子决定簇，这将增强对单克隆抗体治疗的理解和疗效。具体目标集中在评估两种假定的耐药机制：可能促进逃避ADCC细胞毒性作用的致癌信号网络;以及基于肿瘤的免疫突触形成调节以逃避ADCC。高通量功能基因组学筛选用于评估其敲低调节ADCC的基因。验证研究将用于确认筛选结果，然后进行体外研究以确定ADCC调节的具体机制。动物模型研究将验证那些分子决定因素，其调节影响体内ADCC。整个过程的重点是发现ADCC的调节机制，增强单克隆抗体疗法对人类恶性肿瘤靶向治疗的疗效。

DESCRIPTION (provided by applicant): Monoclonal antibody therapy is an important component of the anti-cancer armamentarium, based on the specificity and versatility of antibodies. The anti-tumor effects of monoclonal antibodies are derived from two main mechanisms of action: modulating signal transduction and survival within, and inducing immune responses against tumor cells. Certain monoclonal antibodies can engage immune effectors- primarily natural killer (NK) cells-through Fc receptor-mediated interactions that induce antibody- dependent cellular cytotoxicity (ADCC). Preclinical and clinical evidence suggests that ADCC is important for anti-tumor responses for many therapeutic monoclonal antibodies. However, like most cancer therapeutics, tumors develop resistance to monoclonal antibody therapies. Genetic resistance determinants have been identified in oncogenic signaling networks-e.g., in the EGFR signaling network- whose modulation can enhance therapeutic response-e.g., EGFR-targeted small molecules or monoclonal antibodies-based on decrease in proliferation and enhanced cell death. However, it is plausible that resistance determinants could modulate tumor response to ADCC as well. Such determinants have not been identified. This project aims to elucidate novel tumor-based molecular determinants of ADCC that will enhance understanding and efficacy of monoclonal antibody therapy. The specific aims focus on assessing two putative mechanisms of resistance: oncogenic signaling networks that may promote escape from the cytotoxic effects of ADCC; and tumor-based modulation of immune synapse formation to evade ADCC. High-throughput functional genomics screening is used to assess genes whose knockdown modulates ADCC. Validation studies will be used to confirm screening results, followed by in vitro studies to identify specific mechanisms of ADCC modulation. Animal model studies will verify those molecular determinants whose modulation affects ADCC in vivo. The overall process is focused on discovering mechanisms of modulation of ADCC that enhance efficacy of monoclonal antibody therapies for the targeted treatment of human malignancies.