Predictive Biomarkers and Mechanism of Action for Anti-IGF1R Agents for Cancer

1.了解IGF 1 R抗体对癌症的选择性作用：我们的结果 揭示了癌症中IGF 1 R水平的高度变化。此外，还有一个直接 癌细胞中IGF 1 R水平与抗增殖反应之间的相关性 抗IGF 1 R抗体。表达升高的IGF 1 R的癌细胞（30，000拷贝/ 细胞）对IGF 1 R抗体非常敏感。2.提供一种作用机制， 抗IGF 1 R药物：我们的数据表明，肿瘤细胞对IGF 1 R药物有高度依赖性。 升高的IGF 1 R用于维持体外和体内的高AKT信号传导。的抑制 IGF 1 R与治疗性抗体联合使用导致AKT信号转导的显著减少， IGF 1 R升高的肿瘤细胞。我们确定了第一个模型系统，其中IGF 1 R抗体 诱导肿瘤细胞快速死亡。我们的研究结果说明了一种独特的机制， 抗IGF 1 R诱导的癌细胞死亡。我们的数据进一步显示了IGF 1 R的双重功能， 肿瘤生长和存活。此外，IGF 1 R升高在我们的肿瘤模型中是致病的。3. 鉴定和验证预测抗IGF 1 R药物应答的生物标志物：我们的结果 表明IGF 1 R水平与IGF 1 R的抗增殖活性之间存在直接相关性。 抗IGF 1 R剂。我们的数据进一步表明，IGF 1 R的升高预测了对 基于IGF 1 R抗体的治疗剂。4.为了使生物标志物的临床研究能够在 抗IGF 1 R药物临床试验的相关研究：我们已经开发了一系列 免疫测定，以支持抗IGF 1 R治疗的临床研究，包括 能够精确定量IGF 1 R高定量夹心免疫测定法 标本，以及一个非常实用的免疫组织化学测定能够实施 用的是试验样本的组织切片

1. To understand the selective action of IGF1R antibodies against cancers: Our results revealed a high degree of variation of IGF1R levels in cancers. In addition, there is a direct correlation between the levels of IGF1R in cancer cells and the anti-proliferative response to anti-IGF1R antibodies. Cancer cells expressing elevated IGF1R (>30,000 copies per cells) are very sensitive to IGF1R antibody. 2. To provide a mechanism of action for anti-IGF1R agents: Our data suggest that tumor cells have a high degree of dependence on elevated IGF1R for maintaining high AKT signaling, both in vitro and in vivo. The inhibition of IGF1R with therapeutic antibodies resulted in a dramatic reduction of AKT signaling in tumor cells with elevated IGF1R. We identified the first model system in which IGF1R antibody induces rapid tumor cell death. Our results illustrate a unique mechanism of anti-IGF1R-induced cancer cell death. Our data further showed a dual function for IGF1R in tumor growth and survival. Moreover, the elevated IGF1R is pathogenic in our tumor model. 3. To identify and validate biomarkers predictive of responses to anti-IGF1R agents: Our results indicated a direct correlation between the IGF1R levels and the anti-proliferative activity of anti-IGF1R agents. Our data further suggests that elevated IGF1R predicts the response to IGF1R antibody-based therapeutics. 4. To enable the clinical investigation of biomarkers in correlative studies in clinical trials with anti-IGF1R agents: We have developed a range of immunoassays to support the clinical investigation of anti-IGF1R therapeutics, including a highly quantitative sandwich immunoassay capable of precise quantification of IGF1R in specimens, as well as a very practical immunohistochemistry assay capable of implementation with tissue slides from trial samples.