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

1. 为了了解IGF1R抗体对癌症的选择性作用：我们的研究结果揭示了癌症中IGF1R水平的高度变化。此外，癌细胞中IGF1R的水平与抗IGF1R抗体的抗增殖反应有直接的相关性。表达IGF1R升高的癌细胞（每个细胞超过30,000个拷贝）对IGF1R抗体非常敏感。2. 提供抗IGF1R药物的作用机制：我们的数据表明，肿瘤细胞在体外和体内都高度依赖IGF1R的升高来维持高AKT信号。治疗性抗体抑制IGF1R导致IGF1R升高的肿瘤细胞中AKT信号的显著减少。我们发现了第一个IGF1R抗体诱导肿瘤细胞快速死亡的模型系统。我们的研究结果说明了抗igf1r诱导的癌细胞死亡的独特机制。我们的数据进一步显示了IGF1R在肿瘤生长和存活中的双重功能。此外，升高的IGF1R在我们的肿瘤模型中具有致病性。3. 鉴定和验证预测抗IGF1R药物反应的生物标志物：我们的研究结果表明，IGF1R水平与抗IGF1R药物的抗增殖活性之间存在直接相关性。我们的数据进一步表明，升高的IGF1R预测了对基于IGF1R抗体的治疗的反应。4. 为了在抗IGF1R药物的临床试验中进行相关研究的生物标志物的临床研究：我们已经开发了一系列免疫分析来支持抗IGF1R治疗的临床研究，包括能够精确定量样品中IGF1R的高定量三明治免疫分析，以及能够使用试验样品的组织载玻片实施的非常实用的免疫组织化学分析。

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 (more than 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.