Targeting the IGF Pathway for Treatment of Breast Cancer

靶向 IGF 通路治疗乳腺癌

• 批准号: 7385535
• 负责人: Adrian V Lee
• 金额: $ 15.94万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385535
• 关键词: Address; Antibodies; Apoptosis; Aromatase Inhibitors; Biological; Biological Markers; Biopsy; Blocking Antibodies; Breast Cancer Cell; Breast Cancer Treatment; Cancer cell line; Cell Proliferation; Clinical; Clinical Trials; DNA Damage; Data; Databases; Development; Dose; Exemestane; Genes; Goals; Growth; Hormones; Hybrids; In Vitro; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Ligands; Mediating; Microarray Analysis; Monoclonal Antibodies; Numbers; Other Therapy; Outcome; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Protein Overexpression; Proteins; Range; Resistance; Role; Signal Pathway; Signal Transduction; Somatomedins; Testing; Toxic effect; Tumor Cell Line; Tyrosine Kinase Inhibitor; Week; Xenograft procedure; cell growth; chemotherapy; hormone therapy; in vivo; inhibitor/antagonist; malignant breast neoplasm; neoplastic cell; novel; outcome forecast; pre-clinical; receptor; response; therapeutic target

The insulin-like growth factor receptor (IGF-IR) is hyperactive and overexpressed in many breast cancers, and preclinical data have validated IGF-IR as a therapeutic target ¿ several IGF-IR inhibitors have recently entered clinical trials. We have shown that a new IGF-IR tyrosine kinase inhibitor (TKI) can reverse IGFIR- mediated transformation in vitro and block breast cancer xenograft growth in vivo. However, development of anti-IGF-IR TKIs has long been hindered by concerns about toxicity due to blockade of the highly similar insulin receptor (InsR). Indeed, all IGF-IR TKIs developed thus far show relatively equal potency against InsR. In contrast, monoclonal antibodies that specifically block IGF-IR, without crossreacting with InsR, have recently been developed, and many show preclinical activity. We are participating in a multi-institutional Phase 2 study of the anti-IGF-IR antibody CP-751,871 in combination with the aromatase inhibitor exemestane as first-line treatment in metastatic breast cancer. However, two critical questions remain regarding the targeting of IGF-IR. First, there are no validated biomarkers that predict response to anti-IGF-IR therapy. Second, it is not clear whether InsR, which can signal to many of the same pathways as IGF-IR, and can form IGF-IR/lnsR hybrid receptors, might need to be blocked. We hypothesize that biomarkers of IGF action identified in breast cancer cells will be modified in patient biopsies following treatment with the anti-IGF-IR-specific antibody CP-751,871, and may identify patients who will respond to IGF-IR targeted therapy. However, we predict that the greatest response may require targeting of both IGF-IR and InsR. To test our hypotheses we propose the following specific aims: 1) Identify biomarkers of IGF-IR activity in breast cancer cell lines, and then determine if these biomarkers are altered in patient biopsies from clinical trials of the new IGF-IR blocking antibody CP-751,871. 2) Determine the function of InsR and hybrid IGF-IR/lnsR in breast cancer cell lines, and whether targeting of both IGF-IR and InsR is more effective than targeting IGF-IR alone. 3) Test whether intermittent, rather than continuous, dosing of an IGF-IR/lnsR TKI (BMS-536924) is effective at inhibiting breast cancer growth, and determine combinations with other therapies that provide synergistic benefit. Our long term goal is to understand the role of IGF-IR in breast cancer, and thus advance the clinical development and implementation of IGF-IR inhibitors as effective therapies in breast cancer.

胰岛素样生长因子受体（IGF-IR）在许多乳腺癌中过度活跃和过度表达， 临床前数据已验证 IGF-IR 作为治疗靶标——几种 IGF-IR 抑制剂最近已 进入临床试验。我们已经证明，一种新的 IGF-IR 酪氨酸激酶抑制剂 (TKI) 可以逆转 IGF-IR- 介导体外转化并阻止体内乳腺癌异种移植物生长。然而， 抗 IGF-IR TKI 的开发长期以来一直受到由于阻断 IGF-IR TKI 引起的毒性担忧的阻碍。 高度相似的胰岛素受体（InsR）。事实上，迄今为止开发的所有 IGF-IR TKI 均表现出相对平等 对抗 InsR 的效力。相比之下，单克隆抗体可以特异性阻断 IGF-IR，且不会发生交叉反应 与 InsR 一起，最近已开发出来，并且许多显示出临床前活性。我们正在参与 在抗 IGF-IR 抗体 CP-751,871 与 芳香酶抑制剂依西美坦作为转移性乳腺癌的一线治疗。然而，两个关键 关于 IGF-IR 的靶向性仍存在疑问。首先，没有经过验证的生物标志物可以预测 对抗 IGF-IR 治疗的反应。其次，尚不清楚 InsR 是否可以向许多人发出信号。 与 IGF-IR 相同的途径，并且可以形成 IGF-IR/lnsR 混合受体，可能需要被阻断。我们 假设在乳腺癌细胞中鉴定的 IGF 作用的生物标志物将在 使用抗 IGF-IR 特异性抗体 CP-751,871 治疗后对患者进行活检，并且可能 确定对 IGF-IR 靶向治疗有反应的患者。然而，我们预测最大的 响应可能需要同时靶向 IGF-IR 和 InsR。为了检验我们的假设，我们提出 以下具体目标： 1) 鉴定乳腺癌细胞系中 IGF-IR 活性的生物标志物，然后 确定新 IGF-IR 阻断的临床试验中患者活检中的这些生物标志物是否发生改变 抗体 CP-751,871。 2)确定InsR和杂交IGF-IR/lnsR在乳腺癌细胞系中的功能， 以及同时靶向 IGF-IR 和 InsR 是否比单独靶向 IGF-IR 更有效。 3）测试 IGF-IR/lnsR TKI (BMS-536924) 的间歇给药（而非连续给药）是否有效 抑制乳腺癌生长，并确定与其他提供协同作用的疗法的组合 益处。我们的长期目标是了解 IGF-IR 在乳腺癌中的作用，从而推进 IGF-IR 抑制剂作为乳腺癌有效疗法的临床开发和实施。