The Role of PI3-Kinase Signaling Pathway in Defining Sensitivity and Resistance

PI3-激酶信号通路在定义敏感性和耐药性中的作用

基本信息

批准号：
7248216
负责人：
JEFFREY A MEYERHARDT
金额：
$ 34.79万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7248216
关键词：
1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol 4-Kinase Antibodies Apoptosis Archives Binding Proteins Bioinformatics Biological Markers Biopsy Specimen Cancer Patient Cancer cell line Catalytic Domain Cell Line Cetuximab Characteristics Class Clinical Research Clinical Trials Colon Carcinoma Colorectal Cancer Dana-Farber Cancer Institute Dose Drug Combinations Enzymes Epidermal Growth Factor Receptor Epithelial Excision Gene Expression Profile Gene Mutation Genes Genetic Genetic Transcription Genomics Goals Immunoprecipitation Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Measures Modeling Molecular Profiling Monoclonal Antibodies Mus Mutate Mutation Nude Mice PIK3CA gene Paraffin Paraffin Embedding Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phase II Clinical Trials Phosphatidylinositols Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Proliferative Index Proteins Receptor Protein-Tyrosine Kinases Regulation Resistance Resources Role Sampling Signal Pathway Signal Transduction Signaling Protein Specimen TP53 gene Testing Therapeutic Time Tissues Tumor Bank Tyrosine Western Blotting Xenograft procedure base cancer genetics caspase-3 cell growth comparative genomic hybridization human PIK3CA protein humanized monoclonal antibodies indexing insight killings kinase inhibitor metastatic colorectal preclinical study receptor response therapeutic target tumor tumor xenograft

项目摘要

Clinical studies indicate that a humanized monoclonal antibody against the Epidermal Growth Factor Receptor (EGFR), cetuximab, confers an objective tumor response in a subset of patients with metastatic colorectal cancer. However, most patients do not respond to cetuximab and therefore receive limited or no benefit from this drug. Currently, there is no test that can predict if a cancer will respond to cetuximab. Compelling evidence supports the view that targeting the receptor tyrosine kinases (RTK), particularly those that engage the Phosphoinositide 3-Kinase (PI3K) signaling pathways, is a highly effective strategy for killing for cancers. Accordingly, the therapeutic response to anti-RTK therapy has been shown to be modulated dramatically by the mutational status of key signaling components in the PI3K pathway. The PI3K/Akt signaling pathway drives many epithelial cancers, and its importance in colorectal cancers is underscored by the presence of PIK3CA mutations (the gene encoding for PI3K) in 20-30% of these cancers. PI3K can be activated by multiple different signaling pathways including EGFR, and there is accumulating evidence that EGFR regulates PI3K via distinct mechanisms in cancers sensitive to anti-EGFR therapies. We propose to study the PI3K signaling pathway, biochemically and genetically, in colorectal cancers with the translationa) goal of identifying markers that will predict sensitivity to cetuximab. This will enable the selection of patients that are most likely to benefit from cetuximab. Additionally, these studies may also reveal additional therapeutic targets to enhance cetuximab sensitivity. Our specific aims include: (1) Identify the mechanisms for activating the PI3K/AKT pathway in colorectal cancers; (2) To determine the differences in PI3K regulation between cetuximab sensitive and resistant colorectal cancers in xenograft tumor models; (3) To determine if we can use the information discovered in the first two aims to identify markers that will predict which colorectal cancers will respond to cetuximab. Brief Summary: Cetuximab, a monoclonal antibody against the Epidermal Growth Factor Receptor, is commonly used to treat patients with metastatic colorectal cancer. However, not all patients benefit from this therapy and currently there are no reliable molecular markers to select patients that will benefit. The goal of this project is to find such markers that can be used to select patients most likely to respond to cetuximab.

临床研究表明，针对表皮生长因子的人源化单克隆抗体受体 (EGFR) 西妥昔单抗可在部分转移性患者中产生客观的肿瘤反应结直肠癌。然而，大多数患者对西妥昔单抗没有反应，因此接受的治疗有限或没有受益于这种药物。目前，尚无测试可以预测癌症是否会对西妥昔单抗产生反应。令人信服的证据支持这样的观点：针对受体酪氨酸激酶 (RTK)，特别是那些参与磷酸肌醇 3-激酶 (PI3K) 信号通路，是一种高效的杀灭策略对于癌症。因此，抗 RTK 疗法的治疗反应已被证明受到调节 PI3K 通路中关键信号成分的突变状态具有显着的影响。 PI3K/Akt 信号通路驱动许多上皮癌，其在结直肠癌中的重要性如下： 20-30% 的癌症中存在 PIK3CA 突变（编码 PI3K 的基因）。 PI3K 可以由包括 EGFR 在内的多种不同信号通路激活，并且有越来越多的证据表明在对抗 EGFR 疗法敏感的癌症中，EGFR 通过不同的机制调节 PI3K。我们建议从生化和遗传学角度研究结直肠癌中的 PI3K 信号通路a) 目标是识别可预测西妥昔单抗敏感性的标记物。这将有助于选择患者最有可能从西妥昔单抗中受益。此外，这些研究还可能揭示更多增强西妥昔单抗敏感性的治疗目标。我们的具体目标包括： (1) 确定机制用于激活结直肠癌中的 PI3K/AKT 通路； (2) 确定PI3K的差异异种移植肿瘤模型中西妥昔单抗敏感和耐药结直肠癌之间的调节； (3) 至确定我们是否可以使用前两个目标中发现的信息来识别可以预测的标记哪些结直肠癌会对西妥昔单抗产生反应。简要概述：西妥昔单抗是一种针对表皮生长因子受体的单克隆抗体，通常用于治疗转移性结直肠癌患者。然而，并非所有患者都能受益于此治疗，目前没有可靠的分子标记来选择受益的患者。目标是该项目旨在寻找此类标记物，可用于选择最有可能对西妥昔单抗产生反应的患者。