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

• 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
• 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

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，抗表皮生长因子的人源化单克隆抗体 受体（EGFR），西妥昔单抗，在转移性肿瘤患者的一个子集中赋予客观的肿瘤反应， 结肠直肠癌然而，大多数患者对西妥昔单抗无反应，因此接受有限或不接受西妥昔单抗治疗。 受益于这种药物。目前，没有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，靶向受体酪氨酸激酶（RTK），特别是那些 参与磷酸肌醇3-激酶（PI 3 K）信号通路，是一种非常有效的杀死策略， 治疗癌症因此，已显示对抗RTK疗法的治疗响应被调节， PI 3 K通路中关键信号传导组分的突变状态显著地影响了这一过程。述pi 3 k/Akt 信号通路驱动许多上皮癌，并且其在结直肠癌中的重要性被以下因素强调： PIK 3CA突变（编码PI 3 K的基因）在这些癌症中的20-30%中存在。PI 3 K可以是 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， EGFR通过对抗EGFR疗法敏感的癌症中的不同机制调节PI 3 K。我们建议 研究PI 3 K信号通路，生物化学和遗传学，在结直肠癌与预防a） 目的是确定预测西妥昔单抗敏感性的标志物。这将使患者的选择 最有可能从西妥昔单抗中获益。此外，这些研究还可能揭示出更多的 治疗靶点，以增强西妥昔单抗的敏感性。我们的具体目标包括：（1）确定机制 在大肠癌中激活PI 3 K/AKT通路;（2）确定PI 3 K 异种移植肿瘤模型中西妥昔单抗敏感性和耐药性结直肠癌之间的调节;（3） 确定我们是否可以使用在前两个目标中发现的信息来识别可以预测 哪些结肠直肠癌会对西妥昔单抗有反应。 简介：西妥昔单抗是一种抗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，并非所有患者都能从中受益。 目前还没有可靠的分子标记物来选择将受益的患者。的目标 这个项目是为了找到这样的标记物，可以用来选择最有可能对西妥昔单抗有反应的患者。