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

临床研究表明一种人源化的抗表皮生长因子的单抗 受体(EGFR)西妥昔单抗在一组转移性患者中提供了客观的肿瘤反应 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。 从这种药物中受益。目前，还没有测试可以预测癌症对西妥昔单抗是否有反应。 令人信服的证据支持这样一种观点，即靶向受体酪氨酸激酶(RTK)，特别是那些 参与磷脂酰肌醇3-激酶(PI3K)信号通路，是一种高效的杀戮策略 治疗癌症。因此，抗RTK治疗的治疗反应已被证明是调节的。 PI3K通路中关键信号成分的突变状态显著影响了PI3K信号通路的活性。PI3K/Akt 信号通路驱动许多上皮性癌症，其在结直肠癌中的重要性通过以下方面得到强调 这些癌症中有20%-30%存在PIK3CA突变(编码PI3K的基因)。PI3K可以 被包括EGFR在内的多个不同的信号通路激活，并且有越来越多的证据表明 在对抗EGFR治疗敏感的癌症中，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 目标是确定将预测西妥昔单抗敏感性的标记。这将使患者能够选择 最有可能从西妥昔单抗中受益的药物。此外，这些研究还可能揭示出其他 提高西妥昔单抗敏感性的治疗靶点。我们的具体目标包括：(1)确定机制 在结直肠癌中激活PI3K/AKT通路；(2)确定PI3K的差异 西妥昔单抗敏感和耐药结直肠癌在异种移植瘤模型中的调节； 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将预测 西妥昔单抗对哪些结直肠癌有效。 西妥昔单抗是一种抗表皮生长因子受体的单抗。 常用于治疗转移性结直肠癌患者。然而，并不是所有的患者都从中受益 目前还没有可靠的分子标记来选择将受益的患者。的目标是 该项目旨在寻找这样的标记物，可用于选择最有可能对西妥昔单抗有反应的患者。

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.