Stress Signaling Pathways and Resistance in Colorectal Cancer

描述（申请人提供）：本项目的翻译目标是对PI 3 K/AKT和PDPK 1/TORC之间的新型分子开关进行机制研究，该开关可能导致对PI 3 K和AKT抑制剂的耐药性;以及激活不同下游信号通路的突变KRAS的氨基酸形式，这些下游信号通路可能导致对特定疗法的耐药性，然后是两项新的PI 3 K临床试验，AKT和MEK抑制剂，即1）一项适应性随机化多臂靶向II期临床试验和2）AKT抑制剂MK-2206在PTEN阴性和阳性CRC中的治疗后活检II期试验。本提案中待检验的假设是，磷脂酰肌醇3-激酶（PI 3 K）和RAS信号通路在CRC发展中起主要作用，并且当异常调节时，使CRC对许多新的分子靶向治疗产生耐药性。提出了三个具体目标来验证这一假设，包括：1）确定PI 3 K信号传导的替代途径对CRC靶向治疗的敏感性和抗性的机制; 2）确定不同氨基酸取代形式的突变KRAS的替代下游信号传导对CRC靶向治疗的敏感性和抗性的机制;和3）使用患者肿瘤活检结果在患有晚期CRC的患者中进行AKT、PI 3 K和mut-KRAS信号传导抑制剂的临床试验，以鉴定用于选择患有CRC的患者进行治疗的潜在生物标志物。我们将使用一组CRC细胞系和等基因突变KRAS永生化结肠上皮细胞系进行目的1和2的机制研究。患者来源的CRC肿瘤移植物将有助于直接比较肿瘤对体内药物治疗的反应与患者对目标3中治疗的反应。该项目的长期目标是了解CRC治疗耐药的机制，以便我们可以设计更有效的治疗方法，确定新的治疗药物靶点，并开发生物标志物，以识别最有可能对特定治疗产生反应的CRC患者。

DESCRIPTION (provided by applicant): The translational goal of this project is to conduct mechanistic studies on a novel molecular switch between PI3K/AKT and PDPK1/TORC that could lead to resistance to PI3K and AKT inhibitors; and of amino acid forms of mutant KRAS that activate different downstream signaling pathways that could lead to resistance to specific therapies and then two novel clinical trials with PI3K, AKT and MEK inhibitors, namely 1) an adaptively randomized multiarm targeted Phase II clinical trial and 2) a post-treatment biopsy Phase II trial of the AKT inhibitor MK-2206 in PTEN negative and positive CRC. The hypothesis to be tested in this proposal is that the phosphatidylinositol 3-kinase (PI3K) and RAS signaling pathways play major roles in CRC development and when aberrantly regulated make CRC resistant to many new molecularly targeted therapies. Three specific aims are proposed to test this hypothesis, and include: 1) determine the mechanisms of alternate pathways of PI3K signaling for sensitivity and resistance to targeted therapy for CRC; 2) determine the mechanisms of alternate downstream signaling by different amino acid-substituted forms of mutant KRAS for sensitivity and resistance to targeted therapy for CRC; and 3) conduct clinical trials of inhibitors of AKT, PI3K, and mut-KRAS signaling in patients with advanced CRC using patient tumor biopsy results to identify potential biomarkers for selecting patients with CRC for therapy. We will use a panel of CRC cell lines and isogenic mutant KRAS immortalized colonic epithelial cell lines in mechanistic studies in aims 1 and 2. Patient-derived CRC tumorgrafts will facilitate a direct comparison of tumor responses to drug treatment in vivo with patient response to therapy in aim 3. The long-term goal of this project is to develop an understanding of the mechanisms of resistance to therapy for CRC so that we can design more effective therapies, identify new drug targets for treatment, and develop biomarkers that identify CRC patients most likely to have responses to specific therapies.