Stress Signaling Pathways and Resistance in Colorectal Cancer

描述（由申请人提供）：该项目的转化目标是对PI3K/AKT和PDPK1/TORC之间可能导致PI3K和AKT抑制剂耐药的新型分子开关进行机制研究；以及激活不同下游信号通路的突变KRAS的氨基酸形式，这些途径可能导致对特定治疗的抗性，然后是两项新的PI3K， AKT和MEK抑制剂的临床试验，即1)适应性随机多组靶向II期临床试验和2)治疗后活检AKT抑制剂MK-2206在PTEN阴性和阳性CRC中的II期试验。本提案需要验证的假设是磷脂酰肌醇3-激酶（PI3K）和RAS信号通路在结直肠癌的发展中起主要作用，当异常调节时，结直肠癌对许多新的分子靶向治疗产生耐药性。为了验证这一假设，我们提出了三个具体的目标，包括：1)确定PI3K信号通路对CRC靶向治疗的敏感性和耐药性的替代机制；2)确定不同氨基酸取代形式的KRAS突变体交替下游信号传导对CRC靶向治疗的敏感性和耐药性的机制；3)利用患者肿瘤活检结果，在晚期结直肠癌患者中开展AKT、PI3K和mut-KRAS信号抑制剂的临床试验，以确定选择结直肠癌患者进行治疗的潜在生物标志物。在目的1和目的2中，我们将使用一组结直肠癌细胞系和等基因突变的KRAS永生化结肠上皮细胞系进行机制研究。患者源性CRC肿瘤移植物将有助于直接比较体内肿瘤对药物治疗的反应与患者对治疗的反应。该项目的长期目标是了解结直肠癌耐药的机制，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，并开发生物标志物来识别最有可能对特定治疗有反应的结直肠癌患者。

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.