Stress Signaling Pathways and Resistance in Colorectal Cancer

结直肠癌的应激信号通路和抵抗力

基本信息

批准号：
8420658
负责人：
Scott Kopetz
金额：
$ 31.61万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-18 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420658
关键词：
1-Phosphatidylinositol 3-Kinase AKT Signaling Pathway Accounting Aftercare Amino Acid Substitution Amino Acids Animals Biological Markers Biopsy Biopsy Specimen Cancer Etiology Cancer Model Cancer Patient Cancer cell line Cell Line Cessation of life Clinical Clinical Trials Colon Colorectal Cancer Combined Modality Therapy Conduct Clinical Trials Development Drug Targeting Epithelial Cells Exhibits Goals Human KRAS2 gene Lead Lipids MEKs Mediating Membrane Modeling Molecular Mus Mutation PH Domain PTEN gene Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Phosphatidylinositols Phosphoric Monoester Hydrolases Play Principal Investigator Protein Array Protein Kinase Proto-Oncogene Proteins c-akt Randomized Refractory Research Personnel Resistance Role Sgk protein Signal Pathway Signal Transduction Stress Testing Therapeutic Xenograft procedure cancer therapy design effective therapy in vivo inhibitor/antagonist mutant novel novel strategies programs public health relevance resistance mechanism response therapy resistant tumor

项目摘要

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.

描述（由申请人提供）：该项目的转化目标是对 PI3K/AKT 和 PDPK1/TORC 之间的新型分子开关进行机制研究，该分子开关可能导致对 PI3K 和 AKT 抑制剂的耐药性；突变 KRAS 的氨基酸形式激活不同的下游信号通路，可能导致对特定疗法的耐药性，然后是两项使用 PI3K、AKT 和 MEK 抑制剂的新临床试验，即 1) 一项自适应随机多臂靶向 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。本提案要测试的假设是，磷脂酰肌醇 3 激酶 (PI3K) 和 RAS 信号通路在 CRC 发展中发挥着重要作用，当异常调节时，会使 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检验这一假设，包括：1）确定 PI3K 信号传导替代途径对 CRC 靶向治疗敏感性和耐药性的机制； 2) 确定不同氨基酸取代形式的突变型 KRAS 的替代下游信号传导机制，以提高对 CRC 靶向治疗的敏感性和耐药性； 3) 利用患者肿瘤活检结果，在晚期 CRC 患者中进行 AKT、PI3K 和 mut-KRAS 信号抑制剂的临床试验，以确定潜在的生物标志物，用于选择 CRC 患者进行治疗。我们将在目标 1 和 2 的机制研究中使用一组 CRC 细胞系和同基因突变 KRAS 永生化结肠上皮细胞系。源自患者的 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治疗的反应目标3。该项目的长期目标是加深对CRC治疗耐药机制的了解，以便我们能够设计更有效的疗法，确定新的治疗药物靶点，并开发生物标志物确定最有可能对特定疗法产生反应的结直肠癌患者。