The adaptive kinome in pancreatic cancer

胰腺癌中的适应性激酶组

• 批准号: 8859584
• 负责人: GARY L. JOHNSON
• 金额: $ 57.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8859584
• 关键词: Accounting; Affinity; Aftercare; Biopsy Specimen; Bypass; Cancer Patient; Cancer cell line; Cell Line; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Clinic; Clinical Research; Clinical Trials; Combined Modality Therapy; Computer Simulation; Computing Methodologies; Cytotoxic agent; DNA Sequence Alteration; Data; Effectiveness; Epidemiologic Studies; Genetic Engineering; Genetically Engineered Mouse; Genomics; Goals; Home environment; Knowledge; MEK inhibition; MEKs; Malignant neoplasm of pancreas; Measures; Metformin; Methods; Modeling; Mutation; Nodal; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Pre-Clinical Model; Proteomics; Regimen; Resistance; Resistance development; Risk; Running; Secondary to; Signal Pathway; Signal Transduction; System; Technology; Testing; Therapeutic; Toxic effect; Xenograft Model; Xenograft procedure; base; cancer therapy; chemotherapy; cohort; combinatorial; diabetic patient; exome sequencing; gemcitabine; inhibitor/antagonist; innovative technologies; kinase inhibitor; knowledge base; mouse model; neoplastic cell; novel; pancreatic cancer cells; preclinical study; prevent; public health relevance; research clinical testing; response; tumor; tumor growth

 DESCRIPTION (provided by applicant): Few kinase mutations have been found in pancreatic cancer despite whole exome sequencing studies. Therefore rationally devising novel kinase inhibitor combination therapies requires knowledge of kinome activity, not simply measuring the effect of an inhibitor on one or a few kinases in a pathway. In addition, it is clear that targetin combinations of kinases will be more efficacious than focusing on any single kinase or pathway due to inevitable resistance development. Acquired or selected mutations can decrease affinity for therapeutic kinase inhibitors, but resistance also develops by alternate kinase activation, bypassing the action of a highly specific inhibitor. We have developed an innovative technology to assess the baseline activation state of the kinome and the dynamic changes in kinome activity following targeted inhibition of specific kinases. In this proposal we use this technology to better understand the adaptive kinome response to novel agents that target signaling pathways. As most clinical trials will move forward with a novel agent in combination with a cytotoxic agent, we will also determine the adaptive kinome in response to current cytotoxic agents. We will use a combination of preclinical models including genetically engineered models, patient-derived xenografts and a pilot clinical trial to accomplish this. Thus we will establish a vast knowledgebase of the adaptive kinome that will allow us to determine rational combinations of cytotoxic drugs with novel agents. We will also develop computational methods to handle this large data in order to predict effective combinations to move forward into clinical trial.

 描述(由申请人提供)：尽管进行了完整的外显子组测序研究，但在胰腺癌中发现的激酶突变很少。因此，合理地设计新的激酶抑制剂联合疗法需要了解动态组的活性，而不是简单地测量抑制剂对一个或几个途径中的一个或几个激酶的影响。此外，很明显，由于不可避免的耐药性的发展，靶标蛋白联合使用的激酶将比专注于任何单一的激酶或途径更有效。获得性或选择性突变会降低对治疗性激酶抑制剂的亲和力，但耐药性也会通过交替激活激酶而产生，绕过高度特异的抑制剂的作用。我们开发了一种创新的技术来评估动态组的基线激活状态，以及在靶向抑制特定的激酶后动态组活性的动态变化。在这份提案中，我们使用了这项技术 为了更好地了解针对信号通路的新制剂的适应性动态组反应。由于大多数临床试验将通过一种新的药物与细胞毒剂的组合来推进，我们还将确定对现有的细胞毒药的适应性激动组。我们将使用临床前模型的组合，包括基因工程模型、患者来源的异种移植和试点临床试验来实现这一点。因此，我们将建立一个庞大的适应性基因组知识库，这将使我们能够确定细胞毒药物与新型药物的合理组合。我们还将开发计算方法来处理这些大型数据，以预测有效的组合进入临床试验。