Therapeutic Strategies for Patients With BRAF Mutant Colorectal Cancer

BRAF 突变结直肠癌患者的治疗策略

• 批准号: 8903791
• 负责人: David S. Hong
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-04 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903791
• 关键词: Aftercare; BRAF gene; Biological Markers; Biology; Cancer Center; Cancer Etiology; Cell Line; Cell Proliferation; Cell Survival; Cessation of life; Cetuximab; Clinical Data; Clinical Protocols; Clinical Trials; Colorectal Cancer; Combined Modality Therapy; Data; Development; Drug Kinetics; Drug Targeting; EGFR inhibition; Enrollment; Enzyme Activation; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Event; Goals; Health; Histology; Human; In Vitro; KRAS2 gene; Lead; MAP Kinase Gene; MEKs; Maximum Tolerated Dose; Molecular; Mus; Mutation; Neoplasm Metastasis; Outcome; PIK3CA gene; Pathway interactions; Patients; Pattern; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphotransferases; Plasma; Pre-Clinical Model; Principal Investigator; Progression-Free Survivals; Randomized; Regimen; Resistance; Safety; Serrated Adenoma; Side; Signal Transduction; Southwest Oncology Group; Specificity; Specimen; Testing; Therapeutic; Validation; Xenograft Model; Xenograft procedure; base; colon cancer cell line; colon cancer patients; comparative efficacy; design; effective therapy; in vitro testing; in vivo; inhibitor/antagonist; irinotecan; metastatic colorectal; mutant; overexpression; phase 1 study; phase 2 study; phase II trial; pre-clinical; preclinical study; programs; randomized trial; resistance mechanism; response; therapy resistant; tumor

DESCRIPTION (provided by applicant): The translational goal of this project is to conduct mechanistic studies on BRAFmut mCRC patients and patient derived xenografts of BRAFmut mCRC treated with dual BRAF and EGFR inhibition to understand predictive biomarkers and mechanism on resistance through 1) a phase I/Ib trial of vemurafenib, cetuximab and irinotecan 2) a national SWOG randomized phase II trial of the combination. 3) concurrent patient derived xenografts trials. The hypothesis to be tested in this proposal is that the combination of BRAF and EGFR inhibition will prove efficacious in BRAFV600E colorectal cancer, but that innate and adaptive resistance mechanisms exist; biomarkers and parallel preclinical efforts are needed to better characterize these mechanisms of resistance. This hypothesis will be tested in vitro, in vivo, and in patients with mCRC in a clinical trial. Three specific aims are proposed to test this hypothesis, and include: 1) determine the safety and efficacy of BRAF and EGFR inhibition in patients with mCRC in a phase I/Ib trial and a national phase II randomized trial; 2) use patient-derived specimens to define predictive biomarkers and mechanisms of innate resistance to BRAF and EGFR inhibition; 3) use co-clinical trials with BRAFmut patient-derived xenografts to identify and target mechanisms of acquired resistance. The long-term goal of this project is to develop an understanding of the mechanisms of resistance to therapy for BRAFmut mCRC so that we can design more effective therapies, identify new drug targets for treatment, and develop biomarkers that identify BRAFmut mCRC patients most likely to have responses to specific therapies. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

DESCRIPTION (provided by applicant): The translational goal of this project is to conduct mechanistic studies on BRAFmut mCRC patients and patient derived xenografts of BRAFmut mCRC treated with dual BRAF and EGFR inhibition to understand predictive biomarkers and mechanism on resistance through 1) a phase I/Ib trial of vemurafenib, cetuximab and irinotecan 2) a national SWOG randomized phase II trial of the 组合。 3）并发患者衍生的异种移植试验。该提案中要检验的假设是，BRAF和EGFR抑制作用的组合将在BRAFV600E结直肠癌中有效，但存在先天和适应性抗性机制。需要生物标志物和平行的临床前努力来更好地表征这些抗性机制。该假设将在临床试验中在体外，体内和MCRC患者中进行检验。提出了三个特定的目的来检验这一假设，其中包括：1）在I/IB期试验中确定MCRC患者BRAF和EGFR抑制的安全性和功效，以及一项国家II期随机试验； 2）使用患者衍生的标本来定义对BRAF和EGFR抑制的先天抗性的预测生物标志物和机制； 3）使用与BRAFMUT患者衍生的异种移植物一起使用共同链接试验来识别和靶向获得的抗药性机制。该项目的长期目标是了解BRAFMUT MCRC耐药性的机制，以便我们可以设计更有效的疗法，识别新药物的治疗靶标，并开发出鉴定BRAFMUT MCRC患者最有可能对特定疗法有反应的生物标志物。 OMB No. 0925-0001/0002（Rev. 08/12批准通过8/3​​1/2015）页面延续格式页面