Combination Therapy to Improve MAPK Pathway Inhibitor Efficacy in BRAF and KRAS M

联合治疗可提高 BRAF 和 KRAS M 中 MAPK 通路抑制剂的功效

• 批准号: 8599445
• 负责人: Ryan Bruce Corcoran
• 金额: $ 17.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-18 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599445
• 关键词: Archives; BCL1 Oncogene; BRAF gene; Biological Markers; Biopsy; Cancer Model; Cancer Patient; Cancer cell line; Candidate Disease Gene; Clinical; Clinical Trials; Colorectal Cancer; Combined Modality Therapy; Data; Development; EGFR inhibition; Effectiveness; Epidermal Growth Factor Receptor; Gene Expression; Gene Targeting; Genes; Genetically Engineered Mouse; Goals; Human; KRAS2 gene; Laboratories; MAP Kinase Gene; MEK inhibition; MEKs; Malignant Neoplasms; Mediating; Medicine; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Mutant Strains Mice; Mutate; Mutation; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Play; Population; Preclinical Drug Evaluation; Proteins; Publishing; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tumor Tissue; Work; Xenograft Model; base; cancer cell; cancer therapy; effective therapy; improved; in vitro Model; in vivo; inhibitor/antagonist; insight; killings; meetings; melanoma; metastatic colorectal; mouse model; mutant; novel; novel therapeutics; public health relevance; response; screening; small hairpin RNA; small molecule; success; translational approach; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Activating mutations in BRAF and KRAS, key signaling components of the MAPK pathway, are among the most common oncogenic mutations in human cancer, occurring in ~7% and ~20% of all cancers and in ~10-15% and ~40% of colorectal cancers (CRCs), respectively. Consequently, effective targeted therapy strategies for cancers harboring BRAF and KRAS mutations would have a profound clinical impact, and inhibitors of MAPK signaling, including BRAF and MEK inhibitors, are currently in clinical development. While BRAF inhibitors proved remarkably effective in BRAF mutant melanoma, results have been disappointing in BRAF mutant CRC. Although the reason for this disparity is not fully understood, recent work from our group and others has found that EGFR signaling may play a key role in resistance. Our preliminary studies have also shown that BRAF inhibitor-based targeted therapy combinations, such as combined BRAF/MEK (currently in clinical trials) or combined BRAF/EGFR inhibition, may improve efficacy in BRAF mutant CRC. Although KRAS is the most commonly mutated oncogene, no effective therapies exist for KRAS mutant cancers, largely because the KRAS protein itself has proven difficult to target directly with small molecules. Targeting single downstream KRAS effector pathways (e.g. MEK) has also met limited success in clinical trials, likely because KRAS activates multiple important signaling pathways. Previously, our laboratory and others showed that combined targeting of more than one KRAS effector pathway (MEK and PI3K) can cause dramatic responses in KRAS mutant mouse tumor models, but preliminary data suggests that combined MEK/PI3K inhibition may only be effective in a subset of KRAS mutant cancers, underscoring the need for additional effective inhibitor combinations. The overall hypothesis of this proposal is that the limited efficacy of BRAF and MEK inhibitors in BRAF and KRAS mutant CRC, respectively, involves activation of other key pathways that reduce the extent to which these cancers are "addicted" to MAPK signaling, constraining the effectiveness of these inhibitors as single-agents. We aim to develop novel combination therapy strategies for BRAF and KRAS mutant cancers, focusing specifically on CRC. Building on our recent discovery that EGFR mediates resistance to BRAF inhibitors in BRAF mutant CRC, we will perform a comprehensive analysis of the role of EGFR in BRAF inhibitor resistance, utilizing in vitro models and patient tumor biopsies from a novel targeted therapy trial for BRAF mutant CRC. In KRAS mutant CRC, we will employ a novel pooled shRNA drug screen developed in our laboratory to identify new targets for combination therapy with MEK inhibitors. Novel combinations will be evaluated in cutting-edge mouse models of KRAS mutant CRC with the goal of rapidly identifying effective targeted therapy combinations. New therapeutic strategies for these cancers would represent a major advance in personalized cancer medicine with significant clinical benefit for a large population of cancer patients.

描述（由申请人提供）：BRAF和KRAS（MAPK通路的关键信号传导组分）中的激活突变是人类癌症中最常见的致癌突变之一，分别发生在约7%和约20%的所有癌症中以及约10-15%和约40%的结直肠癌（CRC）中。因此，针对携带BRAF和KRAS突变的癌症的有效靶向治疗策略将具有深远的临床影响，并且MAPK信号传导的抑制剂，包括BRAF和MEK抑制剂，目前正在临床开发中。虽然BRAF抑制剂在BRAF突变型黑色素瘤中证明非常有效，但在BRAF突变型CRC中的结果令人失望。虽然这种差异的原因还不完全清楚，但我们小组和其他人最近的工作发现EGFR信号可能在耐药性中起关键作用。我们的初步研究还表明，基于BRAF受体的靶向治疗组合，如联合BRAF/MEK（目前在临床试验中）或联合BRAF/EGFR抑制，可能会提高BRAF突变型CRC的疗效。虽然KRAS是最常见的突变癌基因，但KRAS突变型癌症没有有效的治疗方法，这主要是因为KRAS蛋白本身已被证明难以用小分子直接靶向。靶向单一下游KRAS效应通路（例如MEK）在临床试验中也取得了有限的成功，可能是因为KRAS激活了多种重要的信号通路。以前，我们的实验室和其他实验室表明，联合靶向一种以上的KRAS效应通路（MEK和PI 3 K）可以在KRAS突变小鼠肿瘤模型中引起显著的反应，但初步数据表明，联合MEK/PI 3 K抑制可能仅在KRAS突变癌症的一个子集中有效，这强调了对其他有效抑制剂组合的需求。该提议的总体假设是，BRAF和MEK抑制剂分别在BRAF和KRAS突变CRC中的有限功效涉及其他关键途径的激活，所述其他关键途径降低这些癌症对MAPK信号传导“成瘾”的程度，从而限制了这些抑制剂作为单一药剂的有效性。我们的目标是为BRAF和KRAS突变癌症开发新的联合治疗策略，特别关注CRC。基于我们最近发现EGFR介导BRAF突变型CRC对BRAF抑制剂的耐药性，我们将利用BRAF突变型CRC新型靶向治疗试验的体外模型和患者肿瘤活检，对EGFR在BRAF抑制剂耐药性中的作用进行全面分析。在KRAS突变型CRC中，我们将采用我们实验室开发的一种新的混合shRNA药物筛选，以确定与MEK抑制剂联合治疗的新靶点。将在KRAS突变型CRC的尖端小鼠模型中评估新型组合，目的是快速鉴定有效的靶向治疗组合。针对这些癌症的新治疗策略将代表个性化癌症医学的重大进展，对大量癌症患者具有显著的临床益处。