Targeted therapies in mutant BRAF melanoma

突变 BRAF 黑色素瘤的靶向治疗

• 批准号: 8774480
• 负责人: Andrew Eric Aplin
• 金额: $ 32.16万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-14 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774480
• 关键词: Adverse effects; Antibodies; BRAF gene; Binding; Cells; Clinical Trials; Data; Dimerization; Disease Progression; Disease Resistance; ERBB3 gene; FDA approved; Future; Goals; Growth; Homo; In Vitro; MAPK3 gene; MEKs; Measurement; Measures; Mediating; Melanoma Cell; Modeling; Molecular; Mutation; Pathway interactions; Patients; Phosphorylation; Progression-Free Survivals; Property; Proteomics; RNA; RNA Splicing; Reporter; Resistance; Role; Serine; Signal Transduction; Skin Cancer; Staging; Staining method; Stains; System; Systems Analysis; Testing; Therapeutic; Variant; Work; Xenograft procedure; base; combinatorial; exome sequencing; improved; in vivo; inhibitor/antagonist; innovation; insight; melanoma; mutant; next generation; novel; pre-clinical; prevent; public health relevance; research study; resistance mechanism; response; tool; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): The RAF inhibitors, vemurafenib (PLX4032/Zelboraf) and dabrafenib, are the current first-line treatment options for late-stage mutant BRAF melanoma. Objective responses to vemurafenib/dabrafenib in patients are associated with greater than 80% inhibition of ERK1/2 signaling, as measured by immunohistochemical staining. However, the long-term efficacy of current RAF inhibitors is limited by acquired resistance in mutant BRAF cells and paradoxical ERK1/2 activation in wild-type BRAF cells. In this proposal, we outline a novel in vivo reporter system to measure ERK1/2 pathway activity in a non-invasive, quantitative and temporal manner in mutant BRAF melanoma cells. We have utilized this system to provide novel mechanistic insight into acquired resistance to vemurafenib. We also show that a new class of RAF inhibitors that do not elicit paradoxical ERK1/2 activation may provide inhibits growth of vemurafenib-resistant melanoma cells. Here, we will propose to further define mechanisms underlying resistance to vemurafenib, and to determine the effects and modes of resistance to this new class of RAF inhibitors. At the completion of our experiments, we expect to have provided the preclinical basis for new first-line for mutant BRAF melanoma and second-line treatment options for vemurafenib/dabrafenib-resistant melanomas.

描述（由申请人提供）：RAF抑制剂Vemurafenib（PLX4032/Zelboraf）和Dabrafenib是晚期突变体BRAF黑色素瘤的当前一线治疗选择。通过免疫组织化学染色测量，对患者的vemurafenib/dabrafenib对患者的vemurafenib/dabrafenib对ERK1/2信号传导的抑制大于80％。然而，当前RAF抑制剂的长期疗效受到突变BRAF细胞获得的耐药性和野生型BRAF细胞中矛盾的ERK1/2激活的限制。在此提案中，我们概述了一种新型的体内报告基因系统，以在突变体BRAF黑色素瘤细胞中以非侵入性，定量和时间方式测量ERK1/2途径活性。我们已经利用该系统来提供对vemurafenib获得的耐药性的新机械洞察力。我们还表明，不引起自相矛盾的ERK1/2激活的新型RAF抑制剂可能会抑制耐维氏尼替尼耐药性黑色素瘤细胞的生长。在这里，我们将提议进一步定义对vemurafenib抗性的机制，并确定对这一新的RAF抑制剂的耐药性和模式。实验完成后，我们希望为vemurafenib/dabrafenib耐药的黑色素瘤的突变体BRAF黑色素瘤和二线治疗方案提供临床前基础。