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抑制剂维罗非尼（PLX 4032/Zelboraf）和达拉非尼是目前晚期突变型BRAF黑色素瘤的一线治疗选择。通过免疫组织化学染色测量，患者对维罗非尼/达拉非尼的客观反应与ERK 1/2信号传导的80%以上抑制相关。然而，当前RAF抑制剂的长期功效受到突变BRAF细胞中获得性耐药性和野生型BRAF细胞中反常的ERK 1/2激活的限制。在这个建议中，我们概述了一种新的体内报告系统，以测量ERK 1/2途径的活性在突变BRAF黑色素瘤细胞中的非侵入性，定量和时间的方式。我们利用该系统为维罗菲尼的获得性耐药性提供了新的机制见解。我们还表明，一类新的RAF抑制剂，不引起矛盾的ERK 1/2激活可能提供抑制生长的维罗非尼耐药黑色素瘤细胞。在这里，我们将提出进一步定义机制的耐药vemurafenib，并确定这种新的RAF抑制剂的效果和耐药模式。在我们的实验完成时，我们期望为突变型BRAF黑色素瘤的新一线治疗和维罗非尼/达拉非尼耐药黑色素瘤的二线治疗选择提供临床前基础。