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Mutant BRAF-regulated transcription factors in melanoma progression

黑色素瘤进展中突变的 BRAF 调节转录因子

基本信息

批准号：
9264500
负责人：
Andrew Eric Aplin
金额：
$ 35.69万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-24 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264500
关键词：
Address Adjuvant Adverse effects Alpha Cell BRAF gene Bioinformatics Cell Adhesion Molecules Cell Cycle Arrest Cell Cycle Progression Cell Proliferation Cells ChIP-seq Cutaneous Melanoma Data Dermal Disease Disease Progression Down-Regulation Early Diagnosis Early treatment Equilibrium Event Gene Chips Goals Growth Heterogeneity In Vitro Incidence Interstitial Collagenase Lead Link LoxP-flanked allele MAPK3 gene Malignant - descriptor Malignant Neoplasms Mediator of activation protein Melanoma Cell Modeling Monophenol Monooxygenase Mus Mutate Mutation Neoplasm Metastasis Nevus Pathway interactions Patients Physiological Plasticizers Play Progression-Free Survivals Property Protein-Serine-Threonine Kinases Publishing Regulation Resistance Role Sampling Series Signal Transduction Skin Skin Cancer Structure TWIST1 gene Testing Therapeutic Transcript Transcription Factor 3 Transcription Repressor/Corepressor Tumor stage Up-Regulation actionable mutation cancer type experimental study improved in vivo inhibitor/antagonist innovation melanoma mimetics mortality mouse model mutant neoplastic cell pluripotency prevent public health relevance trait transcription factor treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Melanoma is the deadliest form of skin cancer. We aim to understand mechanisms underlying disease progression in order to better predict and identify aggressive forms of melanomas. The serine/threonine kinase, BRAF, is somatically mutated in 40-60% of melanomas. BRAF mutations are early events that lead to hyper-activation of MEK-ERK1/2 signaling and melanoma growth and invasion. While BRAF inhibitors are now first-line therapies for metastasized mutant V600E BRAF melanomas, they only delay mortality and are not being administered in the adjuvant setting. Thus, we must enhance our understanding of the mechanisms underlying growth and invasion of early-stage melanomas in order to improve early diagnosis and treatment strategies that prevent metastasis. We have identified transcription factors, TWIST1 and FOXD3, which are regulated by mutant BRAF in melanoma. In this proposal, we seek to determine the role of TWIST1 and FOXD3 in invasion and dormancy during the early steps of melanoma progression. We propose three Specific Aims to determine the role of TWIST1 in invasion of primary melanoma using 3D skin mimetic and mutant BRAF mouse models, to mechanistically understand FOXD3 regulation of SOX2 (a transcription factor linked to induced pluripotency), and to examine the interplay between TWIST1, FOXD3 and SOX2 in vivo. At the completion of our experiments, we expect to have demonstrated that the interplay between mutant BRAF-regulated transcription factors controls mechanisms that underlie melanoma plasticity and steps in the metastatic cascade.