Molecular Signatures of Melanoma: Predicting Response to Therapy & Targeting

黑色素瘤的分子特征：预测治疗反应

• 批准号: 8380218
• 负责人: TODD R. GOLUB
• 金额: $ 23.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8380218
• 关键词: Biological; Biological Assay; Biological Markers; Biology; Biopsy; Biopsy Specimen; Cell Culture Techniques; Cell Line; Chemicals; Clinical; Clinical Trials; Collection; Computer Analysis; Coupled; Databases; Detection; Development; Diagnostic; Disease; Drug Compounding; Enrollment; FDA approved; Formalin; Funding; Future; Gene Expression; Gene Expression Profile; Generic Drugs; Genes; Genetic; Genomics; Goals; Growth; Laboratories; Ligation; Maps; Measures; Mediating; Melanoma Cell; Metastatic Melanoma; Methods; Molecular Profiling; Nature; Oncogenes; Output; Paraffin Embedding; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Preclinical Testing; Procedures; Sampling; Screening procedure; Skin Cancer; Therapeutic; Transcript; Transcriptional Activation; Translating; Translations; Ursidae Family; Work; base; cost; expectation; experience; gain of function; genome-wide; high throughput screening; insight; loss of function; melanoma; new therapeutic target; novel; novel strategies; novel therapeutics; programs; research clinical testing; research study; response; small hairpin RNA; small molecule; therapeutic target; tool; transcription factor

Work over the past SPORE funding period has established the transcription factor MITF as a new melanoma oncogene, and one that represents a promising therapeutic target. We propose here a novel chemical genomic approach toward the development of anti-MITF therapeutics for melanoma. The approach is based on the modulation of gene expression signatures using the Gene Expression-Based High Throughput Screening (GE-HTSO method developed in the Golub laboratory. The expectation is that as a result of this effort, compounds with high potential for clinical translation will be identified. To accomplish these goals, the project has been organized into 3 Specific Aims. In Aim 1, we will define a gene expression signature of MITF activation through a combination of gain-of-function experiments, loss-of-function experiments (shRNA-mediated), and computational analysis of MITF-associated gene expression patterns in melanoma patient samples. We will then convert that MITF activation signature to a Luminex bead assay (of up to 100 transcripts) that is suitable for high throughput, low cost chemical screening. In parallel, we will evaluate the feasibility of measuring the MITF signature in routinely collected formalin-fixed paraffin-embedded melanoma biopsies such that the MITF signature could serve as a future diagnostic biomarker and pharmacodynamic marker of anti-MITF therapeutic response. In Aim 2, we will use the MITF signature in a high throughtput screen to identify small molecule compounds capable of modulating the MITF signature, and by inference, capable of modulating MITF activity. Special emphasis will be placed on screening all ~ 2,000 FDAapproved drugs because these can be most rapidly advanced to preclinical and clinical testing. Our experience with other GE-HTS screens is that unexpected activities of FDA-approved compounds are likely to be discovered in this screen. In Aim 3, we will validate the hits that emerge from the screen, and identify those compounds with the greatest potency, most biological activity in melanoma transformation assays, and as such will prioritize compounds for possible future clinical development.

过去SPORE资助期的工作已经确定转录因子MITF是一种新的黑色素瘤