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Novel targets of treatment for NF1-mutant melanoma

NF1突变黑色素瘤的新治疗靶点

基本信息

批准号：
10289966
负责人：
Iman Osman
金额：
$ 23.77万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-02 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289966
关键词：
Affect BRAF gene Biological Biological Assay Biology CCND1 gene CDK4 gene Cell Cycle Cell Cycle Inhibition Cell Cycle Progression Cell Cycle Proteins Cell Line Cell Proliferation Clinical DNA Sequence Alteration Data Databases Development Enrollment Exploratory/Developmental Grant Frequencies Future Genomics Immune checkpoint inhibitor Immunohistochemistry Immunotherapy In Vitro Literature MDM2 gene MEK inhibition MEKs MKI67 gene Malignant Neoplasms Melanoma Cell Messenger RNA Mitogen-Activated Protein Kinases Modeling Mus Mutation NF1 gene Neurofibromatosis 1 Outcome PTPN11 gene Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphoric Monoester Hydrolases Prognosis Proliferation Marker Proteins Proteomics Reporting Research Signal Transduction Somatic Mutation Specimen Testing The Cancer Genome Atlas Therapeutic Tissues Transcript Tumor Subtype Tumor Suppressor Genes Tumor-Derived Validation cohort digital experimental study in vivo evaluation inhibitor/antagonist innovation interest melanoma molecular subtypes molecular targeted therapies mutant mutational status nano-string neoplastic cell novel novel strategies patient derived xenograft model programs protein expression response subtype-specific therapies targeted agent targeted treatment transcriptomics treatment strategy tumor tumor growth

项目摘要

PROJECT SUMMARY Somatic mutations in the Neurofibromatosis type 1 (NF1) tumor suppressor gene are reported in 15-25% of melanomas and are implicated in activated mitogen-activated protein kinase (MAPK) signaling and tumor growth. The clinical and biological relevance of NF1 mutations is poorly understood. Evidence suggests that NF1-mutant (NF1-MT) melanoma is associated with a higher tumor mutation burden (TMB). However, NF1 mutations are not associated with better response of melanoma to immunotherapy. Studies have also suggested that NF1-MT melanomas are sensitive to MEK or ERK inhibitors, but a recent report showed that NF1 mutations do not predict sensitivity to these drugs. To date no actionable targets have been identified and validated in NF1-MT melanoma, and no subtype-specific therapy that exploits its biology has been developed. Our integrated genomic, transcriptomic, and proteomic analyses suggest that increased cell cycle progression is a hallmark of NF1- mutant melanomas, which might be exploited as a novel treatment strategy. Hence, we hypothesize that NF1- mutant melanomas are biologically distinct from NF1-wild type tumors, and possess a hyper-proliferative phenotype, that cannot be explained only by MAPK activation and characterized by increased cell cycle progression, which renders them vulnerable to pharmacological inhibition of cell cycle progression and cell proliferation, such as agents targeting CDK4/6 or CDC20, alone or in combination with MEK inhibition, or inhibition of Shp2, a phosphatase that contributes to MAPK pathway activation independently of mutant BRAF or NRAS. In this project, we will use melanoma patient tissues, cell lines, and patient-derived tumor models in mice to elucidate the biological and clinical impact of NF1 mutations in melanoma, and to test novel strategies to treat this distinct melanoma molecular subtype by targeting cell cycle progression. Our findings will provide the basis for further development of innovative, subtype-specific strategies for treatment of NF1-mutant tumors.

项目总结