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：
10460574
负责人：
Iman Osman
金额：
$ 19.41万
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/10460574
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 Relapse 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 innovation interest melanoma molecular subtypes molecular targeted therapies multiplex assay 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.

项目概要据报道，15-25% 的患者存在 1 型神经纤维瘤病 (NF1) 肿瘤抑制基因的体细胞突变黑色素瘤，并与激活的丝裂原激活蛋白激酶 (MAPK) 信号传导和肿瘤生长有关。 NF1 突变的临床和生物学相关性尚不清楚。有证据表明 NF1 突变 (NF1-MT) 黑色素瘤与较高的肿瘤突变负荷 (TMB) 相关。然而，NF1突变并不与黑色素瘤对免疫治疗的更好反应有关。研究还表明 NF1-MT 黑色素瘤对 MEK 或 ERK 抑制剂敏感，但最近的一份报告表明 NF1 突变并不能预测对这些药物的敏感性。迄今为止，尚未在 NF1-MT 黑色素瘤中确定和验证任何可行的靶点，目前还没有开发出利用其生物学特性的亚型特异性疗法。我们的综合基因组，转录组和蛋白质组分析表明，细胞周期进展加快是 NF1-的标志突变黑色素瘤，这可能被用作一种新的治疗策略。因此，我们假设 NF1- 突变黑色素瘤在生物学上与 NF1 野生型肿瘤不同，并且具有过度增殖性表型，不能仅通过 MAPK 激活来解释，其特征是细胞周期增加进展，这使得它们容易受到细胞周期进展和细胞的药物抑制增殖，例如靶向 CDK4/6 或 CDC20 的药物，单独或与 MEK 抑制组合，或抑制 Shp2，一种独立于突变体 BRAF 激活 MAPK 通路的磷酸酶或 NRAS。在这个项目中，我们将使用黑色素瘤患者组织、细胞系和患者来源的肿瘤模型小鼠阐明 NF1 突变对黑色素瘤的生物学和临床影响，并测试新策略通过靶向细胞周期进程来治疗这种独特的黑色素瘤分子亚型。我们的研究结果将提供进一步开发治疗 NF1 突变肿瘤的创新、亚型特异性策略的基础。