Novel targets of treatment for NF1-mutant melanoma

NF1突变黑色素瘤的新治疗靶点

• 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
• 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

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 神经纤维瘤病1型(NF1)肿瘤抑制基因的体细胞突变在15%-25%的 黑色素瘤与激活的丝裂原活化蛋白激酶(MAPK)信号转导和肿瘤生长有关。 NF1突变的临床和生物学相关性还知之甚少。有证据表明，NF1突变体 (NF1-MT)黑色素瘤与较高的肿瘤突变负荷(TMB)相关。然而，NF1突变并不是 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，但最近的一份报告显示，NF1突变不能预测 对这些药物的敏感性。到目前为止，还没有在NF1-MT黑色素瘤中发现和验证可操作的靶点， 而且还没有开发出利用其生物学的亚型特异性治疗方法。我们整合的基因组， 转录学和蛋白质组学分析表明，细胞周期进程加快是NF1- 突变的黑色素瘤，这可能被开发为一种新的治疗策略。因此，我们假设NF1- 突变型黑色素瘤在生物学上有别于nf1野生型肿瘤，并且具有高增殖性。 表型，不能仅用MAPK激活来解释，其特征是细胞周期增加 进展，这使它们容易受到药物抑制细胞周期进展和细胞 增殖，如针对CDK4/6或CDC20的药物，单独或与MEK抑制联合使用；或 抑制Shp2，一种独立于突变体BRAF的参与MAPK途径激活的磷酸酶 或者NRAS。在这个项目中，我们将使用黑色素瘤患者的组织、细胞系和患者衍生的肿瘤模型 小鼠阐明NF1突变对黑色素瘤的生物学和临床影响，并测试新的策略 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。我们的发现将提供 为进一步开发治疗NF1突变肿瘤的创新、亚型特异性策略奠定了基础。