Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
Clin Cancer Res. 2021 Apr 1;27(7):2074-2086. doi: 10.1158/1078-0432.CCR-20-3752. Epub 2021 Jan 14.
Treatment of metastatic melanoma has dramatically improved in recent years, thanks to the development of immunotherapy and BRAF-MEK-targeted therapies. However, these developments revealed marked heterogeneity in patient response, which is yet to be fully understood. In this work, we aimed to associate the proteomic profiles of metastatic melanoma with the patient clinical information, to identify protein correlates with metastatic location and prior treatments.
We performed mass spectrometry-based proteomic analysis of 185 metastatic melanoma samples and followed with bioinformatics analysis to examine the association of metastatic location, status, survival, and immunotherapy response with the tumor molecular profiles.
Bioinformatics analysis showed a high degree of functional heterogeneity associated with the site of metastasis. Lung metastases presented higher immune-related proteins, and higher mitochondrial-related processes, which were shown previously to be associated with better immunotherapy response. In agreement, epidemiological analysis of data from the National Cancer Database showed improved response to anti-programmed death 1, mainly in patients with lung metastasis. Focus on lung metastases revealed prognostic and molecular heterogeneity and highlighted potential tissue-specific biomarkers. Analysis of the mutation status and prior treatments with MAPK inhibitors proposed the molecular basis of the effect on immunotherapy response and suggested coordinated combination of immunotherapy and targeted therapy may increase treatment efficacy.
Altogether, the proteomic data provided novel molecular determinants of critical clinical features, including the effects of sequential treatments and metastatic locations. These results can be the basis for development of site-specific treatments toward treatment personalization.
近年来，由于免疫疗法和 BRAF-MEK 靶向治疗的发展，转移性黑色素瘤的治疗有了显著改善。然而，这些进展揭示了患者反应的显著异质性，这仍有待充分理解。在这项工作中，我们旨在将转移性黑色素瘤的蛋白质组谱与患者的临床信息相关联，以确定与转移部位和既往治疗相关的蛋白相关性。
我们对 185 个转移性黑色素瘤样本进行了基于质谱的蛋白质组学分析，并进行了生物信息学分析，以检查转移部位、 状态、生存和免疫治疗反应与肿瘤分子谱的关联。
生物信息学分析显示与转移部位相关的功能高度异质性。肺转移瘤表现出更高的免疫相关蛋白和更高的线粒体相关过程，先前的研究表明这些与更好的免疫治疗反应相关。与预期一致的是，国家癌症数据库中数据的流行病学分析显示，抗程序性死亡 1 的反应得到改善，主要是在肺转移患者中。对肺转移瘤的关注揭示了预后和分子异质性，并强调了潜在的组织特异性生物标志物。对 突变状态和 MAPK 抑制剂的既往治疗分析提出了对免疫治疗反应的分子基础，并提出免疫治疗和靶向治疗的联合可能提高治疗效果。
总之，蛋白质组数据为关键临床特征的新分子决定因素提供了依据，包括序贯治疗和转移部位的影响。这些结果可以为针对特定部位的治疗方法的开发提供依据，以实现治疗的个体化。
