Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry–based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry–based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre.

中文翻译：

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靶向恶性黑色素瘤的转化医学中的临床蛋白质科学。

皮肤黑色素瘤是欧洲第六大最常见的癌症，占所有诊断出的癌症的3.4％。更令人担忧的是，约20％的患者在治疗后死亡时复发。恶性黑色素瘤是一种高度侵袭性的皮肤癌，转移迅速扩散到区域淋巴结（3期）和远端器官（4期）。靶向肿瘤疗法是进行性4期黑色素瘤的标准治疗方法之一，BRAF抑制剂（例如vemurafenib，dabrafenib）与MEK抑制剂（例如曲美替尼）联合可以有效抵抗BRAFV600E突变的黑色素瘤。与常规化疗相比，靶向BRAFV600E抑制作用可显着提高应答率。经过一段时间的癌症控制后，大多数反应迅速的患者会对治疗产生抵抗力并导致致命的进展。已经广泛研究了可能引起对BRAF抑制剂耐药的许多潜在因素。然而，仍然存在的尚未解决的临床问题需要采用替代研究方法来解决潜在的转移性和治疗性黑色素瘤的分子机制。广义地说，蛋白质组学可以通过测量蛋白质产物的相对丰度，翻译后修饰（PTM），蛋白质定位，周转率，蛋白质相互作用和蛋白质功能来解决基因组学无法解决的临床问题。更具体地说，在给定的医学和临床环境下对体液和组织进行蛋白质组学分析可以帮助鉴定癌症生物标志物和新型治疗靶标。为了实现这一目标，需要开发一个强大且可重现的临床蛋白质组学平台，其中包括对患者样品进行自动生物富集，组织切片和组织学检查，有效的蛋白质提取，酶消化，基于质谱的无标记或标记技术的定量蛋白质分析，以及/或用特定的PTM富集肽。通过结合来自例如磷酸蛋白质组学和乙酰组学的数据，不同黑素瘤阶段的蛋白质表达谱可以为理解疾病的生物学和进展提供坚实的框架。当辅以蛋白质组学 从患者特定的基因组和转录组数据生成的定制蛋白质序列数据库有助于解释临床蛋白质组学生物标记数据，从而为疾病进程背后的细胞功能提供更深入，更全面的分子表征。与简化的，以患者为中心的临床蛋白质组学流程并行，基于质谱的成像可以以单细胞分辨率帮助询问组织内药物和药物代谢物的空间分布。这些进展是研究体内药物作用和功效的重要进展，并将有助于开发更有效，更安全的黑色素瘤治疗策略。学术界和医护人员之间的巨大合作导致了人们的发起，建立和发展专门研究黑素瘤和肺癌的前沿癌症研究中心。欧洲癌症月球隆德中心的主要研究重点是在个体化和个性化的水平上了解药物对癌症的影响。同时，该中心提高了人们对与癌症进行不懈斗争的认识，并吸引了全球对该中心进行的出色研究的兴趣。