Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

Abstract

Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cellbased therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/ VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3'-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.

Biomarkers in Malignant Melanoma: Recent Trends and Critical Perspective

“…Here, patients with high S100B levels showed a shorter progression-free disease (55). In patients with lesions of Breslow thickness >1 mm, Swiss and German guidelines recommend S100B quantification every 3-6 months for the first 1-5 years, and every 6-12 months for years [6][7][8][9][10]. Serum concentration appears to correlate with Breslow thickness and tumor burden measured under RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 (8).…”

“…From a pathobiochemical point of view, these biomarkers comprise molecules, including enzymes, soluble proteins and/or antigens, melanin-related metabolites, and circulating cell-free nucleic acids, released by (i) necrosis, (ii) active secretion, and (iii) ectodomain membrane shedding (1) ( Table 1). These molecules exhibit different prognostic and predictive values in melanoma diagnosis, staging, and treatment monitoring (1,4,6,7). On the other hand, biomarkers obtained from histological and immunohistochemical analyses of biopsy material play a very important role in melanoma management.…”

“…Some of them possibly represent melanoma progenitor and/or stem cell-like markers. This includes ATP-binding cassette (ABC) multidrug transporters and the neuroepithelial intermediate filament nestin (1,6). In this regard, immunohistochemical analysis of nestin performed by Akiyama et al in various melanoma specimens revealed a positive association of nestin expression with advanced disease (71).…”

Streamlining Molecular Pathobiology of Malignant Melanoma

“…They are focused on mutations in DNA, RNA and proteins. Such specific and sensitive procedures applied to CMM help refining the diagnosis, classification, outcome prediction, as well as selection and monitoring of therapy [14][15][16][17][18][19][20][21][22][23][24][25][26].…”

“…Such growth factors cooperate and activate distinct parts of the tumorigenic downstream signalling paths and various Epithelial-Mesenchymal Transition (EMT)-associated molecules, including phosphatidylinositol 3'-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappa B (NF-kB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist [26].…”