Melanoma treatment in review

Abstract

Melanoma represents the most aggressive and the deadliest form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. The therapeutic strategy can include single agents or combined therapies, depending on the patient's health, stage, and location of the tumor. The efficiency of these treatments can be decreased due to the development of diverse resistance mechanisms. New therapeutic targets have emerged from studies of the genetic profile of melanocytes and from the identification of molecular factors involved in the pathogenesis of the malignant transformation. In this review, we aim to survey therapies approved and under evaluation for melanoma treatment and relevant research on the molecular mechanisms underlying melanomagenesis.

Keywords: cancer; melanoma; targets; therapy.

Figure 1

FDA-approved drugs for melanoma treatment. Dacarbazine was the first drug approved, in 1974, followed by interferon α-2b, interleukin-2, and ontak in the 1990s. Between 2011 and 2015, 10 therapies were approved, including selective inhibitors, antibodies, and combined targeted therapies. Abbreviation: FDA, US Food and Drug Administration.

Figure 2

Immunotherapies approved by FDA (in white – interferon α-2b/peginterferon α-2b, interleukin-2, ontak, ipilimumab, nivolumab, pembrolizumab, and talimogene laherparepvec) or in trials (in gray – durvalumab, CK-301, avelumab, atezolizumab, gp100 vaccine, resiquimod, and CAR-T cells) for cutaneous melanoma treatment. Immunotherapy induces antitumor immune responses by altering metabolites, growth factors, and cytokines, such as interferon α-2b and interleukin-2, in the TME. Ipilimumab, an anti-CTLA-4 antibody, induces pro-inflammatory T-cell cytokine production, and increases clonal T-cell expansion and infiltration. The anti-PD-1 antibodies, nivolumab and pembrolizumab, block the interaction between PD-1 and PD-L1/PD-L2, similar to the effect of durvalumab, CK-301, avelumab, atezolizumab, which are anti-PDL-1 antibodies. Other immunotherapies can activate the immune system at the TME, such as resiquimod and CAR-T cells, or suppress Tregs, as ontak. Oncolytic virus therapy with talimogene laherparepvec also interferes with the immune system, inducing melanoma cell lysis and consecutively release of tumor-specific antigens. Abbreviations: FDA, US Food and Drug Administration; TME, tumor microenvironment; PD-1, programmed cell death protein 1; PD-L1, PD-1 ligand; CTLA, cytotoxic T lymphocyte-associated antigen; CAR, chimeric antigen receptor; MHC, major histocompatibility complex; TCR, T-cell receptor; Treg, regulatory T-cell; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell.

Figure 3

Targeted therapies approved by FDA (in white – vemurafenib, dabrafenib, trametinib, and cobimetinib) or in trials (in gray – imatinib, sunitinib, dasatinib, nilotinib, bevacizumab, PI-103, BKM120, GSK2636771, INCB050465, IPI-549, MK2206, everolimus, temsirolimus, ribociclib, abemaciclib, palbociclib, SHR6390, and ASN003) for cutaneous melanoma treatment. Mutations on key signaling oncogenes, used as targets for melanoma therapy, are associated with melanoma cell proliferation, cell-cycle progression, and malignant phenotype. Melanoma patients may benefit from combined therapies, using two different targeted therapies or targeted therapy with adjuvant immune therapy or chemotherapy. Abbreviations: FDA, US Food and Drug Administration; mTOR, mammalian target of rapamycin; VEGFR, vascular endothelial growth factor receptor; ERK, extracellular signal-regulated kinase; MITF, microphthalmia-associated transcription factor; CDK, cyclin-dependent kinase; P13K, phosphatidylinositol-3-OH kinase.