title: Developing melanoma therapeutics: overview and update.
abstract: Melanoma is a common, often deadly malignancy, historically associated with limited treatment options for advanced disease. In recent years, systems-based research has resulted in significant clinical advancements. Strategic inhibition of mutated oncoproteins and targeting of immune checkpoints have emerged as very promising approaches. Vemurafenib, which received US Food and Drug Administration (FDA) approval in 2011, selectively inhibits BRAF(V600E) , a hyperactivated mutant signaling kinase in the mitogen-activated protein kinase (MAPK) pathway. Another recently FDA-approved drug, ipilimumab, blocks the cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway from inhibiting T cell activation. Despite this apparent progress, compelling challenges remain for both researchers and clinicians. Responses to therapy remain unacceptably incomplete and, in most cases, resistance mechanisms quickly develop that lead to relapse and subsequent patient mortality. Combining therapeutic modalities may increase the percentage of responding patients as well as the magnitude and durability of response. Notably, combined therapies involving selective BRAF inhibitors (SBIs) and other inhibitors of MAPK-dependent or MAPK-independent resistance pathways appear particularly promising. Preclinical and clinical studies are needed to comprehensively evaluate the optimal combinations of therapies, to identify melanoma subtypes that will be most responsive, and to determine optimal dosing, timing, and route of delivery.
authors: Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: John B
authors: JB
authors: Korman
authors: David E
authors: DE
authors: Fisher
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism; D002986:Clinical Trials as Topic; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000074324:Ipilimumab; D008545:Melanoma / Q000628:therapy*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000077484:Vemurafenib
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D007211:Indoles; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases