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Melanomas can arise within any anatomic territory occupied by melanocytes. Although cutaneous melanoma, which develops from epidermal melanocytes of the skin, represents the most common site of origination, noncutaneous melanocytes such as those lining the choroidal layer of the eye, gastrointestinal, respiratory, and genitourinary mucosal surfaces, or the meninges do occasionally undergo malignant transformation, albeit at a low frequency. Clinical morphologists have traditionally divided the cutaneous disease into several subgroups, including superficial spreading melanoma, acral lentiginous melanoma, nodular melanoma, and lentigo maligna melanoma, and other uncommon variants such as desmoplastic melanoma and nevoid melanoma. Histological patterns have been well described, and microscopic features that correlate with clinical subgroups have been thoroughly codified.
In recent years, much has been learned about the molecular basis of melanoma genesis, progression, and response to therapy. BRAF V600 mutations (present in 50% of melanomas) predict clinical efficacy of RAF inhibitors; activating KIT aberrations may predict response to tyrosine kinase inhibitors such as nilotinib, imatinib, or dasatinib, and some NRAS mutant tumors may exhibit sensitivity to MEK inhibition. Other melanoma gene mutations that offer therapeutic insights include CDNK2A deletions, MITF amplification/alteration resulting in dysregulation of “druggable” antiapoptotic proteins, and PTEN disruption leading to PI3 kinase/AKT activation. The continuing discovery of recurrently mutated melanoma genes and the lack of identified driver mutations in the subtype without NRAS or BRAF mutation indicate that genetic understanding of this malignancy remains incomplete.
Melanoma drug resistance is commonly attributed to abrogation of the intrinsic apoptosis pathway. Therefore, targeting regulators of apoptosis is considered a promising approach to sensitizing melanomas to treatment. The development of small-molecule inhibitors that mimic natural antagonists of either antiapoptotic members of the BCL-2 family or the inhibitor of apoptosis proteins (IAPs), known as BH3- or SMAC-mimetics, respectively, are helping us to understand the mechanisms behind apoptotic resistance. Studies using BH3-mimetics suggest that the antiapoptotic BCL-2 protein MCL-1 and its antagonist NOXA are particularly important regulators of BCL-2 family signaling, while SMAC-mimetic studies indicate that both XIAP and the cIAPs must be targeted to effectively induce apoptosis of cancer cells. Although melanoma is insensitive to these mimetic drugs as single agents, combinations with other therapeutics have yielded promising results, and tests combining them with BRAF-inhibitors, which have revolutionized melanoma treatment, are a clear priority.
Cancer immunotherapies that act as immune-checkpoint inhibitors to block the localized immune suppression mechanisms utilized by tumors are undergoing development and being put to test in clinical trials. The first immunotherapy approved for the treatment of advanced melanoma was ipilimumab, a monoclonal antibody (mAb) that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4) and prevents a distinct mechanism of immune suppression that involves CTLA-4. Recently, immunotherapies targeting another clinically relevant mechanism of immune suppression involving the immune-checkpoint PD-1 receptor and its ligand, PD-L1, are undergoing clinical trials for the treatment of advanced melanoma. By blocking PD-1 receptors with anti-PD-1 mAbs, T cells are unaffected by the PD-L1 expressed on tumor cells and the patient’s T cells are free to respond to melanoma antigens and attack tumor cells. This new class of immunotherapy, based on anti-PD1, is now a validated strategy, irrespective of mutation type or previous treatments.
Creative Biogene, as a leading biotechnology company, is able to offer various melanoma pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.