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Targeted therapy in metastatic melanoma
28 February 2012 • Author(s): Janina Staub and Jochen Utikal, Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg & Skin Cancer Unit, German Cancer Research Center
During the last few years, significant improvements in the treatment of metastatic melanoma were reported, targeting molecules involved in the pathogenesis of melanoma. Different clinical trials were able to prove a prolonged overall survival by introducing new therapeutic agents. Hereby an imunomodulating therapy with the anti-CTLA-4 antibody ipilimumab has been established. Other promising treatment possibilities include targeted therapies for melanoma patients showing certain activating mutations in their tumour cells, e.g. BRAF V600 mutations and their selective inhibition by vemurafenib or the inhibition of the c-Kit receptor by drugs such as imatinib mesylate. This review will provide a brief overview of the latest therapeutic strategies and recent achievements in treating metastatic melanoma, as well as discuss the arising problems with resistance mechanisms to selective therapies. It will also highlight future approaches to combine specific treatments in an attempt to individualise melanoma treatment for every patient with the best possible efficacy and outcome.
Melanoma skin cancer is quickly becoming one of the most common and dangerous cancer types in Europe and the United States. It ranks as the fifth most common newly diagnosed cancer in men and holds the seventh place in women1. While early detected melanoma can be cured surgically, the treatment of metastasised melanoma remains a major challenge.
Until recently, the treatment of metastatic melanoma was performed by chemotherapeutic regimes such as dacarbazine (DTIC) monochemotherapy or different polychemotherapeutic regimes with response rates of less than 40 per cent and no advantage in overall survival. The median overall survival of metastatic melanoma patients treated with DTIC was reported to be six to eight months2,3. Recent data from molecular research points to different mechanisms of melanoma pathogenesis. Theoretically, every activating mutation or deletion in the identified signal transduction pathway (Figure 1) regulating cell survival and proliferation in the healthy melanocyte provides a substrate for targeted therapy.
In clinical practice, however, things are far more complex. The early described NRAS gene mutations, one of the antecedent points of the pathway, has been detected in approximately 20 per cent of melanoma patients4, but no efficacious therapy has resulted as of yet5. Most patients with melanoma (90 per cent) report at least intermittent sun exposure. In 60 per cent of the melanomas, which develop in non-chronically sun-damaged skin, activating mutations of the BRAF gene are seen6 (Figure 2). These mutations have been discovered as a causing agent for melanoma in over 50 per cent of the patients but also give rise to other cancer types, such as colorectal or papillary thyroid cancer in around eight per cent of the cases7. In melanomas developed in chronically sun damaged skin as well as in acral or mucosal melanomas, mutations in the c-Kit gene are found in more than 30 per cent of the patients (Table 1 and Figure 2). And the extremely rare infestation of ocular melanoma exhibits activating mutations of the GNAQ gene in 46 per cent of the affected cases. Therefore, different molecular causes of melanoma require different therapeutic approaches and further investigation of all dysregulating mutations and melanoma subtypes will be required to tailor the targeting more specifically8. This review is to give a brief overview of the new therapeutic strategies and recent progress in the treatment of metastatic melanoma.
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