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Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

DOI: 10.1155/2013/897348

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Abstract:

Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed. 1. Introduction Melanoma derivates from melanocytes—pigment cells of the skin. Melanoma most commonly arises from epidermal skin melanocytes (cutaneous melanoma), but primary tumors can also be found lining the choroidal layer of the eye (uveal melanoma) or the mucosal surfaces of the respiratory, genitourinary, and gastrointestinal surfaces. Similar to other tumors, the progression stage of melanoma is predictive for therapeutic success. Early stage melanomas (thin tumors) result in a 97% 5-year survival rate of the patients, after surgical removal [1]. Conversely, advanced melanoma patients, comprising metastasis in regional lymph nodes or other organs, face 5-year survival rates of less than 10% [1]. Due to the intrinsic tendency of melanoma to early metastasis, even small primary tumors have already led to metastasis and a substantial portion of diagnosed melanoma cases are of late progression stages. Treatment of advanced or metastatic melanoma has proven a challenge, as the conventional therapeutic approaches failed to translate into improved or significant survival rate in phase III clinical trials. Newer treatments were established in the last years that elicit unprecedented response rates in late stage melanoma, for example, up to 80% in the case of BRAF inhibitors. However, almost all tumors become resistant within months, and the treatment is available only for a subset of melanomas. Altogether, despite substantial improvements in therapeutic options during the

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