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Towards new therapeutic approaches for malignant melanoma

Published online by Cambridge University Press:  01 November 2011

Ivan Pacheco
Affiliation:
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
Cristina Buzea
Affiliation:
Department of Physics, Queen's University, Kingston, ON, Canada
Victor Tron*
Affiliation:
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
*
*Corresponding author: Victor Tron, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON K7L2V7, Canada. E-mail: [email protected]

Abstract

Recent progress in understanding the molecular mechanisms of the initiation and progression of melanoma has created new opportunities for developing novel therapeutic modalities to manage this potentially lethal disease. Although at first glance, melanoma carcinogenesis appears to be a chaotic system, it is indeed, arguably, a deterministic multistep process involving sequential alterations of proto-oncogenes, tumour suppressors and miRNA genes. The scope of this article is to discuss the most recent and significant advances in melanoma molecular therapeutics. It is apparent that using single agents targeting solely individual melanoma pathways might be insufficient for long-term survival. However, the outstanding results on melanoma survival observed with novel selective inhibitors of B-RAF, such as PLX4032 give hope that melanoma can be cured. The fact that melanoma develops acquired resistance to PLX4032 emphasises the importance of simultaneously targeting several pathways. Because the most striking feature of melanoma is its unsurpassed ability to metastasise, it is important to implement newer systems for drug delivery adapted from research on stem cells and nanotechnology.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2011

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References

References

1American Cancer Society (2010) Cancer facts and figures. Available at: http://www.cancer.org. 2010; accessed September 2010Google Scholar
2Balch, C.M. et al. (2009) Final version of 2009 AJCC melanoma staging and classification. Journal of Clinical Oncology 27, 6199-6206CrossRefGoogle Scholar
3Mueller, D.W. and Bosserhoff, A.K. (2009) Role of miRNAs in the progression of malignant melanoma. British Journal of Cancer 101, 551-556CrossRefGoogle ScholarPubMed
4Garbe, C. and Leiter, U. (2009) Melanoma epidemiology and trends. Clinics in Dermatology 27, 3-9CrossRefGoogle ScholarPubMed
5Markovic, S.N. et al. (2007) Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clinic Proceedings 82, 364-380CrossRefGoogle ScholarPubMed
6Fortes, C. and de Vries, E. (2008) Nonsolar occupational risk factors for cutaneous melanoma. International Journal of Dermatology 47, 319-328CrossRefGoogle ScholarPubMed
7Haqq, C. et al. (2005) The gene expression signatures of melanoma progression. Proceedings of the National Academy of Sciences of the United States of America 102, 6092-6097CrossRefGoogle ScholarPubMed
8Le Douarin, N.M. (1986) Cell line segregation during peripheral nervous system ontogeny. Science 231, 1515-1522CrossRefGoogle ScholarPubMed
9Slominski, A. et al. (2004) Melanin pigmentation in mammalian skin and its hormonal regulation. Physiological Reviews 84, 1155-1228CrossRefGoogle ScholarPubMed
10Quintana, E. et al. (2008) Efficient tumour formation by single human melanoma cells. Nature 456, 593-598CrossRefGoogle ScholarPubMed
11Schatton, T. et al. (2008) Identification of cells initiating human melanomas. Nature 451, 345-349CrossRefGoogle ScholarPubMed
12Gray-Schopfer, V., Wellbrock, C. and Marais, R. (2007) Melanoma biology and new targeted therapy. Nature 445, 851-857CrossRefGoogle ScholarPubMed
13Miller, A.J. and Mihm, M.C. Jr (2006) Melanoma. New England Journal of Medicine 355, 51-65CrossRefGoogle ScholarPubMed
14Clark, W.H. Jr (1991) Human cutaneous malignant melanoma as a model for cancer. Cancer and Metastasis Reviews 10, 83-88CrossRefGoogle Scholar
15Serrone, L. et al. (2000) Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. Journal of Experimental and Clinical Cancer Research 19, 21-34Google ScholarPubMed
16Garbe, C. et al. (2011) Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 16, 5-24CrossRefGoogle ScholarPubMed
17Sondak, V.K. et al. (2011) Ipilimumab. Nature reviews. Drug Discovery 10, 411-412CrossRefGoogle Scholar
18Agarwala, S. (2003) Improving survival in patients with high-risk and metastatic melanoma: immunotherapy leads the way. American Journal of Clinical Dermatology 4, 333-346CrossRefGoogle ScholarPubMed
19Parkinson, D.R. et al. (1990) Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study. Journal of Clinical Oncology 8, 1650-1656CrossRefGoogle ScholarPubMed
20Hodi, F.S. et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine 363, 711-723CrossRefGoogle ScholarPubMed
21Kirkwood, J.M. et al. (2008) Adjuvant therapy with high-dose interferon alpha 2b in patients with high-risk stage IIB/III melanoma. Nature Clinical Practice. Oncology 5, 2-3CrossRefGoogle ScholarPubMed
22Mocellin, S. et al. (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. Journal of the National Cancer Institute 102, 493-501CrossRefGoogle ScholarPubMed
23http://ClinicalTrials.gov, D.o.c.t.c.i.t.U.S.a.a.t.w.Google Scholar
24Croce, C.M. (2008) Oncogenes and cancer. New England Journal of Medicine 358, 502-511CrossRefGoogle ScholarPubMed
25MacKie, R.M., Hauschild, A. and Eggermont, A.M. (2009) Epidemiology of invasive cutaneous melanoma. Annals of Oncology 20 (Suppl. 6), vi1-7CrossRefGoogle ScholarPubMed
26Thomas, N.E. (2006) BRAF somatic mutations in malignant melanoma and melanocytic naevi. Melanoma Research 16, 97-103CrossRefGoogle ScholarPubMed
27Kamb, A. et al. (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436-440CrossRefGoogle ScholarPubMed
28de Snoo, F.A. and Hayward, N.K. (2005) Cutaneous melanoma susceptibility and progression genes. Cancer Letters 230, 153-186CrossRefGoogle ScholarPubMed
29Ivry, G.B., Ogle, C.A. and Shim, E.K. (2006) Role of sun exposure in melanoma. Dermatolic Surgery 32, 481-492Google ScholarPubMed
30Bataille, V. (2003) Genetic epidemiology of melanoma. European Journal of Cancer 39, 1341-1347CrossRefGoogle ScholarPubMed
31Whiteman, D.C. (2010) Testing the divergent pathway hypothesis for melanoma: recent findings and future challenges. Expert Review of Anticancer Therapy 10, 615-618CrossRefGoogle ScholarPubMed
32Herlyn, M. (2009) Driving in the melanoma landscape. Experimental Dermatology 18, 506-508CrossRefGoogle ScholarPubMed
33Fecher, L.A. et al. (2007) Toward a molecular classification of melanoma. Journal of Clinical Oncology 25, 1606-1620CrossRefGoogle Scholar
34Davies, H. et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417, 949-954CrossRefGoogle ScholarPubMed
35Wellbrock, C. and Hurlstone, A. (2010) BRAF as therapeutic target in melanoma. Biochemical Pharmacology 80, 561-567CrossRefGoogle ScholarPubMed
36Pollock, P.M. and Meltzer, P.S. (2002) A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2, 5-7CrossRefGoogle ScholarPubMed
37Brose, M.S. et al. (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Research 62, 6997-7000Google ScholarPubMed
38Ichii-Nakato, N. et al. (2006) High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. Journal of Investigative Dermatology 126, 2111-2118CrossRefGoogle ScholarPubMed
39Davies, M.A. and Samuels, Y. (2010) Analysis of the genome to personalize therapy for melanoma. Oncogene 29, 5545-5555CrossRefGoogle ScholarPubMed
40Curtin, J.A. et al. (2005) Distinct sets of genetic alterations in melanoma. New England Journal of Medicine 353, 2135-2147CrossRefGoogle ScholarPubMed
41Pollock, P.M. et al. (2003) High frequency of BRAF mutations in nevi. Nature Genetics 33, 19-20CrossRefGoogle ScholarPubMed
42Michaloglou, C. et al. (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720-724CrossRefGoogle ScholarPubMed
43Cotter, M.A. et al. (2007) Absence of senescence-associated beta-galactosidase activity in human melanocytic nevi in vivo. Journal of Investigative Dermatology 127, 2469-2471CrossRefGoogle ScholarPubMed
44Houben, R. et al. (2009) Proliferation arrest in B-Raf mutant melanoma cell lines upon MAPK pathway activation. Journal of Investigative Dermatology 129, 406-414CrossRefGoogle ScholarPubMed
45Wajapeyee, N. et al. (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363-374CrossRefGoogle ScholarPubMed
46Kuilman, T. et al. (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019-1031CrossRefGoogle ScholarPubMed
47Scurr, L.L. et al. (2010) IGFBP7 is not required for B-RAF-induced melanocyte senescence. Cell 141, 717-727CrossRefGoogle Scholar
48Dankort, D. et al. (2009) Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nature Genetics 41, 544-552CrossRefGoogle ScholarPubMed
49Zhao, Y. et al. (2008) Simultaneous knockdown of BRAF and expression of INK4A in melanoma cells leads to potent growth inhibition and apoptosis. Biochemical and Biophysical Research Communications 370, 509-513CrossRefGoogle ScholarPubMed
50Johannessen, C.M. et al. (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968-972CrossRefGoogle ScholarPubMed
51Montagut, C. et al. (2008) Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Research 68, 4853-4861CrossRefGoogle ScholarPubMed
52Nazarian, R. et al. (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973-977CrossRefGoogle ScholarPubMed
53Paraiso, K.H. et al. (2010) Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. British Journal of Cancer 102, 1724-1730CrossRefGoogle ScholarPubMed
54Paraiso, K.H. et al. (2011) PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Research 71, 2750-2760CrossRefGoogle ScholarPubMed
55Smalley, K.S. et al. (2008) Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Molecular Cancer Therapeutics 7, 2876-2883CrossRefGoogle ScholarPubMed
56Villanueva, J. et al. (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18, 683-695CrossRefGoogle ScholarPubMed
57Solit, D.B. and Rosen, N. (2011) Resistance to BRAF inhibition in melanomas. New England Journal of Medicine 364, 772-774CrossRefGoogle ScholarPubMed
58Flaherty, K.T. and McArthur, G. (2010) BRAF, a target in melanoma: implications for solid tumor drug development. Cancer 116, 4902-4913CrossRefGoogle Scholar
59Flaherty, K.T. et al. (2008) A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel. Clinical Cancer Research 14, 4836-4842CrossRefGoogle ScholarPubMed
60Treisman, J. and Garlie, N. (2010) Systemic therapy for cutaneous melanoma. Clinics in Plastic Surgery 37, 127-146CrossRefGoogle ScholarPubMed
61Karasarides, M. et al. (2004) B-RAF is a therapeutic target in melanoma. Oncogene 23, 6292-6298CrossRefGoogle ScholarPubMed
62Eisen, T. et al. (2006) Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. British Journal of Cancer 95, 581-586CrossRefGoogle ScholarPubMed
63Murray, A. et al. (2010) Sorafenib enhances the in vitro anti-endothelial effects of low dose (metronomic) chemotherapy. Oncology Reports 24, 1049-1058Google ScholarPubMed
64Augustine, C.K. et al. (2010) Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy. Molecular Cancer Therapeutics 9, 2090-2101CrossRefGoogle ScholarPubMed
65Hauschild, A. et al. (2009) Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. Journal of Clinical Oncology 27, 2823-2830CrossRefGoogle ScholarPubMed
66Garber, K. (2009) Cancer research. Melanoma drug vindicates targeted approach. Science 326, 1619CrossRefGoogle ScholarPubMed
67Livingstone, E. et al. (2010) PLX4032: does it keep its promise for metastatic melanoma treatment? Expert Opinion on Investigational Drugs 19, 1439-1449CrossRefGoogle ScholarPubMed
68Bollag, G. et al. (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596-599CrossRefGoogle ScholarPubMed
69Flaherty, K., Puzanov, I. and Sosman, J.E.A. (2009) Phase I study of PLX4032: proof of concept for V600E BRAF mutations as a therapeutic target in human cancer. Journal of Clinical Oncology (Meeting abstracts) 27 (Suppl 15) (abstract 9000)CrossRefGoogle Scholar
70Yang, H. et al. (2010) RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Research 70, 5518-5527CrossRefGoogle ScholarPubMed
71Flaherty, K.T. et al. (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. New England Journal of Medicine 363, 809-819CrossRefGoogle ScholarPubMed
72Vultur, A., Villanueva, J. and Herlyn, M. (2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clinical Cancer Research 17, 1658-1663CrossRefGoogle ScholarPubMed
73Kaplan, F.M. et al. (2011) Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene 30, 366-371CrossRefGoogle ScholarPubMed
74Wagle, N. et al. (2011) Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling. Journal of Clinical Oncology 29, 3085-3096CrossRefGoogle ScholarPubMed
75Hatzivassiliou, G. et al. (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431-435CrossRefGoogle ScholarPubMed
76Ciuffreda, L. et al. (2009) Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations. Neoplasia 11, 720-731CrossRefGoogle ScholarPubMed
77Banerji, U. et al. (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clinical Cancer Research 16, 1613-1623CrossRefGoogle ScholarPubMed
78Denton, C.L. and Gustafson, D.L. (2010) Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemotherapy and Pharmacology 67, 349-360CrossRefGoogle ScholarPubMed
79Davies, B.R. et al. (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Molecular Cancer Therapeutics 6, 2209-2219CrossRefGoogle ScholarPubMed
80Solit, D.B. et al. (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358-362CrossRefGoogle ScholarPubMed
81Adjei, A.A. et al. (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. Journal of Clinical Oncology 26, 2139-2146CrossRefGoogle ScholarPubMed
82Berger, M.F. and Garraway, L.A. (2009) Applications of genomics in melanoma oncogene discovery. Hematology/Oncology Clinics of North America 23, 397-414, viiCrossRefGoogle ScholarPubMed
83Curtin, J.A. et al. (2006) Somatic activation of KIT in distinct subtypes of melanoma. Journal of Clinical Oncology 24, 4340-4346CrossRefGoogle ScholarPubMed
84Beadling, C. et al. (2008) KIT gene mutations and copy number in melanoma subtypes. Clinical Cancer Research 14, 6821-6828CrossRefGoogle ScholarPubMed
85Hofmann, U.B. et al. (2009) Overexpression of the KIT/SCF in uveal melanoma does not translate into clinical efficacy of imatinib mesylate. Clinical Cancer Research 15, 324-329CrossRefGoogle Scholar
86Woodman, S.E. and Davies, M.A. (2010) Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochemical Pharmacology 80, 568-574CrossRefGoogle ScholarPubMed
87Garrido, M.C. and Bastian, B.C. (2010) KIT as a therapeutic target in melanoma. Journal of Investigative Dermatology 130, 20-27CrossRefGoogle ScholarPubMed
88Flaherty, K.T., Hodi, F.S. and Bastian, B.C. (2010) Mutation-driven drug development in melanoma. Current Opinion in Oncology 22, 178-183CrossRefGoogle ScholarPubMed
89Jiang, X. et al. (2008) Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clinical Cancer Research 14, 7726-7732CrossRefGoogle ScholarPubMed
90Terheyden, P. et al. (2010) Response to imatinib mesylate depends on the presence of the V559A-mutated KIT oncogene. Journal of Investigative Dermatology 130, 314-316CrossRefGoogle ScholarPubMed
91Hodi, F.S. et al. (2008) Major response to imatinib mesylate in KIT-mutated melanoma. Journal of Clinical Oncology 26, 2046-2051CrossRefGoogle ScholarPubMed
92Lutzky, J., Bauer, J. and Bastian, B.C. (2008) Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell and Melanoma Research 21, 492-493CrossRefGoogle ScholarPubMed
93Wyman, K. et al. (2006) Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 106, 2005-2011CrossRefGoogle ScholarPubMed
94Ugurel, S. et al. (2005) Lack of clinical efficacy of imatinib in metastatic melanoma. British Journal of Cancer 92, 1398-1405CrossRefGoogle ScholarPubMed
95Kim, K.B. et al. (2008) Phase II trial of imatinib mesylate in patients with metastatic melanoma. British Journal of Cancer 99, 734-740CrossRefGoogle ScholarPubMed
96Handolias, D. et al. (2010) Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. British Journal of Cancer 102, 1219-1223CrossRefGoogle ScholarPubMed
97Porkka, K. et al. (2008) Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 112, 1005-1012CrossRefGoogle ScholarPubMed
98Carvajal, R.D. et al. (2009) A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT. Journal of Clinical Oncology 27 (Suppl) (abstr 9001)CrossRefGoogle Scholar
99Hocker, T.L., Singh, M.K. and Tsao, H. (2008) Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside. Journal of Investigative Dermatology 128, 2575-2595CrossRefGoogle ScholarPubMed
100Bush, J.A. and Li, G. (2003) The role of Bcl-2 family members in the progression of cutaneous melanoma. Clinical and Experimental Metastasis 20, 531-539CrossRefGoogle ScholarPubMed
101Tron, V.A. et al. (1995) Immunohistochemical analysis of Bcl-2 protein regulation in cutaneous melanoma. American Journal of Pathology 146, 643-650Google ScholarPubMed
102Tang, L. et al. (1998) Expression of apoptosis regulators in cutaneous malignant melanoma. Clinical Cancer Research 4, 1865-1871Google ScholarPubMed
103Zhuang, L. et al. (2007) Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Modern Pathology 20, 416-426CrossRefGoogle ScholarPubMed
104Keuling, A.M. et al. (2009) RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway. PLoS One 4, e6651CrossRefGoogle ScholarPubMed
105Benimetskaya, L. et al. (2006) Bcl-2 protein in 518A2 melanoma cells in vivo and in vitro. Clinical Cancer Research 12, 4940-4948CrossRefGoogle ScholarPubMed
106Bedikian, A.Y. et al. (2006) Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. Journal of Clinical Oncology 24, 4738-4745CrossRefGoogle ScholarPubMed
107Singh, S. et al. (2009) The role of human endogenous retroviruses in melanoma. British Journal of Dermatology 161, 1225-1231CrossRefGoogle ScholarPubMed
108Serafino, A. et al. (2009) The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation. Experimental Cell Research 315, 849-862CrossRefGoogle ScholarPubMed
109Golan, M. et al. (2008) Human endogenous retrovirus (HERV-K) reverse transcriptase as a breast cancer prognostic marker. Neoplasia 10, 521-533CrossRefGoogle ScholarPubMed
110Wang-Johanning, F. et al. (2007) Expression of multiple human endogenous retrovirus surface envelope proteins in ovarian cancer. International Journal of Cancer 120, 81-90CrossRefGoogle ScholarPubMed
111Depil, S. et al. (2002) Expression of a human endogenous retrovirus, HERV-K, in the blood cells of leukemia patients. Leukemia 16, 254-259CrossRefGoogle ScholarPubMed
112Hahn, S. et al. (2008) Serological response to human endogenous retrovirus K in melanoma patients correlates with survival probability. AIDS Research and Human Retroviruses 24, 717-723CrossRefGoogle ScholarPubMed
113Oricchio, E. et al. (2007) Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression. Oncogene 26, 4226-4233CrossRefGoogle ScholarPubMed
114Hohenadl, C. et al. (1999) Transcriptional activation of endogenous retroviral sequences in human epidermal keratinocytes by UVB irradiation. Journal of Investigative Dermatology 113, 587-594CrossRefGoogle ScholarPubMed
115Reiche, J., Pauli, G. and Ellerbrok, H. (2010) Differential expression of human endogenous retrovirus K transcripts in primary human melanocytes and melanoma cell lines after UV irradiation. Melanoma Research 20, 435-440CrossRefGoogle ScholarPubMed
116Khan, A.S., Muller, J. and Sears, J.F. (2001) Early detection of endogenous retroviruses in chemically induced mouse cells. Virus Research 79, 39-45CrossRefGoogle ScholarPubMed
117Ono, M., Kawakami, M. and Ushikubo, H. (1987) Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D. Journal of Virology 61, 2059-2062CrossRefGoogle ScholarPubMed
118Wang, Y. and Lee, C.G. (2009) MicroRNA and cancer–focus on apoptosis. Journal of Cellular and Molecular Medicine 13, 12-23CrossRefGoogle ScholarPubMed
120Selbach, M. et al. (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58-63CrossRefGoogle ScholarPubMed
121Chen, K. and Rajewsky, N. (2006) Natural selection on human microRNA binding sites inferred from SNP data. Nature Genetics 38, 1452-1456CrossRefGoogle ScholarPubMed
122Calin, G.A. et al. (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the United States of America 101, 2999-3004CrossRefGoogle ScholarPubMed
123Leidinger, P. et al. (2010) High-throughput miRNA profiling of human melanoma blood samples. BMC Cancer 10, 262CrossRefGoogle ScholarPubMed
124Sigalotti, L. et al. (2010) Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies. Journal of Translational Medicine 8, 56CrossRefGoogle ScholarPubMed
125Chen, J. et al. (2010) MicroRNA-193b represses cell proliferation and regulates cyclin D1 in melanoma. American Journal of Pathology 176, 2520-2529CrossRefGoogle ScholarPubMed
126Segura, M.F. et al. (2010) Melanoma MicroRNA signature predicts post-recurrence survival. Clinical Cancer Research 16, 1577-1586CrossRefGoogle ScholarPubMed
127Levy, C. et al. (2010) Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma. Molecular Cell 40, 841-849CrossRefGoogle ScholarPubMed
128Wiggins, J.F. et al. (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Research 70, 5923-5930CrossRefGoogle ScholarPubMed
129Lasithiotakis, K.G. et al. (2008) Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. Journal of Investigative Dermatology 128, 2013-2023CrossRefGoogle ScholarPubMed
130Smalley, K.S. and Herlyn, M. (2005) Targeting intracellular signaling pathways as a novel strategy in melanoma therapeutics. Annals of the New York Academy of Sciences 1059, 16-25CrossRefGoogle ScholarPubMed
131Lorigan, P., Eisen, T. and Hauschild, A. (2008) Systemic therapy for metastatic malignant melanoma – from deeply disappointing to bright future? Experimental Dermatology 17, 383-394CrossRefGoogle ScholarPubMed
132Smalley, K.S. and Flaherty, K.T. (2009) Integrating BRAF/MEK inhibitors into combination therapy for melanoma. British Journal of Cancer 100, 431-435CrossRefGoogle ScholarPubMed
133Smalley, K.S. et al. (2006) Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Molecular Cancer Therapeutics 5, 1136-1144CrossRefGoogle ScholarPubMed
134Tran, M.A. et al. (2008) Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer Research 68, 7638-7649CrossRefGoogle ScholarPubMed
135Krasilnikov, M. et al. (2003) ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis. Oncogene 22, 4092-4101CrossRefGoogle ScholarPubMed
136Lopez-Bergami, P., Fitchman, B. and Ronai, Z. (2008) Understanding signaling cascades in melanoma. Photochemistry and Photobiology 84, 289-306CrossRefGoogle ScholarPubMed
137Tran, M.A. et al. (2008) Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clinical Cancer Research 14, 3571-3581CrossRefGoogle ScholarPubMed
138Bedogni, B. et al. (2004) Topical treatment with inhibitors of the phosphatidylinositol 3′-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice. Cancer Research 64, 2552-2560CrossRefGoogle ScholarPubMed
139Li, J. et al. (2010) Simultaneous inhibition of MEK and CDK4 leads to potent apoptosis in human melanoma cells. Cancer Investigation 28, 350-356CrossRefGoogle ScholarPubMed
140Elbashir, S.M. et al. (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494-498CrossRefGoogle ScholarPubMed
141Tran, M.A., Watts, R.J. and Robertson, G.P. (2009) Use of liposomes as drug delivery vehicles for treatment of melanoma. Pigment Cell and Melanoma Research 22, 388-399CrossRefGoogle ScholarPubMed
142Kawakami, S. and Hashida, M. (2007) Targeted delivery systems of small interfering RNA by systemic administration. Drug Metabolism and Pharmacokinetics 22, 142-151CrossRefGoogle ScholarPubMed
143Chen, S.H. and Zhaori, G. (2010) Potential clinical applications of siRNA technique: benefits and limitations. European Journal of Clinical Investigation 41, 221-232CrossRefGoogle ScholarPubMed
144Fire, A. et al. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811CrossRefGoogle ScholarPubMed
145Alshamsan, A. et al. (2010) The induction of tumor apoptosis in B16 melanoma following STAT3 siRNA delivery with a lipid-substituted polyethylenimine. Biomaterials 31, 1420-1428CrossRefGoogle ScholarPubMed
146Chen, Y. et al. (2010) Targeted nanoparticles deliver siRNA to melanoma. Journal of Investigative Dermatology 130, 2790-2798CrossRefGoogle ScholarPubMed
147Su, J., Chen, X. and Kanekura, T. (2009) A CD147-targeting siRNA inhibits the proliferation, invasiveness, and VEGF production of human malignant melanoma cells by down-regulating glycolysis. Cancer Letters 273, 140-147CrossRefGoogle ScholarPubMed
148Wang, H. et al. (2007) Silencing livin gene by siRNA leads to apoptosis induction, cell cycle arrest, and proliferation inhibition in malignant melanoma LiBr cells. Acta Pharmacologica Sinica 28, 1968-1974CrossRefGoogle ScholarPubMed
149Davis, M.E. et al. (2010) Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067-1070CrossRefGoogle ScholarPubMed
150Zhang, L. et al. (2008) Nanoparticles in medicine: therapeutic applications and developments. Clinical Pharmacology and Therapeutics 83, 761-769CrossRefGoogle Scholar
151Hughes, G.A. (2005) Nanostructure-mediated drug delivery. Nanomedicine 1, 22-30CrossRefGoogle ScholarPubMed
152Zhao, B. et al. (2009) Enhanced photodynamic efficacy towards melanoma cells by encapsulation of Pc4 in silica nanoparticles. Toxicology and Applied Pharmacology 241, 163-172CrossRefGoogle ScholarPubMed
153Timko, B.P., Dvir, T. and Kohane, D.S. (2010) Remotely triggerable drug delivery systems. Advanced Materials 22, 4925-4943CrossRefGoogle ScholarPubMed
154Kim, C.K., Ghosh, P. and Rotello, V.M. (2009) Multimodal drug delivery using gold nanoparticles. Nanoscale 1, 61-67CrossRefGoogle ScholarPubMed
155Cobley, C.M. et al. (2010) Targeting gold nanocages to cancer cells for photothermal destruction and drug delivery. Expert Opinion on Drug Delivery 7, 577-587CrossRefGoogle ScholarPubMed
156Chen, Y. et al. (2010) Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Molecular Therapy 18, 1650-1656CrossRefGoogle ScholarPubMed
157Villares, G.J. et al. (2008) Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA. Cancer Research 68, 9078-9086CrossRefGoogle ScholarPubMed
158Love, K.T. et al. (2010) Lipid-like materials for low-dose, in vivo gene silencing. Proceedings of the National Academy of Sciences of the United States of America 107, 1864-1869CrossRefGoogle ScholarPubMed
159Peer, D. et al. (2007) Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2, 751-760CrossRefGoogle ScholarPubMed
160Xu, L. and Anchordoquy, T. (2010) Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics. Journal of Pharmaceutical Sciences 100, 38-52CrossRefGoogle Scholar
161Bawa, R. (2008) Nanoparticle-based therapeutics in humans: a survey. Nanotechnology Law and Business 5, 135-155Google Scholar
162Gao, W., Chan, J.M. and Farokhzad, O.C. (2010) pH-Responsive nanoparticles for drug delivery. Molecular Pharmaceutics 7, 1913-1920CrossRefGoogle ScholarPubMed
163Buzea, C., Pacheco, II and Robbie, K. (2007) Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2, MR17-MR71CrossRefGoogle ScholarPubMed
164Barbas, A.S. and White, R.R. (2009) The development and testing of aptamers for cancer. Current Opinion in Investigational Drugs 10, 572-578Google ScholarPubMed
165White, R.R., Sullenger, B.A. and Rusconi, C.P. (2000) Developing aptamers into therapeutics. Journal of Clinical Investigation 106, 929-934CrossRefGoogle ScholarPubMed
166Jordan, A. et al. (2006) The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. Journal of Neuro-oncology 78, 7-14CrossRefGoogle ScholarPubMed
167Fink, W. et al. (2004) Clinical phase II study of pegylated liposomal doxorubicin as second-line treatment in disseminated melanoma. Onkologie 27, 540-544Google ScholarPubMed
168Hwang, T.L. et al. (2007) Cisplatin encapsulated in phosphatidylethanolamine liposomes enhances the in vitro cytotoxicity and in vivo intratumor drug accumulation against melanomas. Journal of Dermatological Science 46, 11-20CrossRefGoogle ScholarPubMed
169Basu, S. et al. (2009) Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy. Proceedings of the National Academy of Sciences of the United States of America 106, 7957-7961CrossRefGoogle ScholarPubMed
170Aboody, K.S., Najbauer, J. and Danks, M.K. (2008) Stem and progenitor cell-mediated tumor selective gene therapy. Gene Therapy 15, 739-752CrossRefGoogle ScholarPubMed
171Aboody, K.S. et al. (2006) Targeting of melanoma brain metastases using engineered neural stem/progenitor cells. Neurooncology 8, 119-126Google ScholarPubMed
172Aboody, K.S. et al. (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proceedings of the National Academy of Sciences of the United States of America 97, 12846-12851CrossRefGoogle ScholarPubMed
173Porada, C.D. and Almeida-Porada, G. (2010) Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Advanced Drug Delivery Reviews 62, 1156-1166CrossRefGoogle ScholarPubMed
174Brown, A.B. et al. (2003) Intravascular delivery of neural stem cell lines to target intracranial and extracranial tumors of neural and non-neural origin. Human Gene Therapy 14, 1777-1785CrossRefGoogle ScholarPubMed
175Gutova, M. et al. (2010) Therapeutic targeting of melanoma cells using neural stem cells expressing carboxylesterase, a CPT-11 activating enzyme. Current Stem Cell Research and Therapy 5, 273-276CrossRefGoogle ScholarPubMed
176Studeny, M. et al. (2004) Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. Journal of the National Cancer Institute 96, 1593-1603CrossRefGoogle ScholarPubMed
177Kulesa, P.M. et al. (2006) Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment. Proceedings of the National Academy of Sciences of the United States of America 103, 3752-3757CrossRefGoogle Scholar
178Weber, J. (2011) Immunotherapy for melanoma. Current Opinion in Oncology 23, 163-169CrossRefGoogle ScholarPubMed
179Homsi, J., Grimm, J.C. and Hwu, P. (2011) Immunotherapy of melanoma: an update. Surgical Oncology Clinics of North America 20, 145-163CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Miller, A.J. and Mihm, M.C. Jr (2006) Melanoma. New England Journal of Medicine 355, 51-65CrossRefGoogle ScholarPubMed
Garbe, C. et al. (2011) Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 16, 5-24CrossRefGoogle ScholarPubMed
Croce, C.M. (2008) Oncogenes and cancer. New England Journal of Medicine 358, 502-511CrossRefGoogle ScholarPubMed
Vultur, A., Villanueva, J. and Herlyn, M. (2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clinical Cancer Research 17, 1658-1663CrossRefGoogle ScholarPubMed
Mueller, D.W. and Bosserhoff, A.K. (2009) Role of miRNAs in the progression of malignant melanoma. British Journal of Cancer 101, 551-556CrossRefGoogle ScholarPubMed
Singh, S. et al. (2009) The role of human endogenous retroviruses in melanoma. British Journal of Dermatology 161, 1225-1231CrossRefGoogle ScholarPubMed
Peer, D. et al. (2007) Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2, 751-760CrossRefGoogle ScholarPubMed
Aboody, K.S., Najbauer, J. and Danks, M.K. (2008) Stem and progenitor cell-mediated tumor selective gene therapy. Gene Therapy 15, 739-752CrossRefGoogle ScholarPubMed
Weber, J. (2011) Immunotherapy for melanoma. Current Opinion in Oncology 23, 163-169CrossRefGoogle ScholarPubMed
Database of clinical trials conducted in the USA and around the world can be found at: http://ClinicalTrials.govGoogle Scholar
The miRNA library can be found at: http://www.microRNA.orgGoogle Scholar
Miller, A.J. and Mihm, M.C. Jr (2006) Melanoma. New England Journal of Medicine 355, 51-65CrossRefGoogle ScholarPubMed
Garbe, C. et al. (2011) Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 16, 5-24CrossRefGoogle ScholarPubMed
Croce, C.M. (2008) Oncogenes and cancer. New England Journal of Medicine 358, 502-511CrossRefGoogle ScholarPubMed
Vultur, A., Villanueva, J. and Herlyn, M. (2011) Targeting BRAF in advanced melanoma: a first step toward manageable disease. Clinical Cancer Research 17, 1658-1663CrossRefGoogle ScholarPubMed
Mueller, D.W. and Bosserhoff, A.K. (2009) Role of miRNAs in the progression of malignant melanoma. British Journal of Cancer 101, 551-556CrossRefGoogle ScholarPubMed
Singh, S. et al. (2009) The role of human endogenous retroviruses in melanoma. British Journal of Dermatology 161, 1225-1231CrossRefGoogle ScholarPubMed
Peer, D. et al. (2007) Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2, 751-760CrossRefGoogle ScholarPubMed
Aboody, K.S., Najbauer, J. and Danks, M.K. (2008) Stem and progenitor cell-mediated tumor selective gene therapy. Gene Therapy 15, 739-752CrossRefGoogle ScholarPubMed
Weber, J. (2011) Immunotherapy for melanoma. Current Opinion in Oncology 23, 163-169CrossRefGoogle ScholarPubMed
Database of clinical trials conducted in the USA and around the world can be found at: http://ClinicalTrials.govGoogle Scholar
The miRNA library can be found at: http://www.microRNA.orgGoogle Scholar