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Molecular Classification of Patients With Malignant Melanoma for New Therapeutic Strategies

Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Li Punti-Sassari, Italy

Paolo A. Ascierto

Istituto Nazionale Tumori "Fondazione Pascale," Napoli, Italy

Francesco Tanda, Antonio Cossu

Istituto di Anatomia Patologica, Azienda Unità Sanitaria Locale 1, Sassari, Italy

To the Editor:

In a recent article, Bedikian and colleagues¹ reported that the addition of an antisense oligonucleotide against the bcl-2 mRNA (oblimersen sodium) to a systemic chemotherapy (dacarbazine) for the treatment of advanced melanoma increased overall survival in a subset of patients only (those without an elevated baseline serum lactate dehydrogenase [LDH]).

The article by Bedikian et al raises important questions about the appropriate use of gene-targeted anticancer molecules in combination with conventional drugs. The selection of patients to be addressed to such new biologic therapies remains a critical issue. Indeed, there is a major concern that clinical trials based on heterogeneous populations of patients might cause potentially valuable drugs to be abandoned. In the study by Bedikian and colleagues, the expression of the bcl-2 protein as molecular target of the oblimersen treatment was not assessed in primary melanomas from the enrolled patients,¹ not allowing to make correlations between such a marker and the other disease indicators (clinicopathologic parameters, including the prognostic LDH serum levels, clinical outcome).

This is particularly important in light of the increasing evidences that melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocytic cells. Resistance to apoptosis through the expression of bcl-2 protein (in our experience, higher bcl-2 expression has been observed in melanomas with low-intermediate thickness) has been hypothesized to represent one aspect among the different molecular mechanisms underlying aggressiveness, clinical behavior, and response to therapy of melanoma cells.

On this regard, the MAPK-ERK pathway (including the cascade of N-ras, BRAF, MEK1/2, and ERK1/2 gene products) has been reported to play a major role in both development and progression of malignant melanoma.^2,3 The ERK1/2 proteins, which represent the final components of such a signaling kinase cascade, have been found to be constitutively activated in melanomas and to be probably involved in the aggressive melanoma behavior.⁴ According to published data⁵ and to preliminary evidences by our group, mechanisms leading to the activation of ERK1/2 proteins in melanoma can be a result of the upregulation of various effectors from different molecular pathways, including the proteins acting into either the p16^CDKN2A-cyclinD1-RB cascade or the p14^CDKN2A-MDM2-p53 cascade. Impairments of the p53 pathway, whose final effectors are indeed the bax/bcl-2 proteins, are implicated in defective apoptotic response of melanomas to genotoxic damage and, thus, to anticancer agents.⁵

The demonstrations of functional interactions between the proteins belonging to the different pathways involved into the melanomagenesis (ie, expression levels of p16^CDKN2A may contribute to BRAF-driven proliferation⁶ or the activated BRAF may cooperate with p53 and its downstream proteins involved into the apoptosis⁷) strongly suggest the existence of complex molecular machinery that provides checks and balances in normal melanocytes, whose integrity or defective activity may protect against or favor, respectively, a malignant behavior.

Altogether, these issues seem to emphasize the fact that in melanoma, and probably in all types of cancer, it is unlikely that targeting a single component in the signaling pathway will yield significant antitumor responses. For this purpose, molecular analyses could help us to make a prediction, identifying the subsets of patients who would be expected to be more or less likely to respond to specific therapeutic interventions. Before planning phase III trials using targeted inhibitors in combination with chemotherapy in the near future, tissue sections from each melanoma patients to be included in the study should therefore undergo molecular analyses (ie, immunohistochemistry with antibodies against the main candidate protein within the above-mentioned functional cascades: p16^CDKN2A, p14^CDKN2A, pERK1/2, pRB, p10, p53, cyclinD1). This should be even more opportune in the case of studies using multitargeted agents, which may have more potential effects (such as sorafenib, a kinase inhibitor targeting several types of receptors⁸).

In other words, knowledge of the genetic and molecular differences among melanomas could be valuable in the design of new therapeutic strategies.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

The authors are writing on behalf of the Italian Melanoma Intergroup.

REFERENCES

1. Bedikian AY, Millward M, Pehamberger H, et al: Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: The Oblimersen Melanoma Study Group. J Clin Oncol 24:4738-4745, 2006[Abstract/Free Full Text]

2. Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human cancer. Nature 417:949-954, 2002[CrossRef][Medline]

3. Casula M, Colombino M, Satta MP, et al: BRAF gene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility. J Clin Oncol 22:286-292, 2004[Abstract/Free Full Text]

4. Smalley KS: A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 104:527-532, 2003[CrossRef][Medline]

5. Thompson JF, Scolyer RA, Kefford RF: Cutaneous melanoma. Lancet 365:687-701, 2005[Medline]

6. Michaloglou C, Vredeveld LC, Soengas MS, et al: BRAF^E600-associated senescence-like cell cycle arrest of human naevi. Nature 436:720-724, 2005[CrossRef][Medline]

7. Patton EE, Widlund HR, Kutok JL, et al: BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol 15:249-254, 2005[CrossRef][Medline]

8. Danson S, Lorigan P: Improving outcomes in advanced malignant melanoma: Update on systemic therapy. Drugs 65:733-743, 2005[CrossRef][Medline]

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