VIENNA — There are multiple genetic targets and combinations of therapies that hold great promise for changing the fate of melanoma patients, Christoph Höeller, M.D., said at the 10th World Congress on Cancers of the Skin.
A major focus of targeted therapies has been the protooncogene for Bcl-2, which is linked to chemoresistance, a problem in melanoma patients.
Antisense oligonucleotide therapy targeting Bcl-2 mRNA has increased tumor cell apoptosis and tumor response. But it has still not significantly improved the overall survival of these patients.
Small molecule inhibitors of Bcl-2 are entering phase I and phase III trials, and Bcl-2 RNA interference (RNAi) is in preclinical evaluation. But there's more to targeted therapies than Bcl-2, he said.
Dr. Höeller and colleagues at the Medical University of Vienna recently found that clusterin, a glycoprotein implicated in many cellular functions including apoptosis, varies in expression between melanocytes and melanoma cells (J. Invest. Dermatol. 2005;124:1300–7).
In tissue samples, 45% of melanomas stained positive for clusterin, whereas only 18% of nevi stained positive.
Antisense oligonucleotides directed against clusterin mRNA also significantly decreased the survival of human melanoma cells in mice in the presence of cytotoxic drugs, suggesting that downregulation of clusterin may be helpful in overcoming drug resistance in melanoma.
Mcl-1, another member of the Bcl-2 family that has been found to contribute to chemoresistance in melanoma in vivo, has potential for antisense therapy or combination therapy.
Combined Mcl-1 antisense oligonucleotides plus dacarbazine treatment led to significantly reduced mean tumor weight in severe combined immunodeficiency mice, compared with animals treated with saline plus dacarbazine or control oligonucleotide plus dacarbazine (J. Invest. Dermatol. 2003;120:1081–6).
Other treatment strategies include the use of histone deacetylase inhibitors such as tributyrin, sodium butyrate, and phenylbutyrate.
Histone deacetylase inhibitors are now in phase II studies, having been shown to be active against melanoma cells in in vivo and in vitro models, Dr. Höeller said at the meeting, which was cosponsored by the Skin Cancer Foundation.
Finally, he noted that bortezomib (Velcade), which is approved for patients with multiple myeloma and has a chemosensitizing effect when administered with other antitumoral drugs, may be useful in melanoma.
In a separate presentation, Eva-Bettina Bröcker, M.D., of the University of Würzburg (Germany), reported on a vaccine that targets the protein survivin.
Survivin is normally active only in growing embryos or rapidly dividing cells, but is turned on in a variety of malignancies.
It has become an increasingly popular target because downregulation or loss of expression of survivin is associated with impaired tumor progression.
Among five stage IV melanoma patients vaccinated with the human leukocyte antigen-A2 restricted survivin (96–104) epitope, four patients mounted strong T-cell responses to the epitope as measured by enzyme-linked immunospot assay (Vaccine 2005;23:884–9).