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Annals of Oncology 2009 20(Supplement 6):vi35-vi40; doi:10.1093/annonc/mdp254
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
The online version of this article has been published under an open access model. users are entitle to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and the European Society for Medical Oncology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

This article appears in the following Annals of Oncology issue: Melanoma: Perspectives of the Global Melanoma Task Force [View the issue table of contents]

Articles

Small molecules and targeted therapies in distant metastatic disease

P. Hersey1,*, L. Bastholt2, V. Chiarion-Sileni3, G. Cinat4, R. Dummer5, A. M. M. Eggermont6, E. Espinosa7, A. Hauschild8, I. Quirt9, C. Robert10 and D. Schadendorf11

1 Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, New South Wales, Australia
2 Department of Oncology, Odense University Hospital, Odense, Denmark
3 Department of Oncology, Istituto Oncologico Veneto, Padova, Italy
4 Department of Oncology, Instituto de Oncologia Angel Roffo, Buenos Aires, Argentina
5 Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland
6 Department of Surgical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
7 Department of Oncology, Hospital La Paz, Madrid, Spain
8 Department of Dermatology, University of Kiel, Kiel, Germany
9 Princess Margaret Hospital, Toronto, Canada
10 Department of Dermatology, Institut Gustave Roussy, Villejuif, France
11 Department of Dermatology, University Hospital Essen, Essen, Germany

* Correspondence to: Peter Hersey, Room 443, David Maddison Clinical Sciences Building, Corner King and Watt Streets, Newcastle, NSW 2300 Australia; Tel: +61-2-49138828; Fax: +61-2-49138184; Email: Peter.Hersey{at}newcastle.edu.au

Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.

Key words: B-Raf, c-Kit, inhibitor, melanoma, mTOR, multikinase


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