Open Access

Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review)

  • Authors:
    • Giulia Grazia
    • Ilaria Penna
    • Valentina Perotti
    • Andrea Anichini
    • Elena Tassi
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  • Published online on: June 10, 2014     https://doi.org/10.3892/ijo.2014.2491
  • Pages: 929-949
  • Copyright: © Grazia et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Over the last few years, clinical trials with BRAF and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors have shown significant clinical activity in melanoma, but only a fraction of patients respond to these therapies, and development of resistance is frequent. This has prompted a large set of preclinical studies looking at several new combinatorial approaches of pathway- or target-specific inhibitors. At least five main drug association strategies have been verified in vitro and in preclinical models. The most promising include: i) vertical targeting of either MEK or phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways, or their combined blockade; ii) association of receptor tyrosine kinases (RTKs) inhibitors with other pro-apoptotic strategies; iii) engagement of death receptors in combination with MEK-, mTOR/PI3K-, histone deacetylase (HDAC)-inhibitors, or with anti-apoptotic molecules modulators; iv) strategies aimed at blocking anti-apoptotic proteins belonging to B-cell lymphoma (Bcl-2) or inhibitors of apoptosis (IAP) families associated with MEK/BRAF/p38 inhibition; v) co-inhibition of other molecules important for survival [proteasome, HDAC and Signal transducers and activators of transcription (Stat)3] and the major pathways activated in melanoma; vi) simultaneous targeting of multiple anti-apoptotic molecules. Here we review the anti-melanoma efficacy and mechanism of action of the above-mentioned combinatorial strategies, together with the potential clinical application of the most promising studies that may eventually lead to therapeutic benefit.
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September-2014
Volume 45 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Grazia G, Penna I, Perotti V, Anichini A and Tassi E: Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review). Int J Oncol 45: 929-949, 2014.
APA
Grazia, G., Penna, I., Perotti, V., Anichini, A., & Tassi, E. (2014). Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review). International Journal of Oncology, 45, 929-949. https://doi.org/10.3892/ijo.2014.2491
MLA
Grazia, G., Penna, I., Perotti, V., Anichini, A., Tassi, E."Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review)". International Journal of Oncology 45.3 (2014): 929-949.
Chicago
Grazia, G., Penna, I., Perotti, V., Anichini, A., Tassi, E."Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review)". International Journal of Oncology 45, no. 3 (2014): 929-949. https://doi.org/10.3892/ijo.2014.2491