Novel targeted therapeutic strategies for treating mesothelioma

http://www.ncbi.nlm.nih.gov/pubmed/22289125

Br J Pharmacol. 2012 Jan 31. doi: 10.1111/j.1476-5381.2012.01873.x. [Epub ahead of print]
Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma.
Favoni RE, Daga A, Malatesta P, Florio T.
Source
Department of Translational Oncology Research, Laboratory of Gene Transfer, National Cancer Institute, Department of Experimental Medicine, Department of Internal Medicine, Section of Pharmacology, University of Genoa, Largo Rosanna Benzi, 10 16132 - Genoa, ITALY; Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, 2 16132 - Genoa, ITALY.

Abstract
The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum-derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumor cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumor, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to current carcinogenesis theory, CSCs represent the tumor-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumor mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoral drugs, may contribute to better dissect the biology and multidrug-resistance pathways controlling hMPM growth.