- 1Section of Pharmacology Department of. Internal Medicine (Di.M.I.) University of Genova Viale Benedetto XV, 2 16132 Genova - Italy. federica.barbieri@unige.it.
Abstract
Malignant pleural mesothelioma (MPM) is a deadliest and heterogeneous neoplasia, highly refractory to multimodal therapeutic approach consisting of surgery, chemo- and radio-therapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, without fulfilling expected clinical benefits. Thus, novel molecular targets should be identified from a definite knowledge of the unique biology and most relevant transduction pathways of MPM cells. Cancer stem cells (CSCs) are a subset of malignant precursors responsible for initiation, progression, resistance to cytotoxic drugs, recurrence and metastatic diffusion of tumor cells. CSCs are putative driving factors in MPM development and contribute to its clinical and biological heterogeneity; hence, targeted eradication of CSCs represents an ineludible goal to counteract MPM aggressiveness. In this context, innovative models could be exploited in preclinical studies to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible of the oncogenic transformation of mesothelial cells, often directly induced by asbestos. These include mitogenic and anti-apoptotic signaling, that may also be activated by autocrine and paracrine cytokine pathways involved in cell plasticity, invasion and metastasis. Either signaling pathways affecting proto-oncogene and transcription factor expression, or genetic and epigenetic alterations, such as mutations in cell cycle genes and silencing of tumor suppressor genes, represent promising disease-specific targets. In this review we describe current knowledge of MPM cell biology, focusing on potential targets to be tested in pharmacological studies, and highlighting results and challenges of clinical translation.
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