title: Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies.
abstract: Malignant pleural mesothelioma (MPM) is one of the deadliest and most heterogeneous tumors, highly refractory to multimodal therapeutic approach, including surgery, chemo- and radiotherapy. Preclinical and clinical studies exploring the efficacy of drugs targeting tyrosine kinases, angiogenesis and histone deacetylases, did not fulfil the 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 for 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 preclinical models could be exploited to identify novel intracellular pathway inhibitors able to target CSC viability. Novel drug targets have been identified among key factors responsible for 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 controlling cell plasticity. Both 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.
authors.forename: Stefano
authors.initials: S
authors.lastname: Thellung
authors.forename: Roberto E
authors.initials: RE
authors.lastname: Favoni
authors.forename: Roberto
authors.initials: R
authors.lastname: Würth
authors.forename: Mario
authors.initials: M
authors.lastname: Nizzari
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.affiliation: Section of Pharmacology, Department of. Internal Medicine (Di.M.I.), University of Genova, Viale Benedetto XV, 2 16132 Genova, Italy. federica.barbieri@unige.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas