Molecular pharmacology of malignant pleural mesothelioma: Challenges and perspectives from preclinical and clinical studies

Stefano Thellung, Roberto E. Favoni, Roberto Würth, Mario Nizzari, Alessandra Pattarozzi, Antonio Daga, Tullio Florio, Federica Barbieri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)824-849
Number of pages26
JournalCurrent Drug Targets
Volume17
Issue number7
Publication statusPublished - Jun 1 2016

Keywords

  • Anticancer drug
  • Cancer stem cell
  • Malignant pleural mesothelioma
  • Molecular profiling
  • Signaling pathways
  • Targeted therapy
  • Translational studies

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Clinical Biochemistry
  • Molecular Medicine

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