恶性胸膜间皮瘤的分子药理学：临床前与临床研究的挑战与展望

Title:Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies

Volume: 17 Issue: 7

Author(s): Stefano Thellung, Roberto E. Favoni, Roberto Würth, Mario Nizzari, Alessandra Pattarozzi, Antonio Daga, Tullio Florio and Federica Barbieri

Affiliation:

关键词: 抗癌药物；肿瘤干细胞；恶性胸膜间皮瘤；分子分析；信号转导通路；靶向治疗；转化研究。

摘要: 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.

Cite this article as:

Stefano Thellung, Roberto E. Favoni, Roberto Würth, Mario Nizzari, Alessandra Pattarozzi, Antonio Daga, Tullio Florio and Federica Barbieri , Molecular Pharmacology of Malignant Pleural Mesothelioma: Challenges and Perspectives From Preclinical and Clinical Studies, Current Drug Targets 2016; 17 (7) . https://dx.doi.org/10.2174/1389450116666150804110714