Malignant Mesothelioma: Time to Translate?

Abstract

Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our understanding of its genetics and molecular biology and their translational relevance. Remarkable findings included the discovery of germline and somatic mutations of BRCA1 associated protein-1 (BAP1) in patients, and the genome-wide characterization of pathways altered in mesothelioma that could be potentially exploited to design novel therapeutic approaches. Nevertheless, the clinical translation of these molecular findings has been slow and insufficient. In order to rapidly move translation from the bench to the bedside, we believe that cooperative research efforts have to be further endorsed and promoted at all levels.

Keywords: BAP1; malignant mesothelioma; therapy; translation.

Figure 1 (Key Figure). Potential molecular targets in malignant mesothelioma

The most common genetic mutations in mesothelioma are in the tumor suppressor genes BAP1, NF2, and CDKN2A. Although these molecules cannot be directly targeted, therapies can aim at surrogate intracellular targets whose activity is as a consequence increased or necessary. Promising therapies currently undergoing clinical trials include the use of monoclonal antibodies to target surface molecules specific for mesothelioma (e.g., mesothelin) and immune checkpoint (e.g. CTLA-4, PD1, PDL1). Inhibition of VEGF with the monoclonal antibody bevacizumab has been proven effective in a phase III clinical trial. Other potential soluble targets whose translational relevance is being currently investigated are also shown.