Biological basis for novel mesothelioma therapies

Abstract

Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…Although the data reported in this review provide several information about the MPM TME players and its close connections, many questions related to their clinicopathological impact are still opened and a better knowledge of them may help cancer research for developing TME-based therapeutics able to overcome the poor overall survival of MPM patients, the chemoresistance mechanisms and the relapse of the tumor. Although the last therapy targeting TME in mesothelioma clinical trials including the immunotherapy and the combination immuno/chemotherapy are promising therapeutic approaches [ 148 , 149 , 150 ], the efficacy of these strategies remains limited. A wide consideration of TME as the main player of cancer initiation and progression is required, in order to have in-depth knowledge of TME complexity and to design new drugs that target not only tumor cells but also the TME players supporting cancer.…”

“…PD-1 is generally expressed on the immune cells’ surface and once activated in response to ligand binding, they negatively regulate T cell activation. The anti-PD-1 antibodies, pembrolizumab, nivolumab and durvalumab have shown promising results in clinical trials; however, a heterogenic response among MPM patients was reported [ 147 , 148 ]. To increase the efficacy of these treatment modalities, combinatory strategies are under clinical investigation, with both CTLA-4 and PD-1 inhibitors as well as PD-1 inhibitors plus chemotherapy [ 147 , 149 ].…”

Antagonist of Growth Hormone-Releasing Hormone Potentiates the Antitumor Effect of Pemetrexed and Cisplatin in Pleural Mesothelioma

“…Histologically, PM has been classified into three major subtypes: epithelioid (50–70% of cases), sarcomatoid (10–20% of cases) and biphasic, a combination of epithelioid and sarcomatoid (30% of cases) [ 3 ]. Of note, sarcomatoid mesothelioma has a poor prognosis, with a median survival of 4 months, while epithelioid and biphasic PM have better outcomes, of 13.1 and 8.4 months, respectively [ 1 , 4 ]. The first-line systemic treatment for unresectable PM is the combination of cisplatin and pemetrexed [ 2 , 5 , 6 ].…”

Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis

“…In addition to cytotoxic chemotherapy and ICI agents, several new agents were recently designed to treat MPM. Anetumab ravtansine comprises a human anti-mesothelin IgG1 antibody conjugated via a disulfide-containing linker to the maytansinoid tubulin inhibitor DM4, which disrupts microtubule function and inhibits mitosis [ 30 ]. Mesothelin, a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, is a tumor differentiation antigen frequently expressed at high levels in tumors, such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas, and showing restricted expression in nonmalignant tissues [ 31 ].…”