Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects

Abstract

Malignant mesothelioma is a rare and aggressive cancer that develops in the thin layer surrounding the mesothelium and is mainly caused by asbestos exposure. Despite improvements in patient prognosis with conventional cancer treatments, such as surgery, chemotherapy, and radiotherapy, there are still no curative treatment modalities for advanced disease. In recent years, new therapeutic avenues have been explored. Improved understanding of the mechanisms underlying the dynamic tumor interaction with the immune system has led to the development of immunotherapeutic approaches. Numerous recent clinical trials have shown a desire to develop more effective treatments that can be used to fight against the disease. Immune checkpoint inhibitors, oncolytic adenoviruses, and their combination represent a promising strategy that can be used to synergistically overcome immunosuppression in the mesothelioma tumor microenvironment. This review provides a synthesized overview of the current state of knowledge on new therapeutic options for mesothelioma with a focus on the results of clinical trials conducted in the field.

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

“…The standard treatment for unresectable PM consists of the combination of cisplatin and pemetrexed, which, however, has not proved to be resolutive and only partially improves the patients’ quality of life [ 2 , 6 ]; consequently, novel therapeutic strategies are needed. We have previously demonstrated that GHRH antagonists MIA-602 and MIA-690 alone exert potent and similar antitumor effects in vitro, in human PM cell lines and primary cells, and in vivo, in a xenograft model of human PM [ 29 ].…”

“…Accordingly, our present results show that MIA-690 potentiates the effect of cisplatin/pemetrexed in PM xenografts also on inhibition of NF-kB, assessed as phosphorylation of p65 subunit, and STAT3 phosphorylation. The activation of NF-kB is involved in inflammatory pathways and associated with exposure to asbestos fibers and tumor evolution in mesothelioma [ 2 ]. Furthermore, the transcription factor STAT3, which controls the expression of genes regulating survival, proliferation and self-renewal, is frequently activated in many cancers, including mesothelioma, and is associated with oncogenic characteristics and poor survival [ 2 , 35 ].…”

“…The activation of NF-kB is involved in inflammatory pathways and associated with exposure to asbestos fibers and tumor evolution in mesothelioma [ 2 ]. Furthermore, the transcription factor STAT3, which controls the expression of genes regulating survival, proliferation and self-renewal, is frequently activated in many cancers, including mesothelioma, and is associated with oncogenic characteristics and poor survival [ 2 , 35 ]. Importantly, NF-kB and STAT3 physically and functionally interact in chemotherapy resistant MPM cell lines [ 56 ].…”

“…PM develops in the thin layer surrounding the mesothelium and is mainly caused by the inhalation of asbestos fibers, with a long latency of 20–50 years between exposure to asbestos and the onset of the disease. Inhaled asbestos fibers cause inflammation of the pleura, DNA damage of mesothelial cells with recruitment of macrophages and neutrophils, leading to activation of proliferative and oncogenic pathways and tumorigenesis [ 2 ]. 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 ]. However, PM is often refractory to standard chemotherapy, with response rates of only 40% and a median overall survival of 12 months, likely because of tumor aggressiveness, resistance of mesothelioma cells to chemotherapy and immune-suppressive environment [ 1 , 7 ].…”