The Role of Angiogenesis Inhibitors in The Treatment of Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a highly aggressive and incurable cancer that originates from the mesothelial cells of the pleural cavity. It is associated with a long latency period of inhalation of asbestos fibers of 20-40 years. The subtypes of MPM include epitheloid (60%), sarcomatoid (10%), and biphasic (30%), which comprise both epitheloid and sarcomatoid histological features. The sarcomatoid type has the poorest prognosis with a median overall survival (OS) of 3 months, whereas the epitheloid and biphasic have median survival of only 7% at 3 years. The mechanisms by which asbestosis fibers are carcinogenic are not fully understood. MPM is associated with several genetic mutations in DNA, and alterations in some oncogenes, and tumor suppressor genes; and the activation of signaling pathways involved in cell proliferation and apoptosis. MPM is usually diagnosed very late with advanced disease, and the treatment of unresectable disease is chemotherapy with cisplatin plus pemetrexed; which has a response rate of about 26.3%-41%, and modestly extends survival by 2-3 months. Vascular endothelial growth factor (VEGF) is the most potent endothelial specific mitogen for endothelial cells. It promotes angiogenesis in tumors and propagates cancer growth and metastasis. In pleural mesothelioma, VEGF directly acts as an autocrine mitogen for mesothelial cells, thus orchestrating the growth and local spread of the tumor. Bevacizumab is a humanized monoclonal murine antibody which blocks the immunopathological pathways of VEGF and its receptors on endothelial cells, and mesothelioma cells. Addition of bevacizumab a VEGF inhibitor to cisplatin plus pemetrexed regimen has been shown to extend the median OS for 16-22 months, versus 14-18 months with cisplatin plus pemetrexed. Other anti-angiogenesis agents have been studied for the treatment of MPM, such as nintedanib, and cidiranib, unfortunately, both biologics, resulted in insignificant improvement in OS and the progression-free survival (PFS). There is need to shift gear in the development of biologics for targeted treatment of MPM, such as immune checkpoints, in order to improve OS, PFS, and quality of life for the patients.

Keywords: Malignant pleural mesothelioma; Bevacizumab; Cisplatin; Pemetrexed; Vascular endothelial growth factor

Abbreviations: DVT-Deep Venous Thrombosis; TIA-Transient Ischaemic Attack