Antiangiogeneic Strategies in Mesothelioma

Abstract

There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.

Biomarkers for Malignant Pleural Mesothelioma—A Novel View on Inflammation

“…Antiangiogenic therapeutic approaches have been widely investigated as reviewed recently by Novak et al [150]. Thus, the clinical use of the VEGF inhibitor bevacizumab is now also regarded as promising improvement of the almost 20 year old standard chemotherapy regimen published by Vogelzang et al [151] according to the promising results of the MAPS trial [152].…”

Genomics and Functional Genomics of Malignant Pleural Mesothelioma

“…Likewise, deregulated angiogenesis is an integral component of the highly aggressive behavior, and the chemotherapy-resistant nature of MPM [ 102 , 103 ]. This has been obtrusive by way of augmented expression of HIF-1α (hypoxia-inducible factor 1α) and elevated blood neovascularization as measured via vessel density [ 104 , 105 ]. Furthermore, deregulations in master regulators of angiogenesis, which include increased expression of VEGF (vascular endothelial growth factor) family proteins and their specific receptors (VEGFRs), and the downstream targets of VEGF/VEGFR signaling axis, mainly the RTK signaling mediators PKC (protein kinase C) and Akt, have been implicated in MPM tumorigenesis [ 106 ].…”

“…Similarly, deregulation of FGF and PDGF pathways by virtue of autocrine and paracrine signaling, have been associated with MPM cell survival and angiogenesis [ 107 ]. Despite the negative results with earlier antiangiogenic therapies, newly designed clinical studies targeting VEGF and other growth factor signaling pathways, alone or in combination, are underway [ 105 ].…”

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

“…Recently, the addition of an anti- vascular endothelial growth factor (anti-VEGF) therapy (Bevacizumab) has been shown to enhance OS when given in the first line setting [ 13 ]. And whilst this therapeutic combination is now the new standard of care in France [ 14 ], it has not yet been approved by the FDA, issues with cost and lack of reimbursement prevent it from being added to the SOC in many countries, and other anti-angiogenic combinations have not been successful [ 15 ].…”