Progress in the Management of Malignant Pleural Mesothelioma in 2017

Abstract

Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.

Keywords: BAP1; Immunotherapy; Mesothelin; Mesothelioma; Review; Therapy.

Figure 1. Genetic alterations in the malignant transformation of MPM and potential therapeutic targets

The NF2 gene encodes the merlin protein, which regulates the Hippo pathway. Loss of NF2 function leads to inactivation of the Hippo pathway, activation of the YAP transcriptional coactivator, ultimately promoting cell proliferation and survival. Defactinib is a focal adhesion kinase (FAK) inhibitor created for potential action on the NF2 pathway, but was unsuccessful in MPM treatment.PTEN is a negative regulator of the PI3K/AKT pathway, and loss of PTEN function results in over activation of this pathway, leading to cell growth and proliferation.BAP1 is a tumor suppressor gene. Without it, the EZH2 component of the PRC2 complex is activated, leading to tri-methylation of Histone 3 Lysine 27 (H3K27), and ultimately malignant transformation. Tazemetostat is an EZH2 inhibitor.CDK2NA encodes p14^ARF and p16^INK4a. p14^ARF interacts with MDM2, resulting in MDM2 degradation and ultimate activation of p53 Loss of p14^ARF expression increases MDM2 levels, decreasing p53 function, resulting in increased cell survival. p16^INK4a is essential in hyperphosphorylation and subsequent inhibition of the retinoblastoma pathway. Loss of this cyclin-dependent kinase inhibitor leads to unchecked activation of the retinoblastoma pathway and ultimately cell cycle progression.TP53 encodes p53, and loss of this results in loss of p53 and subsequent cell proliferation and survival.

Figure 2. Potential therapeutic targets of mesothelin surface proteins

This figure demonstrates the proposed mechanisms of mesothelioma treatment specifically targeting mesothelin, including via monoclonal antibodies, immunotoxins, antibody drug conjugates, virus-packed vaccine therapy, and CAR-T cell therapy. TCR = T cell receptor; APC = Antigen presenting cell; CAR = Chimeric antigen receptor; MHC = Major histocompatibility complex

Figure 3. Effect of arginine deprivation on tumor cells

A) In cells with fully functional ASS1, arginine required for the urea cycle can be created from citrulline via the ASS1 enzyme, or via direct uptake from the plasma. B) In cells deficient in ASS1, its ability to convert citrilline to arginine is decreased at baseline. ADI-PEG20 is an enzyme that breaks down arginine in the plasma into citrulline and ammonia. Giving ADI-PEG20 to cells already deficient in arginine further depletes a cell of arginine, inhibiting urea cycle function and eventually leading to cell death. ASS1 = Argininosuccinate synthetase 1; ASL = Argininosuccinate lyase; NH3 = ammonia