**2.4 Wilms' tumor protein**

*Mesothelioma*

at the first-line treatment [11].

**2.2 Arginosuccinate synthetase**

(Clinicaltrials.gov ID NCT02709512).

**2.3 Aurora kinase**

than 95% of malignant pleural mesothelioma (MPM) samples stained positive for VEGF [5]. An increase expression of VEGF was specifically observed in the epithelioid histology, more than biphasic and sarcomatoid. VEGF was not felt to have any prognostic significance in this study [5]. In another study, VEGF was found to be an independent, poor prognostic factor in MPM [6]. The phase III MAPS study showed that the addition of bevacizumab, a humanized anti-VEGF monoclonal IgG1 antibody, to frontline cisplatin/pemetrexed in unresectable malignant pleural mesothelioma improves overall survival (18.8 vs. 16.1; hazard ratio 0.77 [0.62–0.95]; p = 0.0167) compared to cisplatin/pemetrexed alone regardless of tumor histology [7]. Analysis from the MAPS study showed that high VEGF concentrations were associated with worse progression free survival and overall survival but VEGF did not have a clinically meaningful predictive significance of response to bevacizumab [8]. Other antiangiogenic agents like Sorafenib and axitinib have showed limited activity in malignant mesotheliomas [9, 10]. Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of VEGFR-2 and prevents the binding of VEGFR ligands: VEGF-A, VEGF-C, and VEGF-D. A recently published Phase II abstract showed that the addition of Ramucirumab to gemcitabine significantly improved the overall survival in advanced MPM patients who progressed on first-line platinum-pemetrexed chemotherapy. This was observed regardless of patient age, tumor stage (locally advanced vs. metastatic), histotype (epithelioid vs. non-epithelioid), and time to progression

Certain cancer cells have a higher nutritional demand compared to normal cells. Arginine is an amino acid that plays an important role in biological and signaling pathways [12]. Arginine is either synthesized in the body or consumed in the diet. Normal cells synthesize arginine through the urea cycle. Research suggests that certain cancer cells cannot internally make arginine because they lack the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) which ultimately makes them dependent on exogenous supplies of arginine, an important amino acid for cancer survival and growth [13]. ASS is a key enzyme that converts citrulline to arginine. This has led scientists to hypothesize that targeting the arginine synthesis pathway may be an effective therapeutic approach that targets cancer cells and spares normal cells. Mesothelioma is one of the tumors that usually does not express ASS [14]. Arginine degradation is dependent on different enzymes, including an enzyme called arginine deiminase (ADI) that degrades arginine to citrulline. In turn, citrulline can be recycled back to arginine in normal cells through ASS [14]. A pegylated arginine deiminase (ADI-PEG 20) has been developed as an arginine depleting agent and is currently being tested in a randomized, double-blind, phase 2/3 study in subjects with malignant pleural mesothelioma with low argininosuccinate synthetase 1 expression to assess ADI-PEG 20 with pemetrexed and cisplatin

Aurora kinase gene expression is upregulated in mesothelioma tumor tissue and is considered a negative prognostic factor [15–17]. The Aurora proteins are serine/ threonine kinases that function in various stages of mitosis. Aurora kinase proteins A/B play an important role in mitosis, monopolar spindles formation, chromosomal segregation cytokinesis, and polyploidy. These proteins are overexpressed in mesothelioma [18]. Aurora kinase inhibitors, like ZM447439, are able to inhibit cell

**80**

WT-1 is a zinc finger transcription factor protein that is responsible for controlling the expression of genes involved in cellular growth, differentiation, and/or apoptosis [19]. WT1 is a nuclear protein that is processed and highly overexpressed on the cell surface of MPM. Immunohistochemical (IHC) staining for WT1 is routinely used in establishing the diagnosis of mesothelioma. WT-1 protein expression is detected by IHC in 78.1% of MPM and associated with improved overall survival and prognosis [20]. Although WT1 protein is expressed on the cell surface in the context of MHC molecules, which makes it a target for T-cell based immunotherapeutic approach [21]. A randomized phase II trial of adjuvant galinpepimut-S, WT-1 analogue peptide vaccine, after multimodality therapy for patients with WT-1 + MPM showed that a favorable safety profile with suggested improvement in progression-free survival and overall survival and a larger randomized trial is planned [22].
