**Abstract**

We are witnessing enormous efforts to identify prognostic and predictive biomarkers to inform treatment decisions in malignant mesothelioma. In this chapter, we will review and discuss the current literature and supportive evidence for the progress in development and use of biomarkers in malignant mesothelioma. There are currently several clinical trials evaluating treatment options in mesothelioma, and this will be an up-to-date review of these trials from published literature.

**Keywords:** mesothelioma, biomarkers, ASS1, BAP1, CDKN2A, mesothelin, NF-2, PDL-1, VEGF, WT-1

#### **1. Epidemiology of mesothelioma**

Malignant mesothelioma (MM) is an aggressive, rare cancer of pleural (80%), and peritoneal cells and less frequently in the pericardium and tunica vaginalis of the testis. MM has historically been linked to mineral fiber exposure. Asbestos is a collective term given to six mineral fibers including actinolite, amosite, anthophyllite, chrysotile, crocidolite, and tremolite [1]. Exposure to other non-asbestos mineral fibers including erionite and fluoro-edenite has also been linked to MM [2]. However, cases of MM have been found in patients who were not exposed to these mineral fibers. This led researchers to discover other epidemiologies of mesothelioma heavily linked to genetic mutations, including tumor suppressors like BRCA1 associated protein (BAP1) [3].

#### **2. Biomarkers in mesothelioma**

Recent research has been aimed at studying various biomarkers in malignant mesothelioma. Researchers hope that by identifying and studying specific biomarkers, new therapies can be developed that better target the unique pathways of malignant mesothelioma pathogenesis.

#### **2.1 Vascular endothelial growth factor**

The VEGF pathway is believed to play a critical role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumors [4]. In one study, more 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 at the first-line treatment [11].

#### **2.2 Arginosuccinate synthetase**

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 (Clinicaltrials.gov ID NCT02709512).

#### **2.3 Aurora kinase**

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

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*Biomarkers Progress and Therapeutic Implications in Malignant Mesothelioma*

growth in all mesothelioma cell lines [18]. Alisertib (MLN8237) is a selective aurora kinase A inhibitor that is currently being evaluated in pretreated patients with

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

Mesothelin is a tumor differentiation protein that is normally expressed in low amounts on the pleural, peritoneal, and pericardial mesothelial cells. Mesothelin is highly expressed in malignant mesothelioma as well as other cancers like pancreatic, ovarian, and lung adenocarcinoma [23–25]. The differential expression of mesothelin between normal tissues and malignant cells made it an attractive candidate for cancer therapy. Mesothelin targeting agents including chimeric antigen receptor (CAR) T cells and vaccination strategies are currently in development for the treatment of MPM. CRS-207 is a live-attenuated strain of the bacterium *Listeria monocytogenes* that is engineered to express mesothelin. CRS-207 induces antitumor immune responses and increase the susceptibility of neoplastic cells to immune-mediated killing. A phase I study combining CRS-207 and pemetrexed/cisplatin chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated

PD-L1 is overexpressed in 40–50% of mesothelioma and associated with poor outcome. In one study, high PD-L1 expression was associated with non-epithelioid MM, poor clinical outcome, and increased immunological infiltrates [27]. Several PD-L1 and PD1 targeting agents have been studied in mesothelioma with modest activity. Pembrolizumab, nivolumab, and ipilimumab are routinely used in the second-line therapy of malignant mesothelioma. PD-L1 testing is not required for prescribing pembrolizumab or nivolumab in the second-line therapy for patients with PMP [28]. Limited data suggests that high PD-L1 expression (≥25% positive tumor cells) seems to be a predictor of higher overall response rate to nivolumab on nivolumab plus ipilimumab and even better objective response rate when the PD-L1 expression is >50% [29]. Real-world data suggests that the high PD-L1 expression (≥50%) and non-epithelioid histology are associated with an improved objective response rate to pembrolizumab compared to intermediate (5–49%) and negative

PD-L1 expression (<5%) in the second-line therapy of MPM [30].

*DOI: http://dx.doi.org/10.5772/intechopen.93564*

larger randomized trial is planned [22].

**2.6 Programmed death-receptor ligand**

**2.5 Mesothelin**

patients [26].

**2.4 Wilms' tumor protein**

unresectable MPM (Clinicaltrials.gov NCT02293005).

growth in all mesothelioma cell lines [18]. Alisertib (MLN8237) is a selective aurora kinase A inhibitor that is currently being evaluated in pretreated patients with unresectable MPM (Clinicaltrials.gov NCT02293005).
