The Role of Mesothelin as a Diagnostic and Therapeutic Target in Pancreatic Ductal Adenocarcinoma: A Comprehensive Review

Abstract

Mesothelin is a tumor differentiation antigen, which is highly expressed in several solid neoplasms, including pancreatic cancer. Its selective expression on malignant cells and on only a limited number of healthy tissues has made it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. Based on a strong preclinical rationale, a number of therapeutic agents targeting mesothelin have entered clinical trials, including immunotoxins, monoclonal antibodies, antibody-drug conjugates, cancer vaccines, and adoptive T cell therapies with chimeric antigen receptors. In pancreatic cancer, mesothelin has been investigated mainly to address two unmet issues: the urgent need for new laboratory techniques for early tumor detection and the lack of successfully targetable oncogenic alterations for patients' treatment. In this review, we describe the clinicopathological significance of mesothelin expression in pancreatic cancer initiation and progression, we summarize available studies evaluating mesothelin as a potential diagnostic and prognostic biomarker in this disease, and we discuss current evidence and future perspectives of preclinical and clinical studies testing mesothelin as a molecular target for pancreatic cancer treatment.

99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma

“…Using TCGA datasets, we observed an overexpression of mesothelin only in PDAC-derived specimens in comparison to nontumoral samples. In agreement with other previous studies, high expression of mesothelin predicted shorter overall survival of PDAC patients [7,14]. The increase of mesothelin expression in the advanced disease stages of PDAC suggests its relevance as a disease progression biomarker.…”

“…Despite intense clinical efforts, PDAC remains one of the most aggressive malignancies with a five-year survival rate around 5–7% [3]. The advanced stages of PDAC at the diagnosis and the intrinsic resistance to standard therapies give rise to this dismal prognosis [7]. Until today, most clinical trials have failed to demonstrate significant improvement in patient survival [10].…”

“…However, mesothelin is present in a wide range of tumors including ovarian and lung cancers (60–65%), and also PDAC-derived tumors (80–85%) [12]. Several studies demonstrated a crucial role of mesothelin in cell survival, proliferation, and resistance to chemotherapy [7,13].…”

“…Hence, mesothelin has been identified as a diagnostic marker and a relevant therapeutic target. As much as 80–85% of PDAC displayed greater levels of mesothelin [6,7]. No significant elevation of the shed form was detected in the serum of PDAC patients.…”

Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer

“…With this in mind, an article from 2017 [65] summarized the possible targets of CAR T-cells in pancreatic cancer and added CD24, prostate stem cell antigen, and natural killer receptors for the construction of CARs. By showing high expression, mesothelin appears to be the most promising target for CARs [66][67][68][69]. Other research [70] focused on blocking IL-10 with the purpose of tackling the immunosuppressive effect of the tumor microenvironment and enhancing mesothelin CAR T-cell activity.…”