From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic.

Keywords: CAR T-cells; PDAC; antibody-based therapy; mesothelin; vaccines.

Figure 1

Putative roles of MSLN in PDAC progression. MSLN promotes tumor cell survival and proliferation through ERK and PI3K/Akt pathways; and invasiveness and metastasis processes by MMP-7 activity. Metastasis could also be facilitated by interaction with MUC16 expressing cells. However, the underlying mechanisms linking MSLN to EMT and angiogenesis, as well as the other putative partners of MSLN still remain to be elucidated in PDAC. The biological significances of miR-21-5p and miR-198 are also depicted in this schematic illustration.

Figure 2

This schema depicts the different anti-MSLN targeting drugs that are currently under clinical development, including the monoclonal antibody (mAb) amatuximab, SS1P and LMB-100/RG7787 immunotoxins, ²²⁷Th-radiolabeled antibody, antibody-drug conjugates, vaccines and CAR-T-cells.