Abstract
Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (99mTc-A1). Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. 99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of 99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (p < 0.05). In vivo, the 99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (99mTc-Ctl) (p < 0.01). Conclusions: 99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, representing the fourth leading cause of cancer-related deaths worldwide in 2018 [1]
PDAC patients with high MSLN tumoral gene expression had a significant decreased overall survival when compared to patients with low expression (Figure 1B) (n = 177; P = 0.00066; Hazard ratio (HR): 2.05)
To further validate our PDAC in silico dataset study model, greater expression of proliferative markers MKI67, CCNB1, and PCNA were only depicted in tumoral PDAC-derived specimens (Figure S1A, p < 0.05) and their overexpressions were associated with a shorter overall survival (Figure S1B, p < 0.01)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, representing the fourth leading cause of cancer-related deaths worldwide in 2018 [1]. By the year 2030, PDAC is projected to surpass breast, colorectal, and prostate cancer and to become the second most deadly malignancy [2]. The five-year survival rate remains just around 5–7%. One-year survival is achieved in less than 20% of cases [3]. The mesothelin gene encodes a 71 kDa precursor protein. It is processed in a shed form known as Megakaryocyte Potentiating Factor, and a 40 kDa GPI-anchored membrane form, which is the Cancers 2019, 11, 1531; doi:10.3390/cancers11101531 www.mdpi.com/journal/cancers
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