Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer
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Tara Williamson1, Michelle Carvalho de Abreu1,2, Dimitri G. Trembath3, Cory Brayton4, Byunghak Kang4, Thais Biude Mendes1,5, Paulo Pimentel de Assumpção2, Janete M. Cerutti5 and Gregory J. Riggins1
1 Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA
2 Oncology Research Center, Federal University of Pará, Belém, Brazil
3 Department of Pathology and Laboratory Medicine, University of North Carolina Hospitals, Women and Children Hospital, Chapel Hill, NC, USA
4 Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, USA
5 Genetic Basis of Thyroid Tumors Laboratory, Division of Genetics, Universidade Federal de São Paulo, São Paulo, Brazil
|Gregory J. Riggins,||email:||[email protected]|
Keywords: mebendazole; pancreatic cancer; cancer prevention; metastasis; mouse models
Received: May 19, 2021 Accepted: June 14, 2021 Published: July 06, 2021
The five-year survival rate for metastatic pancreatic cancer is currently only 3%, which increases to 13% with local invasion only and to 39% with localized disease at diagnosis. Here we evaluated repurposed mebendazole, an approved anthelminthic drug, to determine how mebendazole might work at the different stages of pancreatic cancer formation and progression. We asked if mebendazole could prevent initiation of pancreatic intraepithelial neoplasia precursor lesions, interfere with stromal desmoplasia, or suppress tumor growth and liver metastasis. In both the KrasLSL.G12D/+; Pdx1-Cre (KC) mouse model of caerulein-induced inflammatory pancreatitis and the KrasLSL.G12D/+; Tp53R172H/+; Pdx1-Cre (KPC) mouse model of advanced pancreatic cancer, mebendazole significantly reduced pancreas weight, dysplasia and intraepithelial neoplasia formation, compared to controls. Mebendazole significantly reduced trichrome-positive fibrotic connective tissue and α-SMA-positive activated pancreatic stellate cells that heralds fibrogenesis. In the aggressive KPC model, mebendazole significantly suppressed pancreatic tumor growth, both as an early and late intervention. Mebendazole reduced the overall incidence of pancreatic cancer and severity of liver metastasis in KPC mice. Using early models of pancreatic cancer, treatment with mebendazole resulted in less inflammation, decreased dysplasia, with the later stage model additionally showing a decreased tumor burden, less advanced tumors, and a reduction of metastasis. We conclude that mebendazole should be investigated further as a component of adjuvant therapy to slow progression and prevent metastasis, and well as for primary prevention in the highest risk patients.
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