Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequ...

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Published in:	Cancers Vol. 16; no. 5; p. 1050
Main Authors:	Asumda, Faizal Z, Campbell, Nellie A, Hassan, Mohamed A, Fathi, Reza, Vasquez Rico, Daniella F, Kiem, Melanie, Vang, Ethan V, Kim, Yo Han, Luo, Xin, O'Brien, Daniel R, Buhrow, Sarah A, Reid, Joel M, Moore, Michael J, Ben-Yair, Vered Katz, Levitt, Mark L, Leiting, Jennifer L, Abdelrahman, Amro M, Zhu, Xinli, Lucien, Fabrice, Truty, Mark J, Roberts, Lewis R
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 05-03-2024 MDPI
Subjects:	Analysis Antibodies Antitumor activity Cancer therapies Cell adhesion & migration Cell growth Chemotherapy Cholangiocarcinoma Development and progression Enzymes Immunotherapy Kinases Liver cancer Metastasis Mutation Phosphorylation Prognosis Protease inhibitors Proteinase inhibitors Serine Serine proteinase Sphingosine Sphingosine 1-phosphate Sphingosine kinase Statistical analysis Thrombin Trypsin Tumors U-Plasminogen activator Urokinase Xenografts United Kingdom Netherlands United States > US cholangiocellular carcinoma patient-derived xenograft (PDX) upamostat opaganib sphingosine kinase WX-UK1 serine protease
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Summary:	Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2072-6694 2072-6694
DOI:	10.3390/cancers16051050