TY - JOUR
T1 - Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts
AU - Asumda, Faizal Z.
AU - Campbell, Nellie A.
AU - Hassan, Mohamed A.
AU - Fathi, Reza
AU - Vasquez Rico, Daniella F.
AU - Kiem, Melanie
AU - Vang, Ethan V.
AU - Kim, Yo Han
AU - Luo, Xin
AU - O’Brien, Daniel R.
AU - Buhrow, Sarah A.
AU - Reid, Joel M.
AU - Moore, Michael J.
AU - Ben-Yair, Vered Katz
AU - Levitt, Mark L.
AU - Leiting, Jennifer L.
AU - Abdelrahman, Amro M.
AU - Zhu, Xinli
AU - Lucien, Fabrice
AU - Truty, Mark J.
AU - Roberts, Lewis R.
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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.
KW - WX-UK1
KW - cholangiocellular carcinoma
KW - opaganib
KW - patient-derived xenograft (PDX)
KW - serine protease
KW - sphingosine kinase
KW - upamostat
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UR - http://www.scopus.com/inward/citedby.url?scp=85187671857&partnerID=8YFLogxK
U2 - 10.3390/cancers16051050
DO - 10.3390/cancers16051050
M3 - Article
AN - SCOPUS:85187671857
SN - 2072-6694
VL - 16
JO - Cancers
JF - Cancers
IS - 5
M1 - 1050
ER -