Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts
单位：[1]Departments of Pediatrics and Pathology, Medical College of Georgia-Augusta University Medical Center, Augusta, GA 30912, USA.[2]Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Rochester, MN 55905, USA.[3]Southwest Medical Associates, Las Vegas, NV 89128, USA.[4]RedHill Biopharma, Ltd., 21 Ha'arba'a St., Tel Aviv 6473921, Israel.[5]Department of Microbiology & Immunology, University of Minnesota, Minneapolis, MN 55455, USA.[6]Study of Human Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.[7]Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.[8]Hepatic Surgery Center and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China.外科学系肝脏外科华中科技大学同济医学院附属同济医院[9]Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.[10]Department of Oncology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.[11]Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.[12]Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.[13]Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310030, China.浙江大学医学院附属第一医院
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.
基金：
This research was funded by RedHill Biopharma. LRR was supported in part by the
National Cancer Institute through the Mayo Clinic Hepatobiliary SPORE (P50 CA 210964). The APC
was funded by the Mayo Foundation.
第一作者单位：[1]Departments of Pediatrics and Pathology, Medical College of Georgia-Augusta University Medical Center, Augusta, GA 30912, USA.
通讯作者：
推荐引用方式(GB/T 7714)：
Asumda Faizal Z,Campbell Nellie A,Hassan Mohamed A,et al.Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts[J].Cancers.2024,16(5):doi:10.3390/cancers16051050.
APA：
Asumda Faizal Z,Campbell Nellie A,Hassan Mohamed A,Fathi Reza,Vasquez Rico Daniella F...&Roberts Lewis R.(2024).Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts.Cancers,16,(5)
MLA：
Asumda Faizal Z,et al."Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts".Cancers 16..5(2024)
