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.
乌帕莫司他是一种口服小分子丝氨酸蛋白酶抑制剂，对胰蛋白酶1、胰蛋白酶2、胰蛋白酶3（PRSS1/2/3）以及尿激酶型纤溶酶原激活物（uPA）具有高效抑制作用。这些酶在多种癌症中均有表达，尤其在组织重塑及后续肿瘤细胞侵袭过程中发挥关键作用。奥帕戈尼布（ABC294640）作为一种新型口服小分子药物，能够选择性抑制鞘氨醇激酶2（SPHK2）催化鞘氨醇磷酸化为鞘氨醇-1-磷酸（S-1-P）的过程。已知鞘氨醇激酶1（SPHK1）与SPHK2均可调控具有增殖诱导作用的S-1-P，但SPHK2在癌症发病机制中具有更为关键的作用。本研究旨在探讨乌帕莫司他与奥帕戈尼布单药及联合用药对裸鼠胆管癌移植瘤的潜在抗肿瘤效应。实验采用源自手术切除胆管癌组织的患者来源移植瘤模型PAX165，该模型高表达SPHK2、PRSS1、PRSS2及PRSS3。将72只小鼠均分为四组，分别给予乌帕莫司他、奥帕戈尼布、两药联合或空白对照治疗。监测小鼠体重及PAX165移植瘤体积变化。结果显示，与对照组相比，乌帕莫司他组、奥帕戈尼布组及联合用药组的肿瘤体积均显著减小。
肿瘤(癌症)患者之家