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Simple Summary: Cholangiocarcinoma (CCA) accounts for approximately 15% of primary liver cancers. CCA has a poor prognosis and, thus, more effective systemic treatments are needed. We tested opaganib and upamostat, drugs that target sphingosine kinase 2 and multiple serine proteases, primarily trypsins, which are highly expressed in CCA tumors. This study demonstrates the results of inhibiting these novel targets with these drugs individually and in combination in a patient-derived CCA xenograft mouse model. 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. [ABSTRACT FROM AUTHOR]

Background Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe coronavirus disease 2019 (COVID-19) pneumonia. The objective of the study was to evaluate the safety of opaganib and its effect on supplemental oxygen requirements and time to hospital discharge in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods This Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in 8 sites in the United States. Forty-two enrolled patients received opaganib (n = 23) or placebo (n = 19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo. Results There were no safety concerns arising in this study. The incidence of ≥Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. A numerical advantage for opaganib over placebo was observed in in this nonpowered study reflected by total supplemental oxygen requirement from baseline to Day 14, the requirement for supplemental oxygen for at least 24 hours by Day 14, and hospital discharge. Conclusions In this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib had a similar safety profile to placebo-treated patients, with preliminary evidence of benefit for opaganib as measured by supplementary oxygen requirement and earlier hospital discharge. These findings support further evaluation of opaganib in this population. [ABSTRACT FROM AUTHOR]

Presents a study which characterized the possible role of second messenger ceramide in ultraviolet-induced apoptosis in both E1A transfectants and parental cells. Review of related literature; Materials and methods used; Results.

Purpose: Suramin, a polysulfonated naphthylurea, has been shown to be effective in the treatment of several cancers. We have reported that suramin, at dose concentrations higher than 140 μ M, exerts growth-stimulatory effects in several non-small-cell lung cancer (NSCLC) cell lines. The purpose of this study was to examine the mechanisms by which suramin exerts this growth-stimulatory effect in NSCLC cells. Methods: NCI-H596 cells were treated with agarose-immobilized suramin, directly or by addition on cell culture inserts, after which growth was determined by [3H]thymidine incorporation. PPADS, a specific purinergic receptor antagonist, was used to determine whether suramin acts via purinergic receptors. The effect of suramin on epidermal growth factor receptor (EGFR) was determined by analyzing receptor phosphorylation and dimerization. XAMR 0721, a suramin analogue containing only one of the two polysulfonated arms, was also analyzed for its effects on growth and EGFR activation. Results: Agarose-immobilized suramin stimulated NCI-H596 cell growth, but only when added directly to the cells. When the suramin-conjugated beads were added to the cells on cell culture inserts, which preclude an interaction with the cell surface but allow interaction with the culture medium, there was no effect on proliferation. PPADS had no effect on the growth stimulation by suramin; however suramin treatment resulted in rapid phosphorylation and dimerization of EGFR. Treatment with XAMR 0721 did not affect growth or tyrosine phosphorylation and dimerization of EGFR. Conclusions: Suramin need not enter NCI-H596 cells to exert its growth-stimulatory effect, nor is this effect mediated by an interaction with soluble growth factors. Rather, it appears that suramin acts via an interaction with EGFR, but not with purinergic receptors. [ABSTRACT FROM AUTHOR]