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  • 1
    Online Resource
    Online Resource
    Abstract 3078: Effects of upamostat and opaganib on cholangiocarcinoma patient derived xenografts
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3078-3078
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3078-3078
    Abstract: Background: Upamostat is an orally available small molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2 and trypsin 3 (PRSS1/2/3) as well as urokinase-type plasminogen activator (uPA) which are expressed in many cancers and mediate cell migration, invasion and tissue remodeling. Opaganib (ABC294640), a novel, orally available small molecule is a specific inhibitor of sphingosine kinase 2 (SPHK2), which phosphorylates sphingosine to sphingosine-1-phosphate (S-1-P). While proliferation induced by S-1-P is regulated by both sphingosine kinase 1 (SPHK1) and SPHK2, SPHK2 appears to be more involved in cancer. We aimed to investigate the potential antitumor effect of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) patient derived xenografts (PDX) in nude mice. Methods: PAX165, a PDX from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2 and PRSS3. 4 groups of 18 mice were treated with either drug or both. Mouse weights and tumor volumes were measured. In addition, experiments were conducted using the chorioallantoic membrane (CAM) of chicken embryos. Results: Table 1 shows the average tumor size for the control, upamostat, opaganib, and upamostat+opaganib groups at the study end point (Day 42). Tumor volumes in the upamostat, opaganib, and upamostat+opagnib groups were significantly decreased compared to the control group. The CAM experiments are ongoing and will be presented at the AACR Annual Meeting. Change in tumor volumes (mean) of CCA PDX after opaganib, upamostat or combination treatmentControlOpaganibUpamostatOpaganib+UpamostatPre-treatment129.9128.7118.8126.8Day 42198.6102.093.3186.09Percent change Day 0-42+53%-21%-21%-32%P value vs. control0.00020.00100.0008 Conclusion: This preclinical study demonstrated that upamostat and opaganib resulted in tumor regression in mice. Body weights of the mice showed no significant inter- or intra- group differences. The combination of upamostat and opaganib treatment showed greater regression compared to either upamostat or opaganib alone. Studies are underway to identify the molecular mechanisms of their interaction. Citation Format: Faizal Z. Asumda, Mohamed A. Hassan, Yo Han Kim, Nellie A. Campbell, Xin Luo, Daniel R. O'Brien, Sarah A. Buhrow, Joel M. Reid, Michael J. Moore, Vered Katz Ben-Yair, Reza Fathi, Mark L. Levitt, Fabrice Lucien-Matteoni, Jennifer L. Leiting, Mark J. Truty, Lewis R. Roberts. Effects of upamostat and opaganib on cholangiocarcinoma patient derived xenografts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3078.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3078
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Tackling NCD in LMIC: Achievements and Lessons Learned From the NHLBI—UnitedHealth Global Health Centers of Excellence Program
    Ubiquity Press, Ltd. ; 2016
    In:  Global Heart Vol. 11, No. 1 ( 2016-03-01), p. 5-
    Details
    In: Global Heart, Ubiquity Press, Ltd., Vol. 11, No. 1 ( 2016-03-01), p. 5-
    Type of Medium: Online Resource
    ISSN: 2211-8179 , 2211-8160
    URL: Article
    DOI: 10.1016/j.gheart.2015.12.016
    Language: Unknown
    Publisher: Ubiquity Press, Ltd.
    Publication Date: 2016
    detail.hit.zdb_id: 2629633-0
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  • 3
    Online Resource
    Online Resource
    The generation of human dendritic and NK cells from hemopoietic progenitors induced by interleukin-15
    Oxford University Press (OUP) ; 1999
    In:  Journal of Leukocyte Biology Vol. 66, No. 4 ( 1999-10-01), p. 659-666
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 66, No. 4 ( 1999-10-01), p. 659-666
    Abstract: Interleukin-15 (IL-15) is a pleiotropic cytokine that induces the generation and differentiation of lymphoid cells and shares many biological activities with IL-2. We have shown here the development of dendritic cells (DC) from human CD34+ hemopoietic precursor cells cultured for 2–4 weeks with IL-15 alone. DC generated with IL-15 have typical morphological, immunocytochemical, phenotypic, and functional characteristics of mature DC. Dual flow cytometry analysis performed weekly demonstrated increasing co-expression of CD1a or CD83 with HLA-DR, CD80, CD86, IL-2R α, β, and γ. Two populations of cells were distinguished among CD34+ progeny. Small and medium-size cells were mainly natural killer (NK) cells (72.6–85.2% CD56+) and low numbers of DC (9.1–21.3% CD1a+). Large cells were mostly DC (75.4–95.4% CD1a+). Isolated CD34+ cells did not express IL-2R subunits but after 2–3 days in culture with IL-15, they were found to express IL-2Rγ. Induced expression of IL-2Rγ on CD34+ cells may explain the primary mechanism of IL-15-regulated differentiation of hemopoietic precursor cells. Thus, our data suggest that IL-15 stimulates CD34+ cells to differentiate into NK and DC and may represent a new growth and survival factor for lymphoid DC. J. Leukoc. Biol. 66: 659–666; 1999.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
    URL: Article
    DOI: 10.1002/jlb.66.4.659
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 1999
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Interleukin-2 induces development of dendritic cells from cord blood CD34+ cells
    Oxford University Press (OUP) ; 1998
    In:  Journal of Leukocyte Biology Vol. 63, No. 5 ( 1998-05-01), p. 620-630
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 63, No. 5 ( 1998-05-01), p. 620-630
    Abstract: Dendritic cells (DC) have been shown to develop along a myeloid or lymphoid lineage of differentiation propagated from bone marrow or early thymic precursor cells with hematopoietic cytokines. In our study, we have induced growth and differentiation of DC from cord blood CD34+ cells initiated in interleukin-2 (IL-2) alone or in IL-2 + stem cell factor (SCF) + tumor necrosis factor α (TNF-α)-supplemented medium and cultured with IL-2 or IL-2 + SCF for 28–35 days. Dendritic morphology and antigenic phenotype of DC grown with IL-2 were characteristic for DC cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Growth and differentiation of DC was followed by an increase in expression of MHC II and co-stimulating molecules CD80 and CD86. We have also shown the expression of the IL-2 receptor (IL-2R) γ-chain in CD34+ cells after 2–3 days of culture with IL-2 alone. The co-expression of the IL-2R α, β, and γ subunits in both DC cultured with IL-2- or GM-CSF-containing cocktail of cytokines was also shown. The time curve for induction of IL-2R demonstrated low levels of subunit expression at the beginning of culture. The number of CD1a cells coexpressing CD25, CD122, and CDγ increased to about 24–68 and to 78–95% after 21 and 28–35 days, respectively. Development of natural killer cells was shown along with DC. The proportion of CD56+ cells and cytotoxicity increased in a time-dependent manner.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
    URL: Article
    DOI: 10.1002/jlb.63.5.620
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 1998
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Abstract B055: New potential therapeutic applications of WX-UK1 as a specific and potent inhibitor of human trypsin-2 and human trypsin-3
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B055-B055
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B055-B055
    Abstract: WX-UK1, a multi-serine protease inhibitor, was believed to function primarily as a synthetic small-molecule inhibitor of urokinase (uPA). We now reveal that WX-UK1 is a potent and rather specific inhibitor of human trypsin-2 and human trypsin-3, and propose that these new molecular targets offer potential for new indications in oncology and other diseases. Initially, we performed a bioinformatic analysis of the ~200 human trypsin-like serine proteases, most of which play crucial roles in homeostasis and disease. Among these we selected a subset for biochemical analysis based on an inspection of modeled 3D structures of WX-UK1:protease complexes and sequence alignment of binding site residues. Samples of the selected proteases were prepared and characterized biochemically with respect to inhibitory constant (Ki) of inhibition by WX-UK1-1 and dissociation constant (Kd). The Ki values were determined from enzymatic activity assays (37°C), and Kd values (affinity) by surface plasmon resonance (BIACORE) (25°C). Serine protease(human)Ki (nM)Mean ± SD (n)Kd (nM)Mean ± SD (n)Urokinase (uPA)874 ± 95 (3)720 ± 300 (3)Trypsin(-1)190 ± 10 (6)74 ± 18 (3)Trypsin-275 ± 3 (6)N.D.Trypsin-319 ± 4 (6)6 ± 4 (11) While previously described as an inhibitor of bovine trypsin, we now show WX-UK1 to be a specific competitive inhibitor of both human trypsin-2 and human trypsin-3 with Ki of 75 and 19 nM, respectively. With a Kd of 6 nM, WX-UK-1 binds human trypsin-3 with a & gt;100-fold binding specificity relative to most other trypsin-like serine proteases tested so far, including uPA, and 10-fold over the classical human trypsin. WX-UK1 (and its oral prodrug, upamostat) was originally developed as an inhibitor of uPA and other members of the S1 family of trypsin-like serine proteases, essential to aspects of tissue remodeling associated with tumor invasion and metastasis. However, with the identification of human trypsin-3 and human trypsin-2 as high-affinity molecular targets, new disease indications on top of oncology indications may be feasible. As a low-nanomolar inhibitor of human trypsin-3, WX-UK1 may have potential utility in the treatment of inflammatory digestive diseases, including irritable bowel syndrome, inflammatory bowel disease, and pancreatitis, for the latter of which there are currently no approved therapies. Furthermore, WX-UK1, as a human trypsin-2 inhibitor, could potentially be used in the treatment of inflammatory lung diseases, including acute respiratory distress syndrome, acute lung injury, α-1 antitrypsin deficiency, and chronic obstructive pulmonary disease (COPD)–a major unmet medical need. Citation Format: Emil Oldenberg, Christine R. Schar, Eva L. Lange, Terry F. Plasse, Danielle T. Abramson, Mark L. Levitt, Reza Fathi, Jan K. Jensen. New potential therapeutic applications of WX-UK1 as a specific and potent inhibitor of human trypsin-2 and human trypsin-3 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B055.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B055
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Opaganib in Coronavirus Disease 2019 Pneumonia: Results of a Randomized, Placebo-Controlled Phase 2a Trial
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. 7 ( 2022-07-04)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. 7 ( 2022-07-04)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac232
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2757767-3
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  • 7
    Online Resource
    Online Resource
    Ceramide does not act as a general second messenger for ultraviolet-induced apoptosis
    Springer Science and Business Media LLC ; 2002
    In:  Oncogene Vol. 21, No. 1 ( 2002-01-03), p. 44-52
    Details
    In: Oncogene, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2002-01-03), p. 44-52
    Type of Medium: Online Resource
    ISSN: 0950-9232 , 1476-5594
    URL: Article
    DOI: 10.1038/sj.onc.1204900
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2002
    detail.hit.zdb_id: 2008404-3
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  • 8
    Online Resource
    Online Resource
    Radiation sensitivity of human lung cancer cell lines
    Elsevier BV ; 1989
    In:  European Journal of Cancer and Clinical Oncology Vol. 25, No. 3 ( 1989-3), p. 527-534
    Details
    In: European Journal of Cancer and Clinical Oncology, Elsevier BV, Vol. 25, No. 3 ( 1989-3), p. 527-534
    Type of Medium: Online Resource
    ISSN: 0277-5379
    URL: Article
    DOI: 10.1016/0277-5379(89)90266-6
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1989
    detail.hit.zdb_id: 2220742-9
    detail.hit.zdb_id: 283367-0
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  • 9
    Online Resource
    Online Resource
    Abstract B30: A phase 1 open label, dose-escalation trial evaluating the safety and tolerability of EF-022, macrophage activator, in subjects with advanced solid malignancies
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. B30-B30
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. B30-B30
    Abstract: Scientific background: Activated macrophages, present in excess during natural inflammatory responses, bear the potential to kill and eradicate cancer cells. Efranat has developed cancer immunotherapy based on macrophage activation using a plasma protein designated EF-022, a modified Vitamin D Binding Protein Macrophage Activator. Methods: We performed an open label single-center phase I study in patients diagnosed with inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have failed to respond to standard therapy or for whom no standard therapy is available. The dose-escalation study was comprised of three cohorts, each receiving intramuscular (IM) injections of EF-022, once weekly for two cycles of treatment. Each cycle consisted of 4 weekly injections. Three dose levels were evaluated: 100 ng, 500ng and 1000ng. Patients were followed for up to 12 months from the start of treatment. The primary study objectives were to determine the safety and tolerability and to define the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Blood and tissue biopsies were obtained for pharmacodynamics evaluation. Results: 12 patients with solid tumors have been enrolled. Median age = 65; male: female = 5:7. Among 12 treated patients, the most frequent drug related adverse events were flu like symptoms and rash and were mostly grade 1 or 2; no serious adverse events (SAE) related to study drug were observed. No DLTs were observed. CT imaging performed at 8 weeks showed stable disease (SD) in 5/12 patients (cholangiocarcinoma, H & N cancer, esophageal-gastric cancer, ovarian cancer and liposarcoma). 11 patients completed 57 days of treatment and 1 patient left the study after 1st cycle of treatment (29 days). Significant reduction in Tregs (CD4+CD127-CD25+) levels and increase in M1/M2 monocyte (CD14+HLA+ /CD16+CD163+) ratio in the blood was detected in most of the patients. In patients demonstrating SD an increase in the M1/M2 macrophage ratio (CD68+CD163-/ CD68+CD163+) was found at the tumor site. Conclusions: Treatment with EF-022 has an acceptable safety profile and resulted in disease stabilization in 42% of patients. Pharmacodynamics markers suggest a reduction of Tregs and increase of the M1/M2 ratio. These findings are being further explored in a dose expansion cohort. ClinicalTrials.gov Identifier: NCT02052492 Citation Format: Talia Golan, Raanan Berger, Aliza Ackerstein, Steve Raskin, Alexander M. Lesokhin, David Sidransky, Mark L. Levitt, Hana Gadassi, Uri Yogev, Michal Shahar. A phase 1 open label, dose-escalation trial evaluating the safety and tolerability of EF-022, macrophage activator, in subjects with advanced solid malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B30.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-B30
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    EGF-Dependent and Independent Programmed Cell Death Pathways in NCI-H596 Nonsmall Cell Lung Cancer Cells
    Elsevier BV ; 1998
    In:  Biochemical and Biophysical Research Communications Vol. 245, No. 3 ( 1998-04), p. 939-945
    Details
    In: Biochemical and Biophysical Research Communications, Elsevier BV, Vol. 245, No. 3 ( 1998-04), p. 939-945
    Type of Medium: Online Resource
    ISSN: 0006-291X
    URL: Article
    DOI: 10.1006/bbrc.1998.8552
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1998
    detail.hit.zdb_id: 1461396-7
    SSG: 12
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