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1. Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts

Author

Asumda, Faizal Z., primary, Campbell, Nellie A., additional, Hassan, Mohamed A., additional, Fathi, Reza, additional, Vasquez Rico, Daniella F., additional, Kiem, Melanie, additional, Vang, Ethan V., additional, Kim, Yo Han, additional, Luo, Xin, additional, O’Brien, Daniel R., additional, Buhrow, Sarah A., additional, Reid, Joel M., additional, Moore, Michael J., additional, Ben-Yair, Vered Katz, additional, Levitt, Mark L., additional, Leiting, Jennifer L., additional, Abdelrahman, Amro M., additional, Zhu, Xinli, additional, Lucien, Fabrice, additional, Truty, Mark J., additional, and Roberts, Lewis R., additional

Published
2024
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2. Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Author

Smith,Charles D, Maines,Lynn W, Keller,Staci N, Katz Ben-Yair,Vered, Fathi,Reza, Plasse,Terry F, and Levitt,Mark L

Subjects
Drug Design, Development and Therapy
Abstract

Charles D Smith,1 Lynn W Maines,1 Staci N Keller,1 Vered Katz Ben-Yair,2 Reza Fathi,2 Terry F Plasse,2 Mark L Levitt2 1Apogee Biotechnology Corporation, Hummelstown, PA, USA; 2RedHill Biopharma LTD, Tel Aviv, IsraelCorrespondence: Charles D Smith, Apogee Biotechnology Corporation, 1214 Research Blvd, Suite 2015, Hummelstown, PA, 17036, USA, Tel +1 843 814 9257, Email CDSmith@apogee-biotech.comAbstract: The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation. Opaganib (aka ABC294640) is a first-in-class clinical drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Recent work demonstrates that opaganib also has antiviral activity against several viruses including SARS-CoV-2. A recently completed multinational Phase 2/3 clinical trial of opaganib in patients hospitalized with Covid-19 demonstrated that opaganib can be safely administered to these patients, and more importantly, resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. Furthermore, acceleration of the clearance of the virus was observed in opaganib-treated patients. Understanding the biochemical mechanism for the anti-SARS-CoV-2 activity of opaganib is essential for optimizing Covid-19 treatment protocols. Opaganib inhibits three key enzymes in sphingolipid metabolism: sphingosine kinase-2 (SK2); dihydroceramide desaturase (DES1); and glucosylceramide synthase (GCS). Herein, we describe a tripartite model by which opaganib suppresses infection and replication of SARS-CoV-2 by inhibiting SK2, DES1 and GCS. The potential impact of modulation of sphingolipid signaling on multi-organ dysfunction in Covid-19 patients is also discussed.Keywords: opaganib, ABC294640, sphingolipid, sphingosine kinase, dihydroceramide desaturase, glucosylceramide synthase

Published
2022

3. Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Pneumonia

Author

Carvalho Neuenschwander, Fernando, primary, Barnett-Griness, Ofra, additional, Piconi, Stefania, additional, Maor, Yasmin, additional, Sprinz, Eduardo, additional, Assy, Nimer, additional, Khmelnitskiy, Oleg, additional, Lomakin, Nikita, additional, Goloshchekin, Boris Mikhailovich, additional, Nahorecka, Ewelina, additional, Calvacante, Adilson Joaquim Westheimer, additional, Ivanova, Anastasia, additional, Zhuravel, Sergey Vladimirovich, additional, Trufanova, Galina Yurevna, additional, Bonora, Stefano, additional, Saffoury, Amer, additional, Mayo, Ami, additional, Shvarts, Yury, additional, Rizzardini, Giuliano, additional, Sobroza de Mello, Rogerio, additional, Pilau, Janaina, additional, Klinov, Alexey, additional, Valente-Acosta, Benjamin, additional, Burlaka, Oleg Olegovich, additional, Bakhtina, Natalia, additional, Bar-Meir, Maskit, additional, Shishimorov, Ivan Nikolaevich, additional, Oñate-Gutierrez, Jose, additional, Rincon, Cristian Ivan Garcia, additional, Martynenko, Tatiana Ivanovna, additional, Abrahão Hajjar, Ludhmila, additional, Procopio, Ana Carolina Nazare de Mendonca, additional, Simon, Krzystof, additional, Santiago, Walter Gabriel Chaves, additional, Fronczak, Adam, additional, Filho, Conrado Roberto Hoffmann, additional, Hussein, Osama, additional, Martynov, Vladimir Aleksandrovich, additional, Chichino, Guido, additional, Blewaska, Piotr, additional, Wroblewski, Jacek, additional, Santana, Sergio Saul Irizar, additional, Agudelo, Andres Felipe Ocampo, additional, Barczyk, Adam, additional, Gerlach, Rachael L., additional, Campbell, Eppie, additional, Bibliowicz, Aida, additional, Fathi, Reza, additional, Anderson, Patricia, additional, Raday, Gilead, additional, Klein, Michal, additional, Fehrmann, Clara, additional, Eagle, Gina, additional, Katz Ben-Yair, Vered, additional, and Levitt, Mark L., additional

Published
2022
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4. Opaganib in Coronavirus Disease 2019 Pneumonia: Results of a Randomized, Placebo-Controlled Phase 2a Trial

Author

Winthrop, Kevin L, primary, Skolnick, Alan W, additional, Rafiq, Adnan M, additional, Beegle, Scott H, additional, Suszanski, Julian, additional, Koehne, Guenther, additional, Barnett-Griness, Ofra, additional, Bibliowicz, Aida, additional, Fathi, Reza, additional, Anderson, Patricia, additional, Raday, Gilead, additional, Eagle, Gina, additional, Ben-Yair, Vered Katz, additional, Minkowitz, Harold S, additional, Levitt, Mark L, additional, and Gordon, Michael S, additional

Published
2022
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5. Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial

Author

Winthrop, Kevin L., primary, Skolnick, Alan W., additional, Rafiq, Adnan M., additional, Beegle, Scott H., additional, Suszanski, Julian, additional, Koehne, Guenther, additional, Barnett-Griness, Ofra, additional, Bibliowicz, Aida, additional, Fathi, Reza, additional, Anderson, Patricia, additional, Raday, Gilead, additional, Eagle, Gina, additional, Ben-Yair, Vered Katz, additional, Minkowitz, Harold S., additional, Levitt, Mark L., additional, and Gordon, Michael S., additional

Published
2021
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10. Abstract 3078: Effects of upamostat and opaganib on cholangiocarcinoma patient derived xenografts

Author

Asumda, Faizal Z., primary, Hassan, Mohamed A., additional, Kim, Yo Han, additional, Campbell, Nellie A., additional, Luo, Xin, additional, O'Brien, Daniel R., additional, Buhrow, Sarah A., additional, Reid, Joel M., additional, Moore, Michael J., additional, Ben-Yair, Vered Katz, additional, Fathi, Reza, additional, Levitt, Mark L., additional, Lucien-Matteoni, Fabrice, additional, Leiting, Jennifer L., additional, Truty, Mark J., additional, and Roberts, Lewis R., additional

Published
2020
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13. Mechanism of interferon beta-induced squamous differentiation and programmed cell death in human non-small-cell lung cancer cell lines

Author

Lokshin, Anna, Mayotte, Jane E., and Levitt, Mark L.

Subjects
Interferon beta -- Usage, Lung cancer, Non-small cell, Cell death -- Physiological aspects, Health
Abstract

Background: Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality due largely to the failure of systemic chemotherapy. Thus, new therapeutic paradigms involving the manipulation of normal physiologic growth-regulatory mechanisms, such as terminal cellular differentiation or programmed cell death, are being explored. Interferons may function as antineoplastic agents, in part because of their effects on cell proliferation and differentiation. We have previously demonstrated the antiproliferative and differentiating effects of interferon beta (IFN [beta]). Purpose: The present investigation was designed to study the mechanism of IFN [beta] on squamous differentiation and/or programmed cell death in cultured NSCLC cells. Methods: Cross-linked envelope competence and trans-glutaminase expression and activity were measured in three NSCLC cell lines (NCI-H226, NCI-H358, and NCI-H596) as common markers for squamous differentiation and programmed cell death. DNA fragmentation, as determined by gel electrophoretic analysis, served as a marker for programmed cell death. In addition, the expression of several regulatory and differentiation-related genes (measured by Northern blot analysis of messenger RNA levels) as well as protein kinase C activity was measured to begin to explore possible mechanisms of IFN[beta] activity. Results: IFN [beta]-induced cross-linked envelope competence occurred in cell lines with squamous features (NCI-H226 and NCI-H596); conversely, DNA fragmentation occurred in cell lines with glandular features (NCI-H358 and NCI-H596). Stimulation of cross-linked envelope competence by IFN [beta] was associated with the induction of tissue transglutaminase activity. Both of these parameters were protein-synthesis independent. As previously observed for NCI-H596, IFN [beta] suppressed the growth of the other two cell lines. Total protein kinase C activity was not altered. Expression of a variety of possibly relevant oncogenes and other genes was variably altered by IFN [beta] Conclusions: IFN [beta] induces programmed cell death in NSCLC cell lines in a phenotype-specific manner. The programmed cell death pathway represented by cross-linked envelope competence is dependent on the expression of the squamous phenotype and is protein-synthesis independent, suggesting post-translational mechanisms. In addition, squamous differentiation itself may be induced. Changes in gene expression, while not necessary for induction of cross-linked envelope competence, may be involved in other aspects of cellular homeostasis, such as growth suppression. Implications: By inducing terminal cellular differentiation or programmed cell death, IFN [beta] may be therapeutically useful in NSCLC. The post-translational nature of IFN [beta]-induced effects suggests that it will be best used in combination with other agents that can regulate these cellular pathways at the pretranslational level, increasing the proportion of cells capable of being driven to a terminal state by this biotherapeutic agent.

Published
1995

16. 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

Author

Golan, Talia, primary, Berger, Raanan, additional, Ackerstein, Aliza, additional, Raskin, Steve, additional, Lesokhin, Alexander M., additional, Sidransky, David, additional, Levitt, Mark L., additional, Gadassi, Hana, additional, Yogev, Uri, additional, and Shahar, Michal, additional

Published
2015
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21. Adjuvant Radiotherapy for Thymic Epithelial Tumor

Author

Kundel, Yulia, primary, Yellin, Alon, additional, Popovtzer, Aron, additional, Pfeffer, Raphael, additional, Symon, Zvi, additional, Simansky, David A., additional, Oberman, Bernice, additional, Sadezki, Siegal, additional, Brenner, Baruch, additional, Catane, Raphael, additional, and Levitt, Mark L., additional

Published
2007
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22. Isolation of Cells Entering Different Programmed Cell Death Pathways Using a Discontinuous Percoll Gradient.

Author

Walker, John M., Driscoll, Barbara, Koty, Patrick P., Zhang, Haifan, Lei, Wendong, and Levitt, Mark L.

Abstract

Cancer is a disease of altered cellular homeostasis. Therefore, pathways for induction of differentiation and programmed cell death are being considered as targets for therapeutic approaches (1,2). Data indicate that those lung cancer patients whose tumors demonstrate squamous differentiation tend to survive longer (3,4). Because lung tumors appear to be metaplastic to an extent (5,6), attainment of the squamous state of differentiation may be feasible for all lung tumors, resulting in control of malignancy through terminal differentiation or programmed cell death (7,8). [ABSTRACT FROM AUTHOR]

Published
2003
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23. Relationship of EGFR Signal-Transduction Modulation by Tyrosine Kinase Inhibitors to Chemosensitivity and Programmed Cell Death in Lung Cancer Cell Lines.

Author

Walker, John M., Driscoll, Barbara, Lei, Wendong, Koty, Patrick P., and Levitt, Mark L.

Abstract

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein of 170 kDa with an extracellular EGF-binding domain and intracellular domain possessing intrinsic tyrosine kinase activity (1-3). Overexpression of the EGFR has been reported in a wide range of human malignancies, including non-small cell lung cancer (NSCLC) (4-6). One early consequence of the binding of EGFR ligands (EGF or transforming growth factor-α [TGF-α]) to EGFR is the induction of receptor dimerization with the subsequent activation of tyrosine kinase activity and trans-phosphorylation at several tyrosine residues in the intracellular domain of the receptor (2,7). The activated receptor transduces signals through tyrosine phosphorylation of itself and other adaptor proteins that mediate the activation of its downstream signal molecules such as mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3K) (8,9). These cascades can then regulate nuclear and cytoplasmic events controlling transformation, mitogenesis, and cell survival (10). Because overexpression of EGFR is a common occurrence in many human cancers, including lung, and increased receptor levels are associated with metastasis and poor clinical prognosis, EGFR represents an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

Published
2003
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24. Induction of Programmed Cell Death with an Antisense Bcl-2 Oligonucleotide.

Author

Walker, John M., Driscoll, Barbara, Koty, Patrick P., Lei, Wendong, and Levitt, Mark L.

Abstract

Limited advances have occurred in lung cancer prevention and treatment (1), which has necessitated the investigation of other means of intervention.As cancer is a disease of altered cellular homeostasis and genetic damage, programmed cell death (PCD) has gained increasing importance as a physiologic mechanism that has relevance to cancer-treatment strategies (2). Dysregulation of PCD in lung cancer renders these cells resistant to chemotherapeutic agents that induce this process (3,4). Therefore, genetic manipulation of PCD regulatory genes may restore the altered homeostasis in these cells and permit these genetically damaged cells to enter PCD.A known regulator of the PCD pathway is Bcl-2, a protein capable of suppressing cell death, which is upregulated in human premalignant and malignant lung lesions (5,6). Bcl-2 has been localized to the nuclear membrane, the endoplasmic reticulum, the cytosol, and the outer mitochondrial membrane (7-11). The exact molecular mechanisms by which Bcl-2 inhibits PCD have not been unequivocally established.Initial results indicate Bcl-2 inactivates inducers of PCD, such as Bax, through heterodimerization and that it is the ratio of Bcl-2, or other functionally similar genes, to the expression of PCD inducers that determines whether a cell will undergo PCD (12,13).When Bcl-2 heterodimerizes with Bax within the outer mitochondria membrane it forms an ion channel, which is functionally different from the ion channel formed by Bax homodimerization (14,15). [ABSTRACT FROM AUTHOR]

Published
2003
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25. Lung Cancer

Author

Levitt, Mark L.

Subjects
Lung Cancer (Book) -- Book reviews, Books -- Book reviews, Health
Published
1994

30. Interleukin-2 induces development of dendritic cells from cord blood CD34+ cells

Author

Bykovskaja, Svetlana N, primary, Buffo, Mary Jo, additional, Bunker, Mark, additional, Zhang, Haifan, additional, Majors, Alana, additional, Herbert, Mary, additional, Lokshin, Anna, additional, Levitt, Mark L, additional, Jaja, Andrew, additional, Scalise, Deborah, additional, Kosiban, Deborah, additional, Evans, Carol, additional, Marks, Stanley, additional, and Shogan, Jeffrey, additional

Published
1998
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34. Ceramide does not act as a general second messenger for ultraviolet-induced apoptosis.

Author

Jiong Deng, Haifan Zhang, Kloosterboer, Freke, Yong Liao, Klostergaard, Jim, Levitt, Mark L., and Mien-Chie Hung

Subjects
SECOND messengers (Biochemistry), APOPTOSIS
Abstract

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.

Published
2002
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38. Book review.

Author

Levitt, Mark L.

Subjects
LUNG Cancer (Book)
Abstract

Reviews the book `Lung Cancer,' edited by Jack A. Roth, James D. Cox and Waun Ki Hong.

Published
1994
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39. Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Based upon FIO 2 Requirements.

Author

Neuenschwander FC, Barnett-Griness O, Piconi S, Maor Y, Sprinz E, Assy N, Khmelnitskiy O, Lomakin NV, Goloshchekin BM, Nahorecka E, Joaquim Westheimer Calvacante A, Ivanova A, Vladimirovich Zhuravel S, Yurevna Trufanova G, Bonora S, Saffoury A, Mayo A, Shvarts YG, Rizzardini G, Sobroza de Mello R, Pilau J, Klinov A, Valente-Acosta B, Olegovich Burlaka O, Bakhtina N, Bar-Meir M, Nikolaevich Shishimorov I, Oñate-Gutierrez J, García Rincón CI, Ivanovna Martynenko T, Hajjar LA, Carolina Nazare de Mendonca Procopio A, Simon K, Gabriel Chaves Santiago W, Fronczak A, Roberto Hoffmann Filho C, Hussein O, Aleksandrovich Martynov V, Chichino G, Blewaska P, Wroblewski J, Saul Irizar Santana S, Felipe Ocampo Agudelo A, Barczyk A, Lask Gerlach R, Campbell E, Bibliowicz A, Fathi R, Anderson P, Raday G, Klein M, Fehrmann C, Eagle G, Ben-Yair VK, and Levitt ML

Abstract

Once a patient has been diagnosed with severe COVID-19 pneumonia, treatment options have limited effectiveness. Opaganib is an oral treatment under investigation being evaluated for treatment of hospitalized patients with severe COVID-19 pneumonia. A randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 57 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n = 230; 500 mg twice daily) or matching placebo (n = 233) for 14 days. The primary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28 and 42 days. Pre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except nominally for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FIO 2 ) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FIO 2 levels at or below the median value (≤60%) had better outcomes after opaganib treatment (n = 117) compared to placebo (n = 134). The proportion of patients with ≤60% FIO 2 at baseline that no longer required supplemental oxygen (≥24 h) by day 14 of opaganib treatment increased (76.9% vs. 63.4%; nominal p -value = 0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs. 17.91%; nominal p -value = 0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs. 16.7%; nominal p -value = 0.019) by day 42. No new safety concerns were observed. While the primary analyses were not statistically significant, post-hoc analysis suggests opaganib benefit for patients with severe COVID-19 requiring supplemental oxygen with an FIO 2 of ≤60%. Further studies are warranted to prospectively confirm opaganib benefit in this subpopulation.

Published
2024
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40. Relationship of EGFR signal-transduction modulation by tyrosine kinase inhibitors to chemosensitivity and programmed cell death in lung cancer cell lines.

Author

Lei W, Koty PP, and Levitt ML

Subjects
Antineoplastic Agents pharmacology, Blotting, Western, Carcinoma, Non-Small-Cell Lung metabolism, Epidermal Growth Factor pharmacology, Humans, Lung Neoplasms metabolism, Phosphorylation, Precipitin Tests, Quinazolines, Tumor Cells, Cultured, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung pathology, Enzyme Inhibitors pharmacology, ErbB Receptors metabolism, Lung Neoplasms pathology, Protein Tyrosine Phosphatases antagonists & inhibitors, Signal Transduction drug effects, Tyrphostins pharmacology
Published
2003
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41. Induction of programmed cell death with an antisense Bcl-2 oligonucleotide.

Author

Koty PP, Lei W, and Levitt ML

Subjects
DNA Primers chemistry, Enzyme-Linked Immunosorbent Assay methods, Genetic Therapy methods, Humans, Lung Neoplasms metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction methods, Tumor Cells, Cultured, Apoptosis, Blotting, Western methods, Lung Neoplasms pathology, Lung Neoplasms therapy, Oligodeoxyribonucleotides, Antisense therapeutic use, Proto-Oncogene Proteins c-bcl-2 genetics
Published
2003
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42. Isolation of cells entering different programmed cell death pathways using a discontinuous Percoll gradient.

Author

Koty PP, Zhang H, Lei W, and Levitt ML

Subjects
Blotting, Western, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Cell Differentiation drug effects, Cell Division drug effects, Centrifugation, Density Gradient, DNA, Neoplasm analysis, Flow Cytometry, Humans, Immunoenzyme Techniques, In Situ Nick-End Labeling, Interferon-beta pharmacology, Lung Neoplasms genetics, Lung Neoplasms metabolism, Poly(ADP-ribose) Polymerases metabolism, Povidone, Silicon Dioxide, Transglutaminases metabolism, Tumor Cells, Cultured pathology, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell pathology, Cell Separation methods, Lung Neoplasms pathology
Published
2003
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