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3. A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities

Author

Narayan, Ravi S., Molenaar, Piet, Teng, Jian, Cornelissen, Fleur M. G., Roelofs, Irene, Menezes, Renee, Dik, Rogier, Lagerweij, Tonny, Broersma, Yoran, Petersen, Naomi, Marin Soto, Jhon Alexander, Brands, Eelke, van Kuiken, Philip, Lecca, Maria C., Lenos, Kristiaan J., In ‘t Veld, Sjors G. J. G., van Wieringen, Wessel, Lang, Frederick F., Sulman, Erik, Verhaak, Roel, Baumert, Brigitta G., Stalpers, Lucas J. A., Vermeulen, Louis, Watts, Colin, Bailey, David, Slotman, Ben J., Versteeg, Rogier, Noske, David, Sminia, Peter, Tannous, Bakhos A., Wurdinger, Tom, Koster, Jan, and Westerman, Bart A.

Published
2020
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4. Data from Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Author

Narayan, Ravi S., primary, Gasol, Ana, primary, Slangen, Paul L.G., primary, Cornelissen, Fleur M.G., primary, Lagerweij, Tonny, primary, Veldman, Hou Y.Y.E., primary, Dik, Rogier, primary, van den Berg, Jaap, primary, Slotman, Ben J., primary, Würdinger, Tom, primary, Haas-Kogan, Daphne A., primary, Stalpers, Lukas J.A., primary, Baumert, Brigitta G., primary, Westerman, Bart A., primary, Theys, Jan, primary, and Sminia, Peter, primary

Published
2023
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5. Supplemental Figures 1-7 and Tables 1-2 from Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Author

Narayan, Ravi S., primary, Gasol, Ana, primary, Slangen, Paul L.G., primary, Cornelissen, Fleur M.G., primary, Lagerweij, Tonny, primary, Veldman, Hou Y.Y.E., primary, Dik, Rogier, primary, van den Berg, Jaap, primary, Slotman, Ben J., primary, Würdinger, Tom, primary, Haas-Kogan, Daphne A., primary, Stalpers, Lukas J.A., primary, Baumert, Brigitta G., primary, Westerman, Bart A., primary, Theys, Jan, primary, and Sminia, Peter, primary

Published
2023
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7. Data from Human Glioma Growth Is Controlled by MicroRNA-10b

Author

Gabriely, Galina, primary, Yi, Ming, primary, Narayan, Ravi S., primary, Niers, Johanna M., primary, Wurdinger, Thomas, primary, Imitola, Jaime, primary, Ligon, Keith L., primary, Kesari, Santosh, primary, Esau, Christine, primary, Stephens, Robert M., primary, Tannous, Bakhos A., primary, and Krichevsky, Anna M., primary

Published
2023
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9. Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma

Author

Bikhezar, Fatima, primary, de Kruijff, Robin M., additional, van der Meer, Astrid J. G. M., additional, Torrelo Villa, Guzman, additional, van der Pol, Susanne M. A., additional, Becerril Aragon, Gabriel, additional, Gasol Garcia, Ana, additional, Narayan, Ravi S., additional, de Vries, Helga E., additional, Slotman, Ben J., additional, Denkova, Antonia G., additional, and Sminia, Peter, additional

Published
2019
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10. Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma

Author

Bikhezar, Fatima (author), de Kruijff, R.M. (author), van der Meer, A.J.G.M. (author), Torrelo Villa, G. (author), van der Pol, Susanne M.A. (author), Becerril Aragon, Gabriel (author), Gasol Garcia, Ana (author), Denkova, A.G. (author), Narayan, Ravi S. (author), Bikhezar, Fatima (author), de Kruijff, R.M. (author), van der Meer, A.J.G.M. (author), Torrelo Villa, G. (author), van der Pol, Susanne M.A. (author), Becerril Aragon, Gabriel (author), Gasol Garcia, Ana (author), Denkova, A.G. (author), and Narayan, Ravi S. (author)

Abstract

Background and purpose: Glioblastoma multiforme (GBM) is the most aggressive subtype of malignant gliomas, with an average survival rate of 15 months after diagnosis. More than 90% of all GBMs have activating mutations in the MAPK/ERK pathway. Recently, we showed the allosteric MEK1/2 inhibitor binimetinib (MEK162) to inhibit cell proliferation and to enhance the effect of radiation in preclinical human GBM models. Because the free drug cannot pass the blood–brain barrier (BBB), we investigated the use of nanocarriers for transport of the drug through the BBB and its efficacy when combined with radiotherapy and temozolomide (TMZ) in glioma spheroids. Methods: In vitro studies were performed using multicellular U87 human GBM spheroids. Polymeric nanocarriers (polymersomes) were loaded with MEK162. The interaction between nanocarrier delivered MEK162, irradiation and TMZ was studied on the kinetics of spheroid growth and on protein expression in the MAPK/ERK pathway. BBB passaging was evaluated in a transwell system with human cerebral microvascular endothelial (hCMEC/D3) cells. Results: MEK162 loaded polymersomes inhibited spheroid growth. A synergistic effect was found in combination with fractionated irradiation and an additive effect with TMZ on spheroid volume reduction. Fluorescent labeled polymersomes were taken up by human cerebral microvascular endothelial cells and passed the BBB in vitro. Conclusion: MEK162 loaded polymersomes are taken up by multicellular spheroids. The nanocarrier delivered drug reduced spheroid growth and inhibited its molecular target. MEK162 delivered via polymersomes showed interaction with irradiation and TMZ. The polymersomes crossed the in vitro BBB model and therewith offer exciting challenges ahead for delivery of therapeutics agents to brain tumours., RST/Applied Radiation & Isotopes, RST/Technici Pool, ChemE/Advanced Soft Matter

Published
2019
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11. Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma

Author

Narayan, Ravi S., primary, Gasol, Ana, additional, Slangen, Paul L.G., additional, Cornelissen, Fleur M.G., additional, Lagerweij, Tonny, additional, Veldman, Hou Y.Y.E., additional, Dik, Rogier, additional, van den Berg, Jaap, additional, Slotman, Ben J., additional, Würdinger, Tom, additional, Haas-Kogan, Daphne A., additional, Stalpers, Lukas J.A., additional, Baumert, Brigitta G., additional, Westerman, Bart A., additional, Theys, Jan, additional, and Sminia, Peter, additional

Published
2018
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13. NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor

Author

Galvani, Elena, Sun, Jing, Leon, Leticia G, Sciarrillo, Rocco, Narayan, Ravi S, Tjin Tham Sjin, Robert, Lee, Kwangho, Ohashi, Kadoaki, Heideman, Daniëlle A M, Alfieri, Roberta R, Heynen, Guus J, Bernards, René, Smit, Egbert F, Pao, William, Peters, Godefridus J, Giovannetti, Elisa, Galvani, Elena, Sun, Jing, Leon, Leticia G, Sciarrillo, Rocco, Narayan, Ravi S, Tjin Tham Sjin, Robert, Lee, Kwangho, Ohashi, Kadoaki, Heideman, Daniëlle A M, Alfieri, Roberta R, Heynen, Guus J, Bernards, René, Smit, Egbert F, Pao, William, Peters, Godefridus J, and Giovannetti, Elisa

Published
2015

14. NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor

Author

Galvani, Elena, primary, Sun, Jing, additional, Leon, Leticia G., additional, Sciarrillo, Rocco, additional, Narayan, Ravi S., additional, Tjin Tham Sjin, Robert, additional, Lee, Kwangho, additional, Ohashi, Kadoaki, additional, Heideman, Daniëlle A.M., additional, Alfieri, Roberta R., additional, Heynen, Guus J., additional, Bernards, René, additional, Smit, Egbert F., additional, Pao, William, additional, Peters, Godefridus J., additional, and Giovannetti, Elisa, additional

Published
2015
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15. Human Glioma Growth Is Controlled by MicroRNA-10b

Author

Gabriely, Galina, primary, Yi, Ming, additional, Narayan, Ravi S., additional, Niers, Johanna M., additional, Wurdinger, Thomas, additional, Imitola, Jaime, additional, Ligon, Keith L., additional, Kesari, Santosh, additional, Esau, Christine, additional, Stephens, Robert M., additional, Tannous, Bakhos A., additional, and Krichevsky, Anna M., additional

Published
2011
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16. Targeting the Akt-pathway to improve radiosensitivity in glioblastoma.

Author

Narayan RS, Fedrigo CA, Stalpers LJ, Baumert BG, and Sminia P

Subjects
Animals, Cell Survival, Chemoradiotherapy methods, DNA Damage, Dacarbazine analogs & derivatives, Dacarbazine pharmacology, Drug Design, Drug Resistance, Neoplasm, Glioblastoma pathology, Humans, Molecular Targeted Therapy, Survival Rate, Temozolomide, Antineoplastic Agents pharmacology, Glioblastoma therapy, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism
Abstract

Glioblastoma multiforme (GMB) is the most malignant and common type of all astrocytic tumors. Current standard of care entails maximum surgical resection of the tumor, followed by radiotherapy and chemotherapy, usually by the alkylating agent Temozolomide (TMZ). Despite this aggressive combination therapy, the survival rate of GBM patients is still low. Deregulation of the phosphatidylinositol 3-kinase (PI3K) / Akt pathway is a frequent occurrence in GBM. Activation of the PI3K-Akt pathway results in disturbance of control of cell growth and cell survival, which contributes to a competitive growth advantage, metastatic competence as well as to therapy resistance. The PI3K-Akt pathway is therefore an attractive therapeutic target in GBM, because it serves as a convergence point for malignant processes and intervention might overcome resistance to chemotherapy and radiation. The present review shows the importance of Akt in GBM and its role in the DNA damage response. Furthermore, an overview is given of specific inhibitors of Akt which are currently being tested in preclinical and in early phase clinical studies.

Published
2013

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