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Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABA A receptor α5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function asα5-GABA A receptor ligands. To compare their...
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| Format: | Article |
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American Scientific Publishers
2017
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| Online Access: | http://hdl.handle.net/1721.1/111797 https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 |
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| author | Calligaris, David Methuku, Kashi Reddy Poe, MichaelM. Francois, Jessica Pierre Tranghese, Frank Changelian, Armen Sieghart, Werner Ernst, Margot Pomeranz Krummel, Daniel A. Cook, M. James Pomeroy, Scott L. Agar, Nathalie Y. R. Sengupta, Soma Poe, Michael M. Jonas, Oliver H. Langer, Robert S Cima, Michael J. |
| author2 | Massachusetts Institute of Technology. Department of Materials Science and Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Materials Science and Engineering Calligaris, David Methuku, Kashi Reddy Poe, MichaelM. Francois, Jessica Pierre Tranghese, Frank Changelian, Armen Sieghart, Werner Ernst, Margot Pomeranz Krummel, Daniel A. Cook, M. James Pomeroy, Scott L. Agar, Nathalie Y. R. Sengupta, Soma Poe, Michael M. Jonas, Oliver H. Langer, Robert S Cima, Michael J. |
| author_sort | Calligaris, David |
| collection | MIT |
| description | Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABA A receptor α5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function asα5-GABA A receptor ligands. To compare their efficacy with that of standard-of-care treatments, we have employed a newly developed microscale implantable device that allows for high-throughput localized intratumor drug delivery and efficacy testing. Microdoses of each drug were delivered into small distinct regions of tumors, as confirmed by tissue mass spectrometry, and the local drug effect was determined by immunohistochemistry. We have identified a benzodiazepine derivative, KRM-II-08, as a new potent inhibitor in several α5-GABA A receptor expressing tumor models. This is the first instance of in vivo testing of several benzodiazepine derivatives and standard chemotherapeutic drugs within the same tumor. Obtaining high-throughput drug efficacy data within a native tumor microenvironment as detailed herein, prior to pharmacological optimization for bioavailability or safety and without systemic exposure or toxicity, may allow for rapid prioritization of drug candidates for further pharmacological optimization. |
| first_indexed | 2024-09-23T13:01:09Z |
| format | Article |
| id | mit-1721.1/111797 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:01:09Z |
| publishDate | 2017 |
| publisher | American Scientific Publishers |
| record_format | dspace |
| spelling | mit-1721.1/1117972022-09-28T11:31:53Z First Calligaris, David Methuku, Kashi Reddy Poe, MichaelM. Francois, Jessica Pierre Tranghese, Frank Changelian, Armen Sieghart, Werner Ernst, Margot Pomeranz Krummel, Daniel A. Cook, M. James Pomeroy, Scott L. Agar, Nathalie Y. R. Sengupta, Soma Poe, Michael M. Jonas, Oliver H. Langer, Robert S Cima, Michael J. Massachusetts Institute of Technology. Department of Materials Science and Engineering Koch Institute for Integrative Cancer Research at MIT Jonas, Oliver H. Cima, Michael J Langer, Robert S Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABA A receptor α5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function asα5-GABA A receptor ligands. To compare their efficacy with that of standard-of-care treatments, we have employed a newly developed microscale implantable device that allows for high-throughput localized intratumor drug delivery and efficacy testing. Microdoses of each drug were delivered into small distinct regions of tumors, as confirmed by tissue mass spectrometry, and the local drug effect was determined by immunohistochemistry. We have identified a benzodiazepine derivative, KRM-II-08, as a new potent inhibitor in several α5-GABA A receptor expressing tumor models. This is the first instance of in vivo testing of several benzodiazepine derivatives and standard chemotherapeutic drugs within the same tumor. Obtaining high-throughput drug efficacy data within a native tumor microenvironment as detailed herein, prior to pharmacological optimization for bioavailability or safety and without systemic exposure or toxicity, may allow for rapid prioritization of drug candidates for further pharmacological optimization. National Cancer Institute (U.S.) (Grant R21CA177391) 2017-10-05T18:59:21Z 2017-10-05T18:59:21Z 2016-06 2017-10-05T12:56:24Z Article http://purl.org/eprint/type/JournalArticle 1550-7033 http://hdl.handle.net/1721.1/111797 Jonas, Oliver et al. “First In Vivo Testing of Compounds Targeting Group 3 Medulloblastomas Using an Implantable Microdevice as a New Paradigm for Drug Development.” Journal of Biomedical Nanotechnology 12, 6 (June 2016): 1297–1302 © 2016 American Scientific Publishers https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 http://dx.doi.org/10.1166/JBN.2016.2262 Journal of Biomedical Nanotechnology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Scientific Publishers PMC |
| spellingShingle | Calligaris, David Methuku, Kashi Reddy Poe, MichaelM. Francois, Jessica Pierre Tranghese, Frank Changelian, Armen Sieghart, Werner Ernst, Margot Pomeranz Krummel, Daniel A. Cook, M. James Pomeroy, Scott L. Agar, Nathalie Y. R. Sengupta, Soma Poe, Michael M. Jonas, Oliver H. Langer, Robert S Cima, Michael J. First |
| title | First |
| title_full | First |
| title_fullStr | First |
| title_full_unstemmed | First |
| title_short | First |
| title_sort | first |
| url | http://hdl.handle.net/1721.1/111797 https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 |
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