Author(s)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.; ... Show more Show less
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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 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.
DepartmentMassachusetts Institute of Technology. Department of Materials Science and Engineering; Koch Institute for Integrative Cancer Research at MIT
Journal of Biomedical Nanotechnology
American Scientific Publishers
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
Author's final manuscript