First In Vivo Testing of Compounds Targeting Group 3 Medulloblastomas Using an Implantable Microdevice as a New Paradigm for Drug Development

Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABA(A) receptor alpha 5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function as alpha 5-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 alpha 5-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 higIthroughput 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.