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 GABAA receptor α5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function as α5-GABAA 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-GABAA 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.
Oliver
O
Jonas
David
D
Calligaris
Kashi Reddy
KR
Methuku
Michael M
MM
Poe
Jessica Pierre
JP
Francois
Frank
F
Tranghese
Armen
A
Changelian
Werner
W
Sieghart
Margot
M
Ernst
Daniel A Pomeranz
DA
Krummel
James M
JM
Cook
Scott L
SL
Pomeroy
Michael
M
Cima
Nathalie Y R
NY
Agar
Robert
R
Langer
Soma
S
Sengupta
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D005260:Female; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging; D019736:Prostheses and Implants; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000970:Antineoplastic Agents; D001569:Benzodiazepines