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Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Morfouace, Marie 
Boulos, Nidal 
Patel, Yogesh T 
Shelat, Anang 

Abstract

Chemotherapies active in preclinical studies frequently fail in the clinic due to lack of efficacy, which limits progress for rare cancers since only small numbers of patients are available for clinical trials. Thus, a preclinical drug development pipeline was developed to prioritize potentially active regimens for pediatric brain tumors spanning from in vitro drug screening, through intracranial and intra-tumoral pharmacokinetics to in vivo efficacy studies. Here, as an example of the pipeline, data are presented for the combination of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in three pediatric brain tumor models. The in vitro activity of nine novel therapies was tested against tumor spheres derived from faithful mouse models of Group 3 medulloblastoma, ependymoma, and choroid plexus carcinoma. Agents with the greatest in vitro potency were then subjected to a comprehensive series of in vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies culminating in preclinical efficacy trials in mice harboring brain tumors. The nucleoside analog 5-fluoro-2'-deoxycytidine (FdCyd) markedly reduced the proliferation in vitro of all three brain tumor cell types at nanomolar concentrations. Detailed intracranial PK studies confirmed that systemically administered FdCyd exceeded concentrations in brain tumors necessary to inhibit tumor cell proliferation, but no tumor displayed a significant in vivo therapeutic response. Despite promising in vitro activity and in vivo PK properties, FdCyd is unlikely to be an effective treatment of pediatric brain tumors, and therefore was deprioritized for the clinic. Our comprehensive and integrated preclinical drug development pipeline should reduce the attrition of drugs in clinical trials.

Description

Keywords

Choroid plexus carcinoma, Ependymoma, FdCyd, G3 medulloblastoma, THU, Animals, Antineoplastic Agents, Apoptosis, Brain, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Deoxycytidine, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Epigenesis, Genetic, Mice, Mice, Nude, Tetrahydrouridine

Journal Title

J Neurooncol

Conference Name

Journal ISSN

0167-594X
1573-7373

Volume Title

126

Publisher

Springer Science and Business Media LLC
Sponsorship
National Cancer Institute (R01CA129541)
National Cancer Institute (P01CA096832)
Cancer Research UK (22492)