title: Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors.
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.
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Morfouace
authors.affiliation: CR UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge, CB2 ORE, UK.
authors.forename: Birgit
authors.initials: B
authors.lastname: Nimmervoll
authors.affiliation: CR UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge, CB2 ORE, UK.
authors.forename: Nidal
authors.initials: N
authors.lastname: Boulos
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Yogesh T
authors.initials: YT
authors.lastname: Patel
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Anang
authors.initials: A
authors.lastname: Shelat
authors.affiliation: Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Burgess B
authors.initials: BB
authors.lastname: Freeman
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Giles W
authors.initials: GW
authors.lastname: Robinson
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Wright
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. clinton.stewart@stjude.org.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.affiliation: CR UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge, CB2 ORE, UK. richard.gilbertson@cruk.com.ac.uk.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. martine.roussel@stjude.org.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D044127:Epigenesis, Genetic / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D013767:Tetrahydrouridine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D013767:Tetrahydrouridine; C007746:5-fluoro-2'-deoxycytidine
keywords: Choroid plexus carcinoma; Ependymoma; FdCyd; G3 medulloblastoma; THU