A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.
Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States of America; Department of Surgery, Duke University, Durham, NC, United States of America.
Kyle G
KG
Halvorson
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
Kelly L
KL
Barton
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States of America.
Kristin
K
Schroeder
Graduate Program in Molecular Cancer Biology, Duke University, Durham, NC, United States of America.
Katherine L
KL
Misuraca
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
Christine
C
Hoeman
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
Alex
A
Chung
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
Donna M
DM
Crabtree
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
Francisco J
FJ
Cordero
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
Raj
R
Singh
Department of Medicine-Oncology, Duke University, Durham, NC, United States of America; Duke Cancer Institute, Pharmaceutical Services-PK/PD Core Laboratory, Durham, NC, United States of America.
Ivan
I
Spasojevic
Department of Electrical and Computer Engineering, Texas Tech University, Lubbock, TX, United States of America.
Noah
N
Berlow
Department of Electrical and Computer Engineering, Texas Tech University, Lubbock, TX, United States of America.
Ranadip
R
Pal
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America; Department of Pathology, Duke University Medical Center, Durham, NC, United States of America; Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, United States of America.
Oren J
OJ
Becher
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D057166:High-Throughput Screening Assays; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000627:therapeutic use*; D015996:Survival Rate; D014227:Triazines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; C545990:BMS 754807; D011720:Pyrazoles; D014227:Triazines