Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program.
BACKGROUND
Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP).


METHODS
AZD2171 was tested at concentrations from 0.1 nM to 1.0 microM against the in vitro panel and was tested against the in vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle.


RESULTS
One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 microM). Evidence of in vivo antitumor activity (primarily tumor growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models.


CONCLUSIONS
AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action.
Maris
John M
JM
Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA. maris@chop.edu
Courtright
Joshua
J
Houghton
Peter J
PJ
Morton
Christopher L
CL
Gorlick
Richard
R
Kolb
E Anders
EA
Lock
Richard
R
Tajbakhsh
Mayamin
M
Reynolds
C Patrick
CP
Keir
Stephen T
ST
Wu
Jianrong
J
Smith
Malcolm A
MA
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor / Q000187:drug effects; D005260:Female; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C500926:cediranib; D007211:Indoles