Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors.
BACKGROUND
Motesanib is a potent inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit receptors. In this report we examine the interaction between motesanib and radiation in vitro and in head and neck squamous cell carcinoma (HNSCC) xenograft models.


METHODS
In vitro assays were done to assess the impact of motesanib on VEGFR2 signaling pathways in human umbilical vein endothelial cells (HUVEC). HNSCC lines grown as tumor xenografts in athymic nude mice were utilized to assess the in vivo activity of motesanib alone and in combination with radiation.


RESULTS
Motesanib inhibited VEGF-stimulated HUVEC proliferation in vitro, as well as VEGFR2 kinase activity. Additionally, motesanib and fractionated radiation showed additive inhibitory effects on HUVEC proliferation. In vivo combination therapy with motesanib and radiation showed increased response compared with drug or radiation alone in UM-SCC1 (P < 0.002) and SCC-1483 xenografts (P = 0.001); however, the combination was not significantly more efficacious than radiation alone in UM-SCC6 xenografts. Xenografts treated with motesanib showed a reduction of vessel penetration into tumor parenchyma, compared with control tumors. Furthermore, triple immunohistochemical staining for vasculature, proliferation, and hypoxia showed well-defined spatial relationships among these parameters in HNSCC xenografts. Motesanib significantly enhanced intratumoral hypoxia in the presence and absence of fractionated radiation.


CONCLUSIONS
These studies identify a favorable interaction when combining radiation and motesanib in HNSCC models. The data presented suggest that motesanib reduces blood vessel penetration into tumors and thereby increases intratumoral hypoxia. These findings suggest that clinical investigations examining combinations of radiation and motesanib are warranted in HNSCC.
Department of Human Oncology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Tim J
TJ
Kruser
Deric L
DL
Wheeler
Eric A
EA
Armstrong
Mari
M
Iida
Kevin R
KR
Kozak
Albert J
AJ
van der Kogel
Johan
J
Bussink
Angela
A
Coxon
Anthony
A
Polverino
Paul M
PM
Harari
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D040301:Vascular Endothelial Growth Factor Receptor-2; C519562:imetelstat