Converging evidence for efficacy from parallel EphB4-targeted approaches in ovarian carcinoma.
EphB4 is a transmembrane receptor tyrosine kinase that plays an important role in neural plasticity and angiogenesis. EphB4 is overexpressed in ovarian cancer and is predictive of poor clinical outcome. However, the biological significance of EphB4 in ovarian cancer is not known and is the focus of the current study. Here, we examined the biological effects of two different methods of EphB4 targeting (a novel monoclonal antibody, EphB4-131 or siRNA) using several ovarian cancer models. EphB4 gene silencing significantly increased tumor cell apoptosis and decreased migration (P < 0.001) and invasion (P < 0.001). Compared with controls, EphB4 siRNA-1,2-dioleoyl-sn-glycero-3-phosphatidylcholine alone significantly reduced tumor growth in the A2780-cp20 (48%, P < 0.05) and IGROV-af1 (61%, P < 0.05) models. Combination therapy with EphB4 siRNA-1,2-dioleoyl-sn-glycero-3-phosphatidylcholine and docetaxel resulted in the greatest reduction in tumor weight in both A2780-cp20 and IGROV-af1 models (89-95% reduction versus controls; P < 0.05 for both groups). The EphB4-131 antibody, which reduced EphB4 protein levels, decreased tumor growth by 80% to 83% (P < 0.01 for both models) in A2780-cp20 and IGROV-af1 models. The combination of EphB4-131 and docetaxel resulted in the greatest tumor reduction in both A2780-cp20 and IGROV-af1 models (94-98% reduction versus controls; P < 0.05 for both groups). Compared with controls, EphB4 targeting resulted in reduced tumor angiogenesis (P < 0.001), proliferation (P < 0.001), and increased tumor cell apoptosis (P < 0.001), which likely occur through modulation of phosphoinositide 3-kinase signaling. Collectively, these data identify EphB4 as a valuable therapeutic target in ovarian cancer and offer two new strategies for further development.
Spannuth
Whitney A
WA
Department of Gynecologic Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77230-1439, USA.
Mangala
Lingegowda S
LS
Stone
Rebecca L
RL
Carroll
Amy R
AR
Nishimura
Masato
M
Shahzad
Mian M K
MM
Lee
Sun-Joo
SJ
Moreno-Smith
Myrthala
M
Nick
Alpa M
AM
Liu
Ren
R
Jennings
Nicholas B
NB
Lin
Yvonne G
YG
Merritt
William M
WM
Coleman
Robert L
RL
Vivas-Mejia
Pablo E
PE
Zhou
Yue
Y
Krasnoperov
Valery
V
Lopez-Berestein
Gabriel
G
Gill
Parkash S
PS
Sood
Anil K
AK
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D036224:Receptor, EphB4 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome
D000912:Antibodies, Neoplasm; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D036224:Receptor, EphB4