Dual targeting of EphA2 and FAK in ovarian carcinoma.
EphA2 gene silencing has been shown to result in antitumor efficacy. Here we considered whether silencing additional targets downstream of EphA2 would further enhance the therapeutic effect. EphA2 targeted siRNA was tested in combination with either FAK or Src targeted siRNA using DOPC nanoliposomes in orthotopic models of ovarian carcinoma. The effects of therapy were determined by changes in tumor weight, proliferation (Ki-67), and microvessel density (CD31). In our initial in vivo study, EphA2 plus FAK silencing resulted in the greatest reduction in tumor growth (by 73%, p < 0.005) as compared to control siRNA alone. In the SKOV3ip1 and HeyA8 ovarian cancer models, EphA2 siRNA-DOPC treatment resulted in a 50-67% decrease in tumor growth (p < 0.02, for both), and FAK siRNA-DOPC resulted in a 61-62% decrease in tumor growth (p < 0.009, p < 0.05, respectively). EphA2 plus FAK siRNA-DOPC treatment resulted in a significant reduction (SKOV3ip1: 76%, p < 0.007, HeyA8: 90%, p < 0.003) in tumor growth compared to control siRNA-DOPC. Combination treatment with EphA2 + FAK siRNA-DOPC resulted in significant decreases in tumor cell proliferation (p < 0.001) and microvessel density compared to control siRNA-DOPC (80%; p < 0.001), or the monotherapy groups (p values <0.001). These data suggest that the antitumor efficacy of in vivo EphA2 targeting is enhanced in combination with FAK silencing. Dual targeting of EphA2 and FAK may have therapeutic implications for ovarian cancer management.
Shahzad
Mian M K
MM
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Lu
Chunhua
C
Lee
Jeong-Won
JW
Stone
Rebecca L
RL
Mitra
Rahul
R
Mangala
Lingegowda S
LS
Lu
Yiling
Y
Baggerly
Keith A
KA
Danes
Christopher G
CG
Nick
Alpa M
AM
Halder
Jyotsnabaran
J
Kim
Hye-Sun
HS
Vivas-Mejia
Pablo
P
Landen
Charles N
CN
Lopez-Berestein
Gabriel
G
Coleman
Robert L
RL
Sood
Anil K
AK
D020533:Angiogenesis Inhibitors / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics; D036104:Receptor, EphA2 / Q000172:deficiency / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D019394:Ki-67 Antigen; D034741:RNA, Small Interfering; D036104:Receptor, EphA2; D051416:Focal Adhesion Protein-Tyrosine Kinases