TY - JOUR
T1 - Dual targeting of EphA2 and FAK in ovarian carcinoma
AU - Shahzad, Mian M.K.
AU - Lu, Chunhua
AU - Lee, Jeong Won
AU - Stone, Rebecca L.
AU - Mitra, Rahul
AU - Mangala, Lingegowda S.
AU - Lu, Yiling
AU - Baggerly, Keith A.
AU - Danes, Christopher G.
AU - Nick, Alpa M.
AU - Halder, Jyotsnabaran
AU - Kim, Hye Sun
AU - Vivas-Mejia, Pablo
AU - Landen, Charles N.
AU - Lopez-Berestein, Gabriel
AU - Coleman, Robert L.
AU - Sood, Anil K.
PY - 2009/6/1
Y1 - 2009/6/1
N2 - 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.
AB - 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.
KW - EphA2
KW - FAK
KW - Ovarian cancer
KW - siRNA therapy
UR - http://www.scopus.com/inward/record.url?scp=68049144915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68049144915&partnerID=8YFLogxK
U2 - 10.4161/cbt.8.11.8523
DO - 10.4161/cbt.8.11.8523
M3 - Article
C2 - 19395869
AN - SCOPUS:68049144915
SN - 1538-4047
VL - 8
SP - 1027
EP - 1034
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 11
ER -