Dual targeting of EphA2 and FAK in ovarian carcinoma.

Abstract

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.

• Authors: Mian M K Shahzad, Chunhua Lu, Jeong-Won Lee, Rebecca L Stone, Rahul Mitra, Lingegowda S Mangala, Yiling Lu, Keith A Baggerly, Christopher G Danes, Alpa M Nick, Jyotsnabaran Halder, Hye-Sun Kim, Pablo Vivas-Mejia, Charles N Landen, Gabriel Lopez-Berestein, Robert L Coleman, Anil K Sood
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 8 Issue 11 Pg. 1027-34 (Jun 2009) ISSN: 1555-8576 [Electronic] United States
• PMID: 19395869 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Ki-67 Antigen
• RNA, Small Interfering
• Receptor, EphA2
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Angiogenesis Inhibitors (genetics)
• Animals
• Apoptosis (genetics)
• Cell Growth Processes (genetics)
• Disease Models, Animal
• Female
• Focal Adhesion Protein-Tyrosine Kinases (deficiency, genetics)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• Immunohistochemistry
• Ki-67 Antigen (metabolism)
• Mice
• Mice, Nude
• Ovarian Neoplasms (enzymology, genetics, pathology, therapy)
• RNA, Small Interfering (genetics)
• Receptor, EphA2 (deficiency, genetics)