A fiber-modified mesothelin promoter-based conditionally replicating adenovirus for treatment of ovarian cancer.
OBJECTIVE
Recently, virotherapy has been proposed as a new therapeutic approach for ovarian cancer. Conditionally replicative adenoviruses (CRAd) may contain tumor-specific promoters that restrict virus replication to cancer cells. Mesothelin, a cell surface glycoprotein, is overexpressed in ovarian cancer but not in normal ovarian tissues. The purpose of this study was to explore the therapeutic utility of a mesothelin promoter-based CRAd in a murine model of ovarian cancer, using noninvasive in vivo imaging.


METHODS
We constructed a mesothelin promoter-based CRAd with a chimeric Ad5/3 fiber (AdMSLNCRAd5/3) that contains an Ad5 tail, Ad5 shaft, and an Ad3 knob. Previously, a chimeric Ad5/3 fiber has shown improved infectivity in many ovarian cancer cells. Viral replication and oncolysis were assessed in a panel of ovarian cancer cell lines. To test the oncolytic efficacy of AdMSLNCRAd5/3 in a murine model, bioluminescence imaging of tumor luciferase activity and survival analysis were done.


RESULTS
AdMSLNCRAd5/3 achieved up to a 10,000-fold higher cell killing effect and up to 120-fold higher levels of viral replication in all human ovarian cancer cells, compared with wild-type Ad5. AdMSLNCRAd5/3 significantly inhibited tumor growth as confirmed by in vivo imaging (P < 0.05). Survival with AdMSLNCRAd5/3 was significantly enhanced when compared with no virus or with a wild-type Ad5-treated group (P < 0.05).


CONCLUSIONS
The robust replication, oncolysis, and in vivo therapeutic efficacy of AdMSLNCRAd5/3 showed that this CRAd is a promising candidate for treating ovarian cancer. Importantly, we have applied in vivo imaging that has allowed repeated and longitudinal measurements of tumor growth after CRAd treatment.
Division of Human Gene Therapy, Department of Medicine, Obstetrics and Gynecology, The University of Alabama at Birmingham, 901 19th Street South, BMR2-508, Birmingham, AL 35294-2180, USA.
Yuko
Y
Tsuruta
Larisa
L
Pereboeva
Martina
M
Breidenbach
Daniel T
DT
Rein
Minghui
M
Wang
Ronald D
RD
Alvarez
Gene P
GP
Siegal
Paul
P
Dent
Paul B
PB
Fisher
David T
DT
Curiel
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D005260:Female; D058851:GPI-Linked Proteins; D005822:Genetic Vectors; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D000090204:Mesothelin; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000628:therapy* / Q000821:virology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C000715528:Msln protein, mouse; D000090204:Mesothelin