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.
Tsuruta
Yuko
Y
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.
Pereboeva
Larisa
L
Breidenbach
Martina
M
Rein
Daniel T
DT
Wang
Minghui
M
Alvarez
Ronald D
RD
Siegal
Gene P
GP
Dent
Paul
P
Fisher
Paul B
PB
Curiel
David T
DT
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