Oncolytic adenoviral gene therapy for ovarian cancer
Lead Research Organisation:
Queen Mary University of London
Department Name: Barts Cancer Institute
Abstract
We are trying to develop new treatments for ovarian cancer using oncolytic viruses. These are common viruses that are altered so that they destroy cancer cells by multiplying within them, but cannot multiply within normal human tissues. Our virus, dl922-947, is derived from an adenovirus, which is very common in the UK population and, under most circumstances, causes only a ‘flu-like illness, even in its natural, active state.
Our research has shown that dl922-947 has considerable potential as a treatment for ovarian cancer. A trial in women with recurrent ovarian cancer will commence in 2009. We now wish to improve the anti-cancer effect of dl922-947.
Our results suggest that dl922-947 can work well in partnership with paclitaxel, a chemotherapy drug commonly used in ovarian cancer, but we wish to understand why, and whether other chemotherapy drugs may also combine well. We also want to understand how the immune system responds to dl922-947 in the abdominal cavity, where ovarian cancer grows. Finally, we will explore why some ovarian cancer cells do not respond well to dl922-947, by studying the patterns of gene expression in sensitive and resistant cells, especially genes that control cell division. Ultimately, this research could lead to more effective treatments for women with ovarian cancer.
Our research has shown that dl922-947 has considerable potential as a treatment for ovarian cancer. A trial in women with recurrent ovarian cancer will commence in 2009. We now wish to improve the anti-cancer effect of dl922-947.
Our results suggest that dl922-947 can work well in partnership with paclitaxel, a chemotherapy drug commonly used in ovarian cancer, but we wish to understand why, and whether other chemotherapy drugs may also combine well. We also want to understand how the immune system responds to dl922-947 in the abdominal cavity, where ovarian cancer grows. Finally, we will explore why some ovarian cancer cells do not respond well to dl922-947, by studying the patterns of gene expression in sensitive and resistant cells, especially genes that control cell division. Ultimately, this research could lead to more effective treatments for women with ovarian cancer.
Technical Summary
Background
Oncolytic adenoviruses are promising new treatments for ovarian cancer. The E1A-CR2 deleted vector dl922-947 replicates selectively in tumour cells with abnormal Rb pathway function. The first clinical trial will commence in 2007. Further development of oncolytic adenoviruses depends upon identification of points in three key stages of the virus life cycle that can be manipulated for therapeutic benefit. An understanding of the role of the immune system in viral clearance from the abdomen is also vital for clinical application of these adenoviruses in ovarian cancer.
Aims and objectives
To improve viral anti-cancer activity by:
1. maximising infectivity by investigating the interaction between dl922-947 and microtubules.
2. increasing viral replication by manipulating genes that are associated with resistance.
3. augmenting the programmed cell death pathways activated by the virus using chemotherapy.
4. generating an immunocompetent murine model of ovarian cancer that supports adenovirus replication.
Design and Methods
The effects of the microtubule-active chemotherapy drugs paclitaxel, epothilone and vinblastine on dl922-947 infectivity will be examined using GFP-fluorescence assays and confocal microscopy. Their effects on cell death pathways will be examined in cytotoxicity assays in vitro and xenograft models in vivo. Cell cycle-regulated genes, including cyclin D2, p18, cdk2, cdc25A and survivin, may be critical regulators of viral activity. Their expression will be knocked down in ovarian cancer cells resistant to dl922-947 using RNA interference (RNAi) and the effects on replication and cytotoxicity examined. Ovarian cancer cells will also be transfected with nuclear-targeted survivin constructs and examined for alterations in cell survival and pRb phosphorylation. Immortalised ovarian surface epithelial cells with both normal and abnormal Rb pathway function will be used to validate results. Phosphatidylinositol 3‘-kinase (PI3K) may play a key survival role following adenoviral infection. Using specific inhibitors and RNAi, the effects of PI3K pathway inhibition on dl922-947 function will be studied, in particular the role of PI3K in the cellular autophagic response. Finally, using a wholly murine system, the effects of intact immune function on adenoviral activity will be studied, particularly the role of T cell and macrophage-mediated viral clearance from the peritoneal cavity.
Future opportunities
The research in this Fellowship will shape future clinical trials of oncolytic adenoviral vectors by identifying ideal chemotherapy/virus combinations. It will also highlight parameters in ovarian cancer that predict for the activity of a novel therapy targeted to the critical G1-S checkpoint that is frequently abnormal in this disease.
Oncolytic adenoviruses are promising new treatments for ovarian cancer. The E1A-CR2 deleted vector dl922-947 replicates selectively in tumour cells with abnormal Rb pathway function. The first clinical trial will commence in 2007. Further development of oncolytic adenoviruses depends upon identification of points in three key stages of the virus life cycle that can be manipulated for therapeutic benefit. An understanding of the role of the immune system in viral clearance from the abdomen is also vital for clinical application of these adenoviruses in ovarian cancer.
Aims and objectives
To improve viral anti-cancer activity by:
1. maximising infectivity by investigating the interaction between dl922-947 and microtubules.
2. increasing viral replication by manipulating genes that are associated with resistance.
3. augmenting the programmed cell death pathways activated by the virus using chemotherapy.
4. generating an immunocompetent murine model of ovarian cancer that supports adenovirus replication.
Design and Methods
The effects of the microtubule-active chemotherapy drugs paclitaxel, epothilone and vinblastine on dl922-947 infectivity will be examined using GFP-fluorescence assays and confocal microscopy. Their effects on cell death pathways will be examined in cytotoxicity assays in vitro and xenograft models in vivo. Cell cycle-regulated genes, including cyclin D2, p18, cdk2, cdc25A and survivin, may be critical regulators of viral activity. Their expression will be knocked down in ovarian cancer cells resistant to dl922-947 using RNA interference (RNAi) and the effects on replication and cytotoxicity examined. Ovarian cancer cells will also be transfected with nuclear-targeted survivin constructs and examined for alterations in cell survival and pRb phosphorylation. Immortalised ovarian surface epithelial cells with both normal and abnormal Rb pathway function will be used to validate results. Phosphatidylinositol 3‘-kinase (PI3K) may play a key survival role following adenoviral infection. Using specific inhibitors and RNAi, the effects of PI3K pathway inhibition on dl922-947 function will be studied, in particular the role of PI3K in the cellular autophagic response. Finally, using a wholly murine system, the effects of intact immune function on adenoviral activity will be studied, particularly the role of T cell and macrophage-mediated viral clearance from the peritoneal cavity.
Future opportunities
The research in this Fellowship will shape future clinical trials of oncolytic adenoviral vectors by identifying ideal chemotherapy/virus combinations. It will also highlight parameters in ovarian cancer that predict for the activity of a novel therapy targeted to the critical G1-S checkpoint that is frequently abnormal in this disease.