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GENE THERAPY Divulgation Abstracts phase B |
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IGGO, |
ISREC, Chemin des Bovéresses 155, CH-1066
Epalinges |
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Title: |
Transcriptional targeting of replicating adenoviruses for cancer gene therapy: non-GMP costs |
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SCIENTIFIC | PUBLICATION | DIVULGATION | BACK TO TOP |
DIVULGATION TEXT AT SUBMISSION (1998):
Many defects in tumour cells are now known at the molecular level. This makes it possible to devise rational strategies for targeting tumour cells without harming normal cells. This usually requires introduction of exogenous DNA into tumour cells, and the most efficient way to do this is with viruses. Unfortunately, the amount of virus which can injected is never enough to infect all of the tumour cells. To get around this problem, we are developing adenoviruses that replicate selectively in tumour cells. In principle, these viruses will replicate and produce more virus until all of the tumour cells are destroyed. A virus of this type is currently in clinical trials for prostate cancer in the US. We are trying to develop a similar virus for colon cancer. If successful, we plan to use it to treat liver metastases from colorectal tumours.
De nombreux défauts au niveau moléculaire sont maintenant connus dans les cellules tumorales. Cela rend possible la mise au point de stratégies rationnelles pour cibler les cellules tumorales sans endommager les cellules normales. Ceci passe habituellement par l'introduction d'ADN exogène dans les cellules tumorales, et la façon la plus efficace de le faire est d'utiliser des virus. Malheureusement, la quantité de virus pouvant être injectée n'est jamais suffisante pour infecter la totalité des cellules tumorales. Afin de contourner ce problème, nous développons des adénovirus se répliquant d'une manière sélective dans les cellules tumorales. En principe, ces virus se répliqueront et produiront plus de virus jusqu'à ce que toutes les cellules tumorales soient détruites. Un virus de ce type est actuellement en phase d'essais cliniques pour le cancer de la prostate aux Etats-Unis. Nous essayons de développer un virus similaire pour le cancer du colon. En cas de réussite, nous prévoyons de l'utiliser pour traiter les métastases du foie provenant de tumeurs colorectales.
DIVULGATION TEXT 1999:
text (font Courier, corps 3)
DIVULGATION TEXT 2000:
Colon cancer is a leading cause of death in the developed world. In many cases surgical treatment of the primary tumour can cure local disease affecting the colon, but the patient is left with tumour metastases. Unlike, for example, breast cancer, these metastases are normally concentrated in the liver. This occurs because the venous blood from the colon is filtered by the liver before entering the general circulation. Successful treatment of liver metastases would significantly improve the survival of patients with colon cancer.
Gene therapy for cancer is in its infancy. What is required is a virus which is highly toxic to tumour cells but does not harm normal cells. If the virus is too effective but not sufficiently selective there is an obvious risk of creating a new pathogen. Hence the field is progressing slowly and the current vectors are all based on relatively innocuous viruses. It is unrealistic to expect miracle cures from these viruses. The challenge is to identify a situation where these viruses could, despite their relatively low efficacy, produce a clinical benefit.
Injection of large amounts of virus directly into tumours has been shown to kill tumour cells and produce local responses, but purely local treatment adds little to the existing range of treatments for cancer. We believe that liver metastasis from colon tumours is a situation where a gene therapy approach could bring something new. This is because the disease is limited to a single organ, the liver, which can be treated with a high local dose of virus by injecting the virus into the hepatic artery.
We have chosen to develop adenovirus vectors to treat colon cancer. The reason for this choice is that the biology of adenoviruses is understood in enormous detail thanks to many decades of intensive study. Colon cancer is also the best understood of any human tumour. This makes it possible to design adenoviruses specifically to target colon tumours. We exploit a universal defect in colon tumours, activation of the wnt signalling pathway, to switch on production of viral genes essential for virus replication. Specifically, we place Tcf transcription factor binding sites in promoters regulating expression of viral early genes. Tcf is constitutively activated by mutations in either the adenomatous polyposis coli gene or the ß-catenin gene in virtually all colon tumours. In the absence of wnt pathway activation, Tcf binds a protein called groucho which represses transcription and should prevent virus replication in normal cells. By regulating replication of the virus we circumvent a major problem in gene therapy, which is that it is impossible to inject large enough amounts of virus to kill all the tumour cells. When the virus replicates it kills the tumour cell and produces thousands of new virus particles within the tumour. In principle the virus can undergo multiple rounds of replication, lysis and reinfection until no tumour cells remain.
We have produced a panel of viruses of this type and are now characterising them in cell lines in vitro. We are also testing them for efficacy in mouse xenografts and for toxicity in rats.
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DIVULGATION TEXT 2001:
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