BTG AND ISREC RELEASE NEW DATA SUPPORTING USE OF ADENOVIRAL TREATMENT FOR COLORECTAL CANCER
09 October 2006 - BTG

Virtually all colon tumours and, to a lesser degree, tumours associated with skin, gastric, liver and thyroid cancers, possess a genetic defect which leads to the activation of a specific signal transduction pathway. Researchers were able to alter the common cold virus, named adenovirus, to selectively replicate within and destroy cells in which this pathway is activated. Since there are few normal tissues in which the pathway is active, this represents a potential approach to treat specific cancers while preserving healthy cells.

“Standard chemotherapies are inherently non-selective. Despite important advances in understanding the molecular basis of cancer, few treatments have been devised which target the known defects in tumour cells,” commented Richard Iggo, M.D., Ph.D., at ISREC. “Adenoviruses like ours, which replicate within cancer cells, have advantages over existing approaches because they may enable use of smaller doses and have fewer side effects, while still achieving the selectivity of highly-targeted cancer therapies.”

“BTG has established itself as a leader in identifying and advancing promising new cancer therapies into the marketplace as demonstrated by the commercial success of our out-licensed products Campath, Tomudex and Zinecard,” said Ellen F. Evans, Vice President and Business Manager of Oncology at BTG. “We believe that this adenovirus therapy is an important new approach and look forward to continuing its development with our collaborators at ISREC. Based on these encouraging results, we expect that an optimised adenovirus will be developed for evaluation in patients with advanced colorectal cancer.”

Specific Research Findings
The studies were designed to engineer replicating adenoviruses that were more highly selective for cell lines with an activated wnt signal transduction pathway. Scientists at ISREC placed Tcf binding sites in the adenovirus E1A promoter alone and in conjunction with the E2/E3 promoter regions. Previous studies reported by ISREC have demonstrated the selectivity of adenovirus constructs carrying the mutations in the E2/E3 promoter regions alone.

The research indicates that the addition of mutations to the E1A promoter region results in a 100-fold increase in selectivity for wnt activated (or colon cancer) cells. Furthermore, selectivity was increased by 100,000-fold when mutations were inserted in both the E1A and E2/E3 promoter regions. Neither virus was able to replicate in cell lines where the wnt pathway was inactive.

The paper, entitled “Adenoviruses with Tcf binding sites in multiple early promoters show enhanced selectivity for tumor cells with constitutive activation of the wnt signalling pathway,” was published in the March 2002 issue of Gene Therapy (Volume 9, Issue 4). Senior authors on the paper are Richard Iggo, M.D., Ph.D. and Christophe Fürer, M.Sc. of the Oncogene Group at the Swiss Institute for Experimental Cancer Research.

Background on Colorectal Cancer
Cancers of the colon and rectum are the second highest cause of cancer deaths in the United Kingdom. This year, approximately 33,000 people in the United Kingdom will be diagnosed with colorectal cancer and the average person has about a 1 in 20 chance of developing colorectal cancer during his or her life.

Colorectal cancer is caused when cells in the colon or rectum become abnormal and divide without control or order. Cancer cells can invade and destroy the tissue around them. They can also break away from the ‘parent’ tumour and spread to form new tumours in other parts of the body. The most common treatments for colon cancer are surgery, chemotherapy and radiation therapy.

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