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Gene
and Oncogene Targeting Team
Team Leader:
Professor Caroline J Springer
Gene
targeting
Conventional cytotoxic
chemotherapy, for long the mainstay of cancer treatment, has always
suffered the shortcoming of producing serious side effects. Antibody-
or gene-directed enzyme prodrug therapy (ADEPT or GDEPT) aim to
solve this problem. In ADEPT and GDEPT the cytotoxic drugs have
been converted into non-toxic prodrugs that do not in themselves
cause side effects. An enzyme capable of regenerating the actual
drug from the prodrug is targeted to the tumour either by having
the enzyme coupled to an antibody that binds selectively to tumours
(ADEPT), or by having the gene for the enzyme expressed by a tumour
selective gene vector (GDEPT). Our aim is to express the prodrug-activating
enzyme carboxypeptidase G2 (CPG2) in replicating adenoviral, or
bacterial vectors, and to use these vectors to target CPG2 to
tumours following injection either intravenously, or directly
into the tumour. We then intend to administer prodrug following
CPG2 expression so it will be activated to cytotoxic drug selectively
in the tumours. Both the adenoviruses and the bacteria have been
modified so that they are no longer pathogenic in themselves.
The rationale for the attractiveness of the adenoviral vector
approach is that the replicating adenovirus has been modified
so that it can target specific tumour types, such as prostate,
breast and colon. The bacteria selectively target all solid tumours,
and we have measured ratios of CPG2 activity of between 1,000:1
and 10,000:1 in tumour:liver, where liver is the next highest
tissue after tumour to be targeted. CPG2 has advantages over other
enzyme prodrug converting GDEPT systems in that it releases a
drug directly from the prodrug with no further cellular processing
requirements. In addition, a large number of prodrugs can be designed
that are converted to a range of different classes of drugs. Thus
the prodrug/drug system selected can be tailored for the tumour
type.
Oncogene targeting
The Cancer Genome Project
has identified mutations in the enzyme B-RAF as its first major
discovery. Mutations are present in 70% of melanomas, 10% of colorectal
cancers and a smaller number of others cancers including early
ovarian cancer. The mutations lead to activation of this enzyme,
resulting in the tumour cell being in a state of continual growth.
We aim to discover an inhibitor of B-RAF, preferably with selectivity
for the mutant form for use in malignant melanoma and potentially
other tumour types. Inhibitors of B-RAF should reverse the cells'
tumour-forming characteristics, and probably will induce the cells
to self-destruct.
Details
of our current research
programme in both these areas are available in the Projects
Database.
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Centre
Structure
Target
Identification, Validation & Selection:
Development
of Preclinical Drug & Gene Therapy:
Clinical
Evaluation of New Treatments:
Last Modified
15/4/05
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