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NEW SENSITIVE AND ACCURATE TEST FOR PROSTATE CANCER.
Dr. Christiane Fenske St George's, University of London |
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THE DIAGNOSTIC TEST
The Prostate Research Group at St George's University of London, have developed a blood test for the diagnosis of prostate cancer using a highly sensitive molecular technique. By measuring levels of only 4 markers, we are able to diagnose prostate cancer with over 95% accuracy.
Two of these markers (E2F3 and HIF-1a) are up-regulated early on in disease development and one (MMP9) in the late metastatic stages. The fourth (RECK), being down regulated, adds strength to any calculations when it's measurement is combined as a ratio with those of the other 3 markers.
When used in different combinations, the test can diagnose the different stages of disease with over 80% accuracy. Specific combinations may also be useful in monitoring response to therapy - differentiating, via changes in specific marker levels between metastatic disease (e.g. lack of response to therapy resulting in up-regulated levels) and no evidence of malignancy (down-regulated levels due to response).
TOWARDS TEST VALIDATION
Steps have been taken with the aim of introducing the test to routine use.
• Further Statistical Analysis focusing on calculations, our procedures,
and approaches has confirmed our findings, increasing confidence in
the accuracy of our diagnostic test, and offering an extremely optimistic
view of further validation procedures.
• The validation and use of a blood tube now allows blood to be
sampled at a clinic or surgery, followed by transportation in normal
mail to a routine laboratory, without compromising effectiveness of
the test results.
• Control experiments have confirmed that any variations we detect
in the levels of our markers are due to the prostate cancer, and not
due to ay other clinical issues e.g. inflammation.
• Are the changes in the levels of markers that we see because
the markers are turned up or down according to the stage of the disease?
Or because the numbers of cells vary? We are in the process of being
able to count cells in patient blood samples to be able to answer this
question
Commercial development
Our excellent results in all these areas have brought us to a point where the test can be developed and standardized, bringing the test into routine use.
INVESTIGATION OF ADDITIONAL MARKERS
Targeted therapy
Several new markers (HER2 and VEG-F) which have been investigated may
also offer the possibility of targeted therapy.
One of these is HER2, which has already been used in the treatment of
breast cancer (via an antibody marketed under the name herceptin).
Both these markers are part of a pathway affecting the levels of our
test markers (RECK, MMP9, HIF-1a).
We are currently carrying out research to find out to what extent they
may play a role in prostate cancer and to determine their potential
inclusion in our test.
It may be the case that specifically targeting one marker has a knock
on effect on markers in the same pathway, resulting in increased effectiveness
of treatment, but with decreased risk of side effects.
Early screening role
Our experiments in alternative splicing (an early mutation for many
cancers), have unfortunately not confirmed out original findings.
However, two additional markers have been recently reported, which are
up-regulated by as much as 5 years before prostate cancer is even diagnosed
and, therefore, may act as early risk indicators for prostate cancer
(EPCA and IGF-1).
Research experiments are currently being designed with a view to following
up these exciting reports
Our ultimate research aims are to include these markers into our diagnostic test, allowing its use in a potential prostate cancer screening programme.
STATISTICAL APPROACHES
Further statistical approaches are currently being investigated to determine
the degree of interaction between prostate cancer risk factors e.g.
marker expression levels, age, Gleason score (giving an idea of disease
aggressiveness), ethnicity, and the extent of their effect.
The ultimate application will be that by taking all factors into consideration, specific, accurate diagnosis of cancer stage, cancer type, potential speed of progression, response to therapy including success of surgery, may be achieved with minimal invasion, minimal cost, minimal doubt.
PROJECT CONCLUSIONS
- We have developed a blood-based prostate cancer diagnostic test able to diagnose prostate cancer (as opposed to BPH or inflammatory disease) with 95% accuracy, thus minimising need for biopsy.
- Following a diagnosis of cancer, subsequent testing will identify the stage of the cancer. The test is now ready for validation, standardisation and formatting, prior to introduction for routine diagnosis.
- Additional aspects include being able to decide the most effective treatment and also to monitor whether it has effect.
- Current research is being carried out on specific markers which may be used in different (more effective?) types of treatment, involving specific targeted therapy. Others, due to very early changes, offer the potential of prostate cancer screening - identifying prostate cancer risk up to 5 years before disease onset. These markers are still at the early stages of our analysis.
GLOSSARY
| RT-PCR | reverse transcriptase polymerase chain reaction |
| qRT-PCR | quantitative reverse transcriptase polymerase chain reaction |
| NEOM | no evidence of malignancyn |
| BPH | benign prostatic hyperplasia |
| LocCap | localised cancer |
| MetCap | metastatic cancer |
Research report summary dated 26 March 2007 (the full report can
be viewed
here in this .pdf file.)
Project 2005/12