| CLINICAL
DATA TO CORRELATE GENETIC FINDINGS WITH NEW DRUG TARGETS
Dr Rosalind Eeles, Dr Lynne O'Brien The Institute of Cancer Research & Royal Marsden Foundation NHS Trust |
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The UK Genetic Prostate Cancer Study is the largest study in the UK involving over 350 urologists and oncologists in the search for genetic changes which increase the risk of developing prostate cancer. We have already found genetic changes in a gene (BRCA2) that predispose to prostate cancer in some men who are diagnosed at less than 55 years of age and we now know that men who are older than this are less likely to have alterations in this gene.
It is known that certain drugs called PARP inhibitors specifically target cells with BRCA2 genetic abnormalities and trials using these drugs in patients who harbour alterations in this gene are on-going. This is one of the first examples of tailored treatments as a result of the new findings in genetics. We are also finishing an experiment funded by Prostate UK to determine why such cells may be resistant to radiation and therefore may need such new types of drug treatment.
We are currently conducting (using alternative funding) a very large experiment to look at over half a million genetic changes in thousands of blood samples (over 5000 samples) from men in the UK Genetic Prostate Cancer Study to find the sorts of changes which are more common and are likely to be present in a large proportion of the population. This experiment aims to find out the prostate cancer risk associated with such genetic changes, however, these data would also be useful to identify new drug targets and to tailor treatment to those patients who are likely to have a reponse.
Funding is provided by Prostate UK, in this application, to collect detailed clinical data from the men whose blood samples we are analysing to be able to capitalize on results from these genetic data for the development of new treatments. This will enable us to use the genetic data to identify new drug targets to determine if the drugs developed from the genetic changes found are more likely to be useful for certain types of prostate cancer than others, and thereby determine which patient groups are more likely to benefit in prostate cancer treatment trials.
INTERIM REPORT
The collection of data on the clinical status of the prostate cancer cases in this study is now complete. This has enabled the experiment to concentrate on those with early onset of the disease in addition to those with a family history to give the first set of genetic clues. It is known that early onset disease is clinically significant as it will progress within the lifetime of the individual.
We have discovered that a genetic variant on chromosome 7, which is in the LMTK2 gene, provides a clue that this gene is important in the development of early onset disease.
The LMTK2 gene codes for a protein called a kinase which is involved in cancer cell signalling. Before this discovery it was not known that this kinase could be involved in prostate cancer. This therefore has already given us a drug target which was the primary aim of the Prostate UK part of the funding for this project. The next step, and Phase 2 of the project, is twofold: (i) to liaise with our drug development unit on how this can be translated into a new drug discovery and (ii) to follow up 47 000 genetic hits from the first experiment to try to find further targets.
FINAL REPORT
The recent genome-wide association studies found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19, and X were associated with increased prostate cancer risk. We have evaluated the most significant genetic changes in the regions on these chromosomes in a world-wide consortium of 13 groups (The PRACTICAL STUDY).
Our grant from Prostate UK has enabled us to collate some of the data from the samples from British patients. In total, blood DNA from 7,370 men with prostate cancer and 5,742 male controls were analysed for genetic variants using Taqman and Sequenom genetic analysis methods. As the men were from thirteen groups world-wide, we were also able to assess whether the variants that were previously found in white men were also seen in men of Hispanic and Black origin.
The results show that six of the seven genetic variants still show clear evidence of association with prostate cancer, and that the most significant area of change in the genome previously described (the MSMB associated variant on chromosome 10) also increased risk in black patients.
Preliminary analysis has indicated that the variant associated with MSMB is also associated with prognosis. The MSMB gene codes for a protein which may be a useful new prostate cancer marker as it is associated with prognosis.
The genetic variant on chromosome 7 associated with a kinase, LMTK2, was confirmed, and we will be undertaking further work to assess how this could be developed as a drug target.
These data show that our previously discovered genetic variants are also
applicable to men in ethnic minority groups who develop prostate cancer,
and that the variants warrant further work to try to identify their role
as new markers and new drug targets.
Research Summary Final Report, 25 May 2008.
Project 2006/12