BioWorld International Correspondent
LONDON - A new class of drugs to treat up to one in five cases of breast cancer, and possibly some cases of prostate and ovarian cancer, will enter Phase I trials in patients within a few months. The drugs, which inhibit DNA-repair enzymes, are highly selective in killing certain types of tumor cell. Scientists predict that they are unlikely to have severe side effects.
Alan Ashworth, director of the Breakthrough Research Centre at the Institute of Cancer Research in London, told BioWorld International: "The discovery of these agents gives us a completely different way of thinking about targeted therapy for cancer. In the past, targeted therapy has meant denying the tumor something that it needs in order to keep growing. Now, we are targeting therapy at the defect that has caused the cancer in the first place."
The new drugs, known as PARP inhibitors, work specifically against inherited breast cancers caused by mutations in the genes BRCA1 and BRCA2, which account for about 1 percent to 2 percent of all breast cancers. However, between 10 percent and 20 percent of all breast cancers have similar characteristics to the tumors caused by mutations in BRCA1 and BRCA2, without having the mutations.
In the UK, where 41,000 women are diagnosed with breast cancer each year, that could increase the number of women with tumors likely to respond to the new drugs to somewhere between 5,000 and 9,000.
Ashworth said: "It is likely that some cases of prostate and ovarian cancer will also be suitable for this treatment. There may be other types of cancer, too, for which these drugs will be effective, but this is an emerging field."
The work has been funded by the cancer research charities Breakthrough Breast Cancer and Cancer Research UK. KuDOS Pharmaceuticals, of Cambridge, UK, a privately owned spinout from Cancer Research UK, is collaborating with researchers on developing the new therapy.
KuDOS has been developing the PARP inhibitor program since 2000. Steve Jackson, the company's founder and chief scientific officer, said: "This is the first time that a PARP inhibitor has shown significant promise as a treatment for breast cancer. This discovery could well be the tip of the iceberg, as the DNA-repair technology behind this program has the potential to treat a range of other cancers that display similar characteristics."
The latest research by Ashworth and his colleagues is published in the April 14, 2005, issue of Nature. The title of the paper is "Targeting the DNA-repair defect in BRCA mutant cells as a therapeutic strategy."
Every cell in the human body develops about 10,000 genetic faults every 24 hours. They are repaired by base excision repair, in which the unwanted base in DNA is snipped out and the correct one inserted. PARP, which stands for poly(ADP-ribose) polymerase, is one of the enzymes involved in base excision repair.
Occasionally, if the fault is not repaired in time, or if there are too many of them, a break in both strands of the DNA can develop. Such breaks are repaired by the proteins encoded by the BRCA genes. The BRCA pathway does not come into play very often, but inhibiting PARP is one way to turn it on.
Crucially, for tumor cells that lack BRCA, inhibiting PARP means that the cells are left with no means of repairing their faulty DNA, and they die. But normal cells have at least one functional copy of the gene.
Ashworth said: "The key issue is that cells that lack BRCA function are about 1,000 times more sensitive to PARP inhibition than are normal cells. This gives us a very large therapeutic window, which means that we can kill BRCA mutant cells without touching normal cells." By contrast, he added, the therapeutic window for traditional chemotherapy for cancer is much smaller, with cancer cells only about 1.2 times more sensitive to the drugs used than normal cells.
The researchers anticipate that drugs that inhibit PARP will have few side effects, because mice lacking any functional copies of PARP appear to be completely normal, and do not develop tumors any earlier than wild-type mice.