New use found for promising cancer drugs
clinical testing in cancer, but may also prevent a serious and
life-threatening complication of bone marrow transplants.
Scientists at the University of Michigan's Comprehensive Cancer Center in the US say that if HDAC inhibitors work as well in cancer patients as they did in mice, they could reduce the risk of death, hospitalisation and serious side effects associated with bone marrow transplants used to treat leukaemia and other haematological cancers.
Patients with leukaemia who elect to undergo bone marrow transplant have their entire immune system destroyed by chemotherapy and then reconstituted using bone marrow from a donor. But in some cases, the donated immune system can mount an attack on the new host, a phenomenon known as graft versus host disease (GVHD).
While HDAC inhibitors have shown promise in human clinical trials. the U-M scientists have found that low doses of the same drugs have an anti-inflammatory effect by preventing the production of inflammatory cytokines, which cause the extensive cell damage seen in GVHD patients.
More than 5,000 people in the US receive bone marrow transplants from an unrelated donor annually, and between 500 and 1,000 Americans die from GVHD each year. And only about 25 per cent of bone marrow transplant patients have a perfectly-matched sibling donor, so the new research could be good news for the other 75 per cent.
"No one has looked at this class of drugs in a post-bone-marrow-transplant setting before, but two other groups have found similar anti-inflammatory effects in mouse models used for research on lupus and sepsis," notes Pavan Reddy, an assistant professor of internal medicine in the U-M Medical School and one of the lead authors of the new study.
In a first experiment, three groups of mice were given standard bone marrow transplants. Mice received bone marrow from either allogeneic (genetically dissimilar) or syngeneic (genetically identical) donors.
Between day 3 and day 7 after the transplant, U-M scientists gave low doses of an HDAC inhibitor called suberoylanilide hydroxamic acid (SAHA) to one group of experimental mice that received allogeneic transplants. This compound is leading the field amongst the HDAC inhibitors in the clinic and was originated by Aton Pharma, snapped up last week by US drug major Merck & Co.
The drug improved survival rates in post-transplant mice by 60 per cent, according to the study, which is published online in the early edition of the Proceedings of the National Academy of Sciences.
Although some SAHA-treated mice still developed GVHD, they had milder symptoms and less intestinal damage than mice that did not receive the drug. Importantly, SAHA had no effect on how donor T cells responded to host antigens by binding to cancer cells and killing them.
To find out whether the drug or the graft-versus-leukaemia effect was responsible for tumour-free survival of mice in the study, Reddy et al conducted a second series of experiments. This time, they gave experimental mice a lethal dose of leukaemia cells, in addition to either an allogeneic or syngeneic bone marrow transplant. All mice given a syngeneic transplant and SAHA died, while 50 percent of mice receiving an allogeneic transplant and the drug survived.
"In syngeneic transplants, the donor cells are genetically identical to the host, so they won't react to foreign antigens on host cancer cells," Reddy explains. The fact that all the syngeneic transplant mice died of cancer suggests that donor T cells and the graft's immune response to leukaemic cells - and not the drug - were killing the malignant cells.
Co-author James Ferrara, professor of internal medicine and paediatrics at the U-M Medical School, noted that the attraction of the HDAC inhibitors is that they have relatively little toxicity and the doses required to generate an anti-inflammatory effect are 50- to 100-fold lower than the doses needed to kill cancer cells.
He estimates that clinical trials of HDAC inhibitors in bone marrow transplant patients are still several years away, however, as more work must be carried out in mouse models to work out the best timing and dosage for the drug.
