QIMR receives grant to aid drug development for bone marrow transplant patients

Major international grant to aid development of new drugs to protect bone marrow stem cell transplants in cancer patients

A $6.8 million Seeding Drug Discovery Award from the Wellcome Trust (UK) has paved the way for a consortium of Australian and New Zealand research teams aiming to develop a new class of immune-suppressive drugs that protect transplanted bone marrow stem cells against immune destruction.

The grant will support researchers at the Peter MacCallum Cancer Centre, The Auckland Cancer Society Research Centre, Monash University School of Biomedical Sciences, Queensland Institute of Medical Research and developers, Medicines Development, to capitalise on recent groundbreaking research into the perforin protein, a powerful toxin expressed by killer cells of the immune system.

Project lead, Professor Joe Trapani, Executive Director of Cancer Research at Peter Mac, who has studied perforin for well over 20 years, says while perforin is required to remain healthy, it can also have serious undesired effects.

‘If we don’t make enough perforin, the body can’t effectively fight off many viruses. But perforin can also mark the wrong cells for elimination, such as when the immune system attempts to rid the body of donated organ tissue or bone marrow following a transplant,’ explains Professor Trapani.

Transplantation of bone marrow from a family member or an unrelated donor restores vital platelet and white blood cell levels in patients with lymphoma or leukaemia after treatment with high-dose chemotherapy, however, the immune system can reject the ‘foreign’ transplanted tissue, and perforin is key to this process.

‘In 2010, with Monash University School of Biomedical Sciences researcher Professor James Whisstock’s team, we finally unravelled perforin’s molecular structure and confirmed what we had suspected for some time, that perforin destroys cells, by punching large holes in the cell surface,’ says Professor Trapani.

In 2004, Professor Trapani’s lab invented a way to make large amounts of pure perforin protein and, together with Auckland medicinal chemists, Professor Bill Denny and Dr Julie Spicer, identified a number of synthetic ‘drug-like’ compounds that powerfully block perforin’s function in the test tube.

With an understanding of its molecular structure in-hand and the Wellcome Trust funding, the research teams can now further develop these perforin blocking compounds for testing in humans.

Queensland Institute of Medical Research’s Professor Geoff Hill says the first generation of perforin inhibitors have been shown to prolong the survival of bone marrow stem cells in his pre-clinical models.

‘If we can translate these results into humans, a greater number of cancer patients will be able to undergo stem cell transplantation, as the perforin inhibitor will enable them to be matched with more varied donors.
‘Essentially, this will mean patients with blood cancers will be able to recover their infection-fighting white blood cells and platelets, critical for normal blood clotting, more rapidly after transplantation,’ says Professor Hill.

Professor Trapani says, if the research team meets the scientific milestones set under the terms of the Wellcome Trust award, initial clinical trials in human cancer patients will take place by 2016.

The perforin inhibitor project is funded under the Wellcome Trust’s Seeding Drug Discovery Initiative which aims to facilitate early-stage drug discovery.