Breast cancer drugs could be used to target leukaemia's Achilles' heel
Drugs that have shown promise in treating breast and ovarian cancer patients who carry the BRCA ‘cancer genes’ could be used to improve the outlook for other types of cancer such as leukaemia, researchers from the Division of Cancer Studies have suggested.
In mice with acute myeloid leukaemia (AML), drugs called PARP inhibitors reduced leukaemia growth by around 90%, doubling survival times. Similar effects on cell growth were seen in leukaemia patients’ cells studied in the laboratory.
The results were so promising that the researchers believe PARP inhibition may represent a new approach to targeting this type of leukaemia. It is diagnosed in around 2,400 people each year in the UK and currently only one in five survive past five years.
The research was funded by the blood cancer charity Bloodwise with additional funding from Cancer Research UK.
PARP inhibitors can shrink tumours in cancer patients who have a faulty version of either the BRCA1 or BRCA2 gene. Faulty BRCA proteins cannot repair DNA damage in cells as they normally would, potentially leading to cancer. These cancer cells rely on poly ADP-ribose polymerase (PARP) proteins to ‘patch up’ just enough critical DNA so that they can survive and continue to multiply. When PARP is also blocked, the cancer cells become so damaged that they are forced to self-destruct.
In a report published in the journal Nature Medicine, scientists at King’s College London have shown that the PARP inhibitor olaparib can also selectively kill certain AML cells, despite the absence of BRCA errors. The researchers think this works because when the faulty proteins AML1-ETO and PML-RARα drive AML growth, they also suppress key DNA damage repair processes.
When the researchers also looked at mice with mixed lineage leukaemia (MLL), a traditionally chemotherapy-resistant subtype of AML, they found that they were resistant to PARP inhibitors. This is because DNA repair is not suppressed in this cancer. Another protein, Hoxa9, activates other DNA damage repair pathways in these leukaemia cells, keeping them alive. But when the scientists used a drug to block Hoxa9, as well as a PARP inhibitor, DNA repair was wiped out and the leukaemia cells then self-destructed.
When subjected to PARP inhibitors, the leukaemia cells became so genetically damaged that they entered a process of programmed cell death, just like in cancers with faulty BRCA. Unlike traditional chemotherapy, PARP inhibitors specifically target the cancer cells without damaging healthy tissue.
Professor Eric So, who led the research at King’s College London, said: 'PARP inhibitors could potentially offer a completely different approach to specifically target certain subtypes of acute myeloid leukaemia. New treatments are desperately needed for this aggressive type of leukaemia, which has very poor survival rates – especially in older patients where intensive chemotherapy is often not possible.'
Dr Matt Kaiser, Head of Research at Bloodwise, said: 'PARP inhibitors are exciting as they appear to target just the cancer cells, which could spare patients from the gruelling side-effects of traditional treatments. But until this study, their potential was thought to be limited mostly to cancers where BRCA faults play a role.
'While this approach seems promising from these laboratory studies, it is still very early days. We need to see how real patients respond to these drugs and how effective they are. PARP inhibitors such as olaparib are already being used to treat patients with other cancers and have been shown to be safe. This should speed up the time it takes for this potentially effective new treatment to enter clinical trials.'
Professor Steve Jackson, Cancer Research UK expert at the University of Cambridge Gurdon Institute, said: 'PARP inhibitors are designed to target a weakness in cancer cells by stopping DNA being effectively repaired. It's fantastic to see how PARP inhibitors such as olaparib - the world's first PARP inhibitor which was developed through Cancer Research UK-funded work could treat a wider range of cancers than first thought.'
The findings will be published online in Nature Medicine under the title ‘Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors’. Corresponding author: Professor Eric So, Department of Haematological Medicine, King’s College London.