PARP inhibition may represent a new treatment approach in acute myeloid leukemia
PARP inhibitors have previously demonstrated potential in the treatment of patients with breast or ovarian cancer who also harbor BRCA mutations. Now, a preclinical study has indicated that these inhibitors could have further indications for the treatment of cancer, after determining that PARP inhibition reduced cancer growth by approximately 90% in mice with acute myeloid leukemia (AML) and also doubled survival. Details of the investigation, carried out at King’s College London (UK), were recently published in Nature Medicine.
“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,” commented Steve Jackson of the University of Cambridge (UK).
Specifically, the King’s team tested PARP inhibitor olaparib in mice with AML, concluding that the drug can selectively kill certain AML cells, despite the absence of BRCA errors. The team suggest that olaparib may be capable of halting cancer growth as the faulty proteins that enable AML growth – AML1-ETO and PML-RARα – also curb key DNA repair processes.
The team tested this theory in mice with chemotherapy-resistant mixed lineage leukemia, finding that the disease was resistant to PARP inhibition, as DNA repair is not suppressed in this disease as in AML, owing to the protein Hoxa9 promoting other DNA repair pathways. However, a combination of a PARP inhibitor with an agent that blocks Hoxa9 was able to prevent DNA repair and bring about cancer cell death in these animals.
Leader of the research, Eric So (King’s College London) commented: “PARP inhibitors could potentially offer a completely different approach to specifically target certain subtypes of AML. New treatments are desperately needed for this aggressive type of leukemia, which has very poor survival rates – especially in older patients where intensive chemotherapy is often not possible.”
Matt Kaiser, Head of Research at Bloodwise, the blood cancer charity that helped fund the study, commented on the results and also highlighted the need for further clinical work: “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,” he continued. “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.”
