There are existing therapies used for the treatment of childhood leukaemias that are effective, however, they are highly toxic and 12% of children die due to toxicity associated with these treatments. Many children who are treated successfully and enter remission experience a variety of debilitating side effects such as seizures, stroke, bone damage, development of additional cancers in adulthood, heart disease, and learning and behavioural difficulties later in life.
This highlights that existing treatments for childhood leukaemia are too toxic, and that new less toxic treatments are urgently needed. To meet this goal, new targets for drugs need to be identified, particularly for childhood AML. We have identified one such new target, a molecule called BAALC. High levels of this molecule in AML and ALL cells is associated with worse patient survival, increased likelihood of relapse, and indicates that the existing treatments for leukaemia will not work. Excitingly, we have shown that leukaemia cells with high levels of this molecule are extremely sensitive to an existing class of drugs called PARP inhibitors. Currently, PARP inhibitors are used to treat patients with ovarian, breast and non-small cell lung cancers, but have not been investigated as potential treatments for childhood leukaemias.
As these drugs are already in use, and have been shown to be safe, this raises the exciting possibility that PARP inhibitors can be quickly translated into clinical practice for the treatment of childhood cancer. In the laboratory, these drugs kill leukaemia cells expressing high amounts of BAALC, whilst sparing normal blood cells, meaning that they are likely to be less toxic than the existing treatments for childhood leukaemia.
This project will examine the usefulness of these drugs as a treatment for childhood leukaemia. The main aim of this study is to investigate the efficacy of PARP inhibitors, alone and in combination with other therapies, in laboratory models of childhood leukaemia. If successful, this project will progress into clinical trials, to assess PARP inhibitors as new treatments for high BAALC expressing leukaemia. PARP inhibitors are safe and well-tolerated in cancer patients and offer the potential for reduced treatment-related toxicities, which will improve the quality of life of children with leukaemia.