Translating BET Bromodomain Inhibitors for Acute Myeloid Leukemia Therapy
Background
Acute myeloid leukemia (AML) accounts for 20% of childhood leukemia and has a long-term survival of only 50%. Thus, new therapies are urgently needed. A new class of drugs, BET bromodomain inhibitors, target proteins that regulate the architecture of DNA and hold significant promise for treatment of pediatric leukemia. At the same time, the relevance of altered metabolism in AML has also come to the forefront. Much work is still needed to effectively implement these discoveries in the clinic.
Project Goal
Based on our preliminary data, in this proposal we will determine the effects of BET bromodomain inhibitors on metabolism in the cellular organelle called the mitochondria. For successful clinical implementation of BET bromodomain inhibitors, combinations of drugs will likely be needed as has uniformly been the case for curing patients with cancer. Thus, we will test combinations of compounds that alter cell metabolism with BET bromodomain inhibitors. Finally, it will be critical to develop assays to measure response to these drugs in early clinical trials. Our third aim focuses on the development and implementation of assays to measure individual patient response to BET bromodomain inhibitors to allow for personalized and thus more effective AML therapy.
2016 Project Update
We are studying the effects of BET bromodomain inhibitors on metabolism in the cellular organelle called the mitochondria and have been studying a particular pathway in the mitochondria that is disrupted by BET bromodomain inhibitors. We now have new data showing the critical importance of these mitochondrial proteins in AML and are working to develop and test novel compounds to specifically inhibit this protein. For successful clinical implementation of BET bromodomain inhibitors, combinations of drugs will likely be needed as has uniformly been the case for curing patients with cancer. Thus, we have been testing rational combinations of compounds that alter cell metabolism with BET bromodomain inhibitors. Finally, it will be critical to measure response to these drugs in early clinical trials. We have developed an assay to measure individual patient response to BET bromodomain inhibitors in patients with leukemia to allow for personalized and thus more effective AML therapy. We are working to integrate these assays into two upcoming pediatric cancer clinical trials.
"ALSF funding has been critical in efforts to improve survival of children suffering from cancer. I am extremely grateful for ALSF’s support of young scientists at this critical point in our careers. Your support will go a long way in elucidating the intracellular metabolic consequences of BET inhibitors, developing successful combination therapies and seeing this drug's successful testing in clinical trials. With the support of ALSF, I hope to contribute to our ability to cure pediatric acute myeloid leukemia."
