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BET Bromodomain Inhibition as Epigenetic Therapy in Pediatric Leukemia

Cold Spring Harbor Laboratory
Christopher Vakoc, MD, PhD
Grant Type: 
'A' Award Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

New drugs are desperately needed for the treatment of pediatric leukemia. Leukemia is one of the most common and devastating cancers that can occur in children. While many infants and children diagnosed with acute leukemia can have durable remissions and even cures, the side effects of chemotherapy often lead to enduring harm to patients' health. Our research seeks to develop novel drugs for pediatric leukemia using a host of powerful genetic technologies, most notably, an approach called RNA interference screening. Our approach allows us to ask cancer cells "What proteins do you need to grow?" with as little bias as possible. Using this approach, we recently identified the protein BRD4 as an 'Achilles Heel' found in many forms of leukemia. Our current evidence suggests that new drugs, developed by our collaborators, that bind and inhibit BRD4 have remarkable anti-leukemia activity in experimental models.

In this proposal, we seek to explore the efficacy of BRD4-inhibitors in a broad collection of pediatric leukemia patient specimens. The overall goal of these efforts is to identify which pediatric leukemia patients are most likely to benefit from using these agents, such that these drugs can be introduced into clinical trials. The information obtained in this research proposal will have direct relevance to how these drugs are used in the pediatric leukemia patients in the clinic. Furthermore, I hope that funding through the ALSF will allow me to develop approaches for the study of pediatric cancer that can be utilized throughout my research career.

Update - September 2014

Christopher Vakoc answered questions about his research.

What were you initially studying with your grant funded by ALSF?
Our laboratory identified the BET protein BRD4 as a novel therapeutic target in acute leukemia and, during the course of our studies, noted that leukemia samples obtained from pediatric patients were particularly sensitive to drugs that target BRD4. Since BRD4 inhibitors have recently entered phase I clinical studies in adult leukemia patients, we considered it a high priority to investigate more deeply the pre-clnical activity of BRD4 inhibitors in pediatric leukemia patient populations. In particular, we have been interested in identifying treatment biomarkers to identify suitable patients that will respond to these agents.

What have you found?
First, we have identified several genetic subtypes of leukemia that are sensitive to BRD4-inhibition, which includes the Mixed Lineage Leukemias that are of particularly poor prognosis. On the biomarker side, we have found that epigenomic annotation of enhancers across the leukemia genome can be utilized to predict therapeutic effects of BRD4 inhibitors.

What does this mean for children with cancer and their families?
Our findings justify clinical studies of BRD4 inhibitors in pediatric leukemia, particularly in Mixed Lineage Leukemia subtypes.

What are your next steps?
We are continuing to investigate the molecular mechanisms of BRD4 function in leukemia with the hope of optimization of BRD4 inhibitors for improved efficacy.

What has this grant from ALSF allowed you to do that you wouldn’t be able to do otherwise?
Support from ALSF is allowing us to deepen our analysis of pediatric leukemia epigenetics, which otherwise would not have been possible.

Why did you choose to work in this field/on this topic?
I have been interested in pediatric malignancies since my PhD dissertation research in Gerd Blobel's lab at the Children's Hospital of Philadelphia, where we investigated basic mechanisms of normal hematopoiesis. In recent years, these basic interests have evolved into a more focused pursuit of novel therapies in hematological malignancies.