Co-targeting BET bromodomain proteins and aberrant Ras signaling in pediatric AML
Kevin Shannon
MDThe Regents of the University of California, San Francisco
Project Term: July 1, 2019 - June 30, 2022
We will test rational drug combinations in accurate preclinical model systems that reflect the distinct genomic features of pediatric AML. The use of genetically accurate mouse models to inform clinical translation is particularly important in pediatric AML given its relatively low incidence and difficulties inherent in testing drug combinations in children. Our preliminary studies have identified combined BET and MEK inhibition as a particularly promising combination for pediatric AML.
Acute myeloid leukemia (AML) is an aggressive pediatric cancer for which current treatments only cure ~50% of patients. The drugs used to treat AML and the overall survival rates have not changed substantially in over two decades. For these reasons, new therapeutic strategies are urgently needed for children and adolescents with AML. Clinical trials and laboratory studies performed by many researchers indicate that no single drug can cure AML by itself. Instead, new drug combinations are required, but these are very difficult to test in pediatric patients. Recent DNA sequencing studies have shown that the frequency of many mutations differs between pediatric and adult AML. Specifically, mutations in “epigenetic” genes and TP53 are much less common in pediatric AML while mutations in RAS genes are more common. This suggests that certain drugs might work better in pediatric AML. Our lab recently tested two targeted drugs – a BET inhibitor and a MEK inhibitor - in mouse mice AMLs with RAS gene mutations. These drugs were highly effective together in these leukemias, which closely resemble pediatric AML. Our goal is to bring new drugs into the clinic to treat pediatric AMLs with RAS mutations through the following aims: (1) to test BET and MEK inhibitors in human AML patient derived xenografts; (2) to discover biomarkers of sensitivity to these drugs and to understand how they work together to kill AML cells; and, (3) to discover how AML cells develop resistance to these drugs.