Children’s Hospital of Philadelphia Research Update

Sarah K Tasian, MD

Precision Therapies for High-Risk Pediatric Acute Myeloid Leukemia

We are so appreciative to TeamConnor for its wonderful support of our research studies in childhood acute myeloid leukemia (AML). We have focused intensively this year on the work in our Aim 1, which is studying a set of targeted drugs called MEK inhibitors in our preclinical models of childhood AML that have specific genetic mutations. In the past several months, we have optimized MEK inhibitor dosing in the laboratory (in vitro) in our AML and some acute lymphoblastic leukemia (ALL) cell lines that have RAS mutations or do not have RAS mutations. We then optimized dosing in our cell line and specialized patient-derived xenograft mouse models of RAS-mutant and RAS-normal childhood AML (in vivo). We found that the MEK inhibitor trametinib had superior effects in killing AML cells than did other tested MEK inhibitors. We also built several new xenograft mouse models this year to augment our studies. Finally, we performed detailed genetic analyses of our AML mouse models, including some new models that will be used in Aim 2. We obtained approval to share our xenograft model cells with our collaborators in the Irving laboratory in Newcastle, UK for their part of the project and have organized a shipment there. We unfortunately had a systemic bacterial infection in our animal facility that required elimination of 95% of our mouse studies this summer for two months. After a major depopulation and deep cleaning, our animal facility is now fully functional again. We have just re-purchased new mice to renew our in vivo studies again in earnest.