Cooperating Signaling Networks Regulate Cell Survival of Pediatric Ph-like ALL
B cell acute lymphoblastic leukemia (B-ALL) is the most common cancer in children. Despite significant improvements in chemotherapy combinations, approximately 20% of children with high-risk B-ALL will fail their treatments. It is now clear that there are different subtypes of ALL with different genetic mutations. These mutations activate and disrupt pathways within the leukemia cells that allows the cells to grow out of control. Our laboratory is specifically interested in the Philadelphia chromosome-like (Ph-like) ALL subtype, which is associated with a high risk of relapse and poor overall survival. Based on our preliminary data, we predict that Ph-like ALL cells are driven by three separate pathways that can be inhibited by targeted drugs called kinase inhibitors. Many of these drugs are already approved by the FDA for treatment of other diseases and have known, safe doses in children.
Project Goal: The goal of our study is to characterize the components of these cellular pathways and identify new treatment strategies that attack multiple pathways at the same time, which may result in better leukemia cell killing and prevention of chemotherapy resistance. We predict that this approach will be far more effective than the currently used chemotherapy regimens alone, and ultimately can improve cure rates for children with Ph-like ALL.
Project Update 2021: We identified that this specific subtype is not dependent on a single oncogene which turns the cell into an aggressively growing disease, but instead is dependent on oncogene induced signals and oncogene independent stimuli. Performing experiments to specifically delete these oncogene dependent and independent signals validated a complicated network that induces drug resistance in these cells. We were able to publish our findings in the Journal of Clinical Investigation demonstrating that it is required to inhibit three major signaling pathways to eradicate leukemia cells in preclinical animal experiments. We are now aiming to translate our findings into clinical testing.
