Development of Targeted Therapies in High Risk Childhood Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Despite significant advances in curing ALL in most children, approximately 20% of these patients will relapse, and nearly all relapsed patients will die from their leukemias. Our research focuses upon studying blood and bone marrow samples from children with certain types of high-risk ALL with the goal of improving our understanding of the functional consequences of specific genetic mutations. In the laboratory, we investigate how pediatric ALL samples are 'miswired' through the protein communication networks within the cells and how we may disrupt faulty wiring networks with novel medications called signal transduction inhibitors (STIs). We have previously used a specialized laboratory technique called phosphoflow cytometry to examine whether or not different proteins within the wiring networks are turned 'on' within the leukemia cells following stimulation with different types of biologic signals. We are currently using specialized mouse models of childhood ALL with mutations in the CRLF2 and JAK genes to test specific STI medications which target the miswired networks in these leukemias that we identified in our earlier studies of patient samples. At the same time, we are also using phosphoflow cytometry as a biomarker to study the faulty wiring in the blood samples from children with relapsed leukemias who are enrolled on a Children's Oncology Group Phase I clinical trial of a new STI medication called a JAK inhibitor to correlate the biochemical wiring effects with patients' clinical responses. Through this work, we hope to improve our understanding of the critical biologic mechanisms involved in these leukemias and to identify new targeted STI-based therapies for children with high-risk ALL.
Project Update (Feb. 2013):
This grant has allowed us to study problems in the lab that we initially saw in our young patients, and we are already taking what we have learned in the lab back to children with leukemia in the form of new therapies. About 85% of children with leukemia are cured with modern medicine, but that percentage simply isn't good enough. Treating children who relapse is very complex, and these children often suffer a lot of side effects from additional intensive treatments. We are thus working hard in the lab to develop personalized treatments (targeted therapies) for "high-risk" leukemias — eventually, we hope to use these new treatments to attack those Achilles' heels of leukemia cells so we might prevent children from ever relapsing.
ALSF's support has allowed us to figure out how certain protein networks within leukemia cells are hyperactive and "miswired," and we are studying how to interrupt those miswired networks with new drugs. Based on what we initially discovered in our lab studies, we tested a targeted therapy for the first time in children with relapsed leukemias through a Children's Oncology Group Phase I trial, and it has proven safe and well-tolerated. We are now developing the next clinical trial to combine this treatment with chemotherapy with the goal of improving cure rates and, hopefully, decreasing long-term side effects for children with high risk leukemias. Our ALSF funding has allowed us to make progress very efficiently and has provided me (as a young physician-scientist) with vital support to compete successfully for additional grant funding so that we may continue to advance our understanding of pediatric leukemias and to develop these new treatment strategies.