Characterization of Signal Transduction Pathways and Preclinical Testing of Signal Transduction Inhibitors in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (Ph-like ALL)

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Children and adults with the Philadelphia chromosome-like subtype (Ph-like ALL) have high risk of relapse and poor outcomes when treated with conventional chemotherapy.

Researchers at the Center for Childhood Cancer Research (CCCR), including Sarah K. Tasian, MD, are characterizing perturbations in signal transduction networks in high-risk pediatric leukemias, including ALL and acute myeloid leukemia (AML). Their aim is to identify hyperactive leukemia-associated signaling networks that can be treated with targeted kinase inhibitors that may help to improve clinical outcomes.

Sarah K. Tasian, MD and other investigators have demonstrated hyperactivity of specific cancer signaling networks in subtypes of childhood Ph-like ALL, including activated JAK/STAT and PI3K/mTOR signaling. Prior studies by the Tasian Laboratory and other CCCR investigators reported preclinical efficacy of specific kinase inhibitors in models of childhood Ph-like ALL.

Ongoing studies in the Tasian Laboratory are currently evaluating the efficacy of PI3K pathway inhibitors in Ph-like and other genetic subtypes of ALL. Results to date demonstrate effectiveness of targeting PI3K pathway signaling, as well as suggest that rationally designed combination regimens of kinase inhibitors may also be effective therapies for children with Ph-like ALL.

Results from these laboratory studies to date have directly led to clinical trials testing kinase inhibitors in children with high-risk types of ALL.