Targeting Tumor Suppressor MicroRNAs in Pediatric Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, ~15% of children will relapse with recurrent disease and poor outcomes. Why some children develop resistant disease remains unclear.
To address this question, we are studying genetic pathways that cause relapse with the goal of designing therapies to treat children with resistant ALL. Our focus is microRNAs (miRs), which are tiny genes that regulate expression of other genes. A subset of miRs function by blocking or repressing genes that cause cancer, and are therefore called "tumor suppressor miRs" or TS-miRs. In cancer, these protective genes are frequently down-regulated, or silenced, and their loss could drive relapse and poor outcomes. Based on these discoveries, we hypothesize that: 1.) Down-regulation of TS-miRs is important in relapsed ALL, 2.) Replacing TS-miRs will be effective therapy. To date, there are no studies to identify TS-miRs specific for relapse in ALL.
To test our hypotheses and fill this knowledge gap, we propose the following Specific Aims: 1.) To identify TS-miRs specific for relapse in a common form of childhood ALL in collaboration with the Children's Oncology Group, 2.) To determine how these TS-miRs function in ALL relapse, and, 3.) To begin studies to replace TS-miRs using innovative nanoparticles in preclinical models in collaboration with the Hopkins' Nanomedicine Center. Results from our studies could provide a new paradigm for therapy for children with relapsed ALL and improve outcomes.