Pharmacogenomics and Pharmacoproteomics of Rac Inhibition in High-Risk B-Cell Acute Lymphoblastic Leukemia
Principle Investigator: Nicolas Nassar, PhD
Activation of the small GTPase Rac is a hallmark of several human ailments including cancer, cardiovascular, and neurodegenerative diseases. We have identified a small molecule inhibitor of Rac activation. Our inhibitor is efficacious in several mouse models of cancer including abnormal Philadelphia chromosome leukemia and some hard to treat solid tumors. Most importantly, our inhibitor is effective against chemotherapy-resistant leukemic cells derived from pediatric patients.
Through this research, we are continuing the characterization of our inhibitor’s mechanism of action using primary leukemia cells obtained from the pediatric avatar program at Cincinnati Children’s. Our goal is to determine the set of genes that become deregulated by our molecule at various treatment time points. Such pharmacogenomics studies will allow us to decide the sequence of genomic events leading to cell death. We also are identifying global changes in protein phosphorylation events using ultrasensitive mass spectroscopy following treatment of pediatric patient cells with our lead. By combining changes at the genome and phosphoproteome levels, we expect to better our understanding of the mechanism of action of our drug and to identify the group of patients who will be responsive to its action. Our long-term goal is to provide novel targeted therapy to treat leukemia without the toxicity associated with current salvage therapy approaches.