Dr. Li of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center studies a high-risk subtype of B-Cell acute lymphoblastic leukemia (B-ALL), occurring in about 15 percent of B-ALL patients that is dependent on the activity of the Janus kinase 2 (JAK2) signaling pathway. Current FDA-approved drugs that disrupt JAK2 activity, called type I JAK2 inhibitors, have almost no activity in this subtype of B-ALL, likely because other kinases can activate JAK2 and stimulate the signaling pathway.
Dr. Li aims to develop mechanisms to stop JAK2 signaling through two distinct strategies: first, she will test a panel of novel type II JAK2 inhibitors. Type II inhibitors lock JAK2 in the inactive conformation so that it cannot be activated by other proteins. Dr. Li has identified a type II JAK2 inhibitor that shows promise in mouse models of B-ALL. This inhibitor increases overall survival and reduces cancer growth but cannot be tested in humans due to its poor chemical properties. She will use this initial compound as a model for design of a novel type II inhibitor that is more suitable for human use. Dr. Li will also explore targeting JAK2 to the proteasome, a protein complex that destroys proteins by breaking their peptide bonds. As JAK2 is known to mutate and develop resistance to inhibitors, Dr. Li’s lab hopes to avoid the possibility of JAK2 reactivation by destroying JAK2 before it can initiate signaling. Importantly, an effective JAK2 degrader could reduce relapse in this subtype of B-ALL.
Dr. Li began her work in June of 2018. In the first year, Dr. Li expects to identify two to three lead compounds for further drug development. She will determine their suitability for human clinical studies by the end of the second year. By the end of year three, she expects to initiate drug development work with the goal of translating her research into pediatric clinical trials.