Development of a Novel Mer Tyrosine Kinase Inhibitor for Treatment of ALL
Overall survival for children diagnosed with acute lymphoblastic leukemia (ALL) has dramatically improved over recent years due to optimization of dosing and timing of standard chemotherapeutics. However, this intensified treatment is associated with increased short-term side effects and long-term, irreversible toxicities, which occur in up to 25% of pediatric patients and include cognitive and developmental disabilities, infertility, damage to organs, and secondary cancers. In addition, subsets of patients are refractory to therapy or have disease relapse. Thus, novel therapeutics are needed to further improve efficacy and decrease therapy related toxicity.
The Mer receptor tyrosine kinase is abnormally expressed in ALL cells where activation of Mer and downstream pro-survival pathways promotes leukemia progression and resistance to many chemotherapy agents commonly used for treatment of ALL. We have developed a first in class inhibitor of Mer called UNC2025. UNC2025 is very potent, can be administered orally, and is well-tolerated in animals with minimal and manageable side-effects. Treatment with UNC2025 significantly prolongs survival in a mouse model of B-cell ALL and increases the sensitivity of ALL cells to chemotherapeutics.
This project focuses on studies to determine the therapeutic activity of this novel inhibitor by itself and in combination with chemotherapy using mouse models derived from ALL patient samples. We also propose to develop biomarkers of therapeutic response with UNC2025. These studies will provide critical data to enable further development of this drug for use in clinical trials in the next two years.