Targeting SYK Kinase in B-Lineage ALL With CD19-Specific C-61 Nanoparticles
Children's Hospital Los Angeles
Principal Investigator: Fatih Uckun, M.D., Ph.D.
B-linage Acute Lymphoblastic Leukemia (ALL) is the most common form of cancer in children and adolescents. Although the cure rate has improved in recent years, a significant challenge still remains in patients with poor prognosis as well as in those with relapsed disease. It is well documented that the recurrence of leukemia occurs frequently in patients who are resistant to chemotherapy due to resistance to apoptosis. The resistance is often caused by constitutively active spleen tyrosine kinase (SYK) that triggers the anti-apoptotic PI3K, NFκB, HSPA5/GRP78 and STAT3 signaling pathways. Recently, Dr. Uckun's group has discovered the pentapeptide mimic 1,4-Bis (9-0 dihydroquinidinyl) phthalazine / hydroquinidine 1,4-phathalazinediyl diether (C-61) as a selective substrate binding site inhibitor of SYK. In this project, Dr. Uckun's team is developing rationally- designed C-61 nanoparticle constructs for more effective delivery of C-61 to leukemia cells in an attempt to further improve its potency and broaden its therapeutic window. Throughout the project, the anti-leukemic activity of the generated C-61 nanoparticles will be evaluated using in vitro and in vivo assay platforms.
The goal of this project is to develop effective and paradigm-shifting treatment strategy for B-lineage Acute Lymphoblastic Leukemia, the most common form of childhood cancer.