SYK as a New Therapeutic Target in B-Cell Precursor Acute Lymphoblastic Leukemia.
The identification of SYK as a master regulator of apoptosis controlling the activation of the PI3-K/AKT, NFκB, and STAT3 pathways-three major anti-apoptotic signaling pathways in B-lineage leukemia/lymphoma cells-prompts the hypothesis that rationally designed inhibitors targeting SYK may overcome the resistance of malignant B-lineage lymphoid cells to apoptosis and thereby provide the foundation for more effective multi-modality treatment regimens for poor prognosis B-precursor acute lymphoblastic leukemia (BPL). In recent preclinical proof-of-concept studies, a liposomal nanoparticle (LNP) formulation of a SYK substrate-binding site inhibitor, known as C61, has been developed as a nanomedicine candidate against poor prognosis and relapsed BPL. This nanoscale formulation of C61 exhibited a uniquely favorable pharmacokinetics and safety profile in mice, induced apoptosis in radiation-resistant primary leukemic cells taken directly from BPL patients as well asin vivoclonogenic BPL xenograft cells, destroyed the leukemic stem cell fraction of BPL blasts, and exhibited potentin vivoanti-leukemic activity in xenograft models of aggressive BPL. Further development of C61-LNP may provide the foundation for new and effective treatment strategies against therapy-refractory BPL.
Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, USA ; Children's Center for Cancer and Blood Diseases, CHLA, Los Angeles, USA.
Fatih M
FM
Uckun
Children's Center for Cancer and Blood Diseases, CHLA, Los Angeles, USA.
Sanjive
S
Qazi
Apoptosis; Kinase; Leukemia; Nanomedicine; Phosphorylation; STAT3; SYK