TITLE:
SYK as a New Therapeutic Target in B-Cell Precursor Acute Lymphoblastic Leukemia
AUTHORS:
Fatih M. Uckun, Sanjive Qazi
KEYWORDS:
STAT3; SYK; Kinase; Phosphorylation; Apoptosis; Leukemia; Nanomedicine
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.5 No.1,
January
17,
2014
ABSTRACT: 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 as in vivo clonogenic BPL xenograft cells, destroyed the leukemic stem cell fraction of
BPL blasts, and exhibited potent in vivo anti-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.