Abstract
We report preclinical proof of principle for effective treatment of B-precursor acute lymphoblastic leukemia (ALL) by targeting the spleen tyrosine kinase (SYK)–dependent antiapoptotic blast cell survival machinery with a unique nanoscale pharmaceutical composition. This nanoscale liposomal formulation (NLF) contains the pentapeptide mimic 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C61) as the first and only selective inhibitor of the substrate binding P-site of SYK. The C61 NLF exhibited a very favorable pharmacokinetic and safety profile in mice, induced apoptosis in primary B-precursor ALL blast cells taken directly from patients as well as in vivo clonogenic ALL xenograft cells, destroyed the in vivo clonogenic fraction of ALL blast cells, and, at nontoxic dose levels, exhibited potent in vivo antileukemic activity against patient-derived ALL cells in xenograft models of aggressive B-precursor ALL. Our findings establish SYK as an attractive molecular target for therapy of B-precursor ALL. Further development of the C61 NLF may provide the foundation for therapeutic innovation against therapy-refractory B-precursor ALL.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4348-4354 |
| Number of pages | 7 |
| Journal | Blood |
| Volume | 121 |
| Issue number | 21 |
| DOIs | |
| State | Published - May 23 2013 |
| Externally published | Yes |
Bibliographical note
Funding Information:The authors thank Ms Catherine Yao (University of Illinois at Urbana-Champaign) for preparation of the cartoon image of 25A. The authors thank Drs Stuart Siegel and Dorothea E. Myers for a critical review of the manuscript. The authors further thank Mrs Parvin Izadi of the Children’s Hospital, Los Angeles Bone Marrow Laboratory, Mrs Tsen-Yin Lin of the CHLA fluorescence activated cell sorting Core, Dr Nickolas Chelyapov of the University of Southern California NanoBiophysics Core Facility, as well as Ernesto Barron and Anthony Rodriguez of the USC Norris Comprehensive Cancer Center Cell and Tissue Imaging Core for their assistance. This work was supported in part by Department of Health and Human Services grants (P30CA014089, U01-CA-151837, R01CA-154471, and R21-CA-164098) (F.M.U.) from the National Cancer Institute, and the National Institute of Health’s Director’s New Innovator Award (1DP2OD007246) (J.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. This work was also supported in part by a 2011 V Foundation Translational Research Award (F.M.U., P.G., A.T.), Nautica Triathlon and its producer Michael Epstein (F.M.U.), Ronald McDonald House Charities of Southern California (F.M.U.), Couples Against Leukemia Foundation (F.M.U.), a William Lawrence & Blanche Hughes Foundation grant (F.M.U.), 2011 and 2012 Saban Research Institute Merit Awards (F.M.U.), and the Turkish Academy of Sciences (K.S.).
Publisher Copyright:
© 2013 by The American Society of Hematology.
