We recently discovered the pentapeptide mimic 1,4-Bis (9-0 dihydroquinidinyl) phthalazine / hydroquinidine 1,4-phathalazinediyl diether (C-61) as a tyrosine kinase inhibitor targeting the substrate-binding P-site of SYK as a novel drug candidate against B-lineage acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. In the proposed translational multidisciplinary research project, we will prepare 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, including quantitative in vitro apoptosis assays, murine BCL-I leukemia model in immunocompetent mice, and SCID mouse xenograft models of human B-lineage ALL.
Under Specific Aim 1, we will develop potent and stable liposomal 1st generation nanoparticle constructs of C-61 by optimizing the intemal core environment and inner monolayer of the large unilamellar liposomal vesicles for maximized C-61 entrapment.
Under Specific Aim 2, we will develop potent 2nd generation liposomal nanoparticle constructs of C-61 with improved pharmacodynamic features by modifying the outer monolayer of the large unilamellar liposomal vesicles with poly(ethylene glycol)-modified lipids.
Under Specific Aim 3, we will develop CD19- directed 3rd generation nanoparticle constructs of C-61 by incorporating anti-CD19 scFv covalently attached to PEGylated phospholipids in the outer layer of the lead 2nd generation nanoparticles.
Under Specific Aim 4, we will study the anti-leukemic activity of the lead CD19-specific 3rd generation C-61 nanoparticle constructs in side by side comparison to standard chemotherapy drugs.
Under Specific Aim 5, we will study the effects of standard anti-leukemia drugs on toxicity, pharmacokinetics, and efficacy of the lead CD19-specific 3rd generation C-61 nanoparticle constructs. The development of cell-type specific nanoparticles targeting SYK-dependent anti-apoptotic survival mechanism in CD19-f- leukemic cells will be a significant step forward to overcome chemotherapy resistance in childhood B-lineage ALL. The successful completion of this research project may provide the foundation for a more effective and potentially paradigm-shifting treatment strategy for B-lineage ALL, the most common form of childhood cancer. New nanotechnology discoveries that will result from our research are anticipated to significantly contribute to the mission of the NCI Alliance for Nanotechnology in Cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151837-05
Application #
8716686
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M1))
Program Officer
Abrams, Natali
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$417,323
Indirect Cost
$156,496
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Uckun, Fatih M; Ma, Hong; Ozer, Zahide et al. (2014) A PREVIOUSLY UNKNOWN UNIQUE CHALLENGE FOR INHIBITORS OF SYK ATP-BINDING SITE: ROLE OF SYK AS A CELL CYCLE CHECKPOINT REGULATOR. EBioMedicine 1:16-28
Myers, Dorothea E; Yiv, Seang; Qazi, Sanjive et al. (2014) CD19-antigen specific nanoscale liposomal formulation of a SYK P-site inhibitor causes apoptotic destruction of human B-precursor leukemia cells. Integr Biol (Camb) 6:766-80
Uckun, Fatih M; Qazi, Sanjive (2014) SYK as a New Therapeutic Target in B-Cell Precursor Acute Lymphoblastic Leukemia. J Cancer Ther 5:124-131
Ma, Hong; Qazi, Sanjive; Ozer, Zahide et al. (2013) Regulatory phosphorylation of Ikaros by Bruton's tyrosine kinase. PLoS One 8:e71302
Qazi, Sanjive; Uckun, Fatih M (2013) Incidence and biological significance of IKZF1/Ikaros gene deletions in pediatric Philadelphia chromosome negative and Philadelphia chromosome positive B-cell precursor acute lymphoblastic leukemia. Haematologica 98:e151-2
Uckun, Fatih M; Ma, Hong; Ishkhanian, Rita et al. (2013) Constitutive function of the Ikaros transcription factor in primary leukemia cells from pediatric newly diagnosed high-risk and relapsed B-precursor ALL patients. PLoS One 8:e80732
Uckun, Fatih M; Qazi, Sanjive; Cely, Ingrid et al. (2013) Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia. Blood 121:4348-54
D'Cruz, Osmond J; Uckun, Fatih M (2013) Protein kinase inhibitors against malignant lymphoma. Expert Opin Pharmacother 14:707-21
Goldberg, Michael S; Hook, Sara S; Wang, Andrew Z et al. (2013) Biotargeted nanomedicines for cancer: six tenets before you begin. Nanomedicine (Lond) 8:299-308
Tang, Li; Gabrielson, Nathan P; Uckun, Fatih M et al. (2013) Size-dependent tumor penetration and in vivo efficacy of monodisperse drug-silica nanoconjugates. Mol Pharm 10:883-92

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