We are proposing to develop a new strategy to overcome radiation resistance in B- lineage acute lymphoblastic leukemia (ALL) using C-61, a novel SYK kinase substrate binding (P)-site inhibitor, for targeting and disrupting the anti-apoptotic SYK-STAT3 signaling network in leukemic B-cell precursors. It is our central working hypothesis that the treatment outcome of relapsed B-lineage ALL patients can be improved by inhibition of the SYK-STAT3 molecular target. This would be accomplished by using C-61 in combination with total body irradiation (TBI) in the context of HSCT.
Under Specific Aim 1, we will examine the effects of the SYK P-site inhibitor C-61 on in vitro radiation resistance of primary ALL cells from relapsed B-lineage ALL patients using quantitative flow cytometric apoptosis assays and clonogenic assays. We hypothesize that C- 61 will markedly enhance radiation-induced apoptosis of primary B-lineage ALL cells and augment radiation- induced death of their clonogenic fraction by increasing their radiation sensitivity and impairing their capacity to repair sublethal radiation damage.
Under Specific Aim 2, we will examine the effects of C-61 on in vivo radiation resistance of primary ALL cells from relapsed B-lineage ALL patients using SCID mouse xenograft models of relapsed B-lineage ALL and sublethal total body irradiation (TBI). Our hypothesis is that C-61 plus TBI regimens will be more effective than TBI alone in improving the event-free survival outcome of SCID mice challenged with primary B-lineage ALL cells.
Under Specific Aim 3, we will examine the association between the kinase expression profiles of primary ALL cells from relapsed B-lineage ALL patients and their in vitro as well as in vivo radiation resistance. In an effort aimed at identifying a composite biomarker profile that will help select patients most likely to benefit from C-61, we will correlate the kinase protein expression and activity levels of SYK, BTK, and JAK kinases of primary B-lineage ALL cells with their radiation resistance, sensitivity to C-61 induced radiosensitization in vitro, as well as C-61 induced potentiation of the anti-leukemic potency of sublethal TBI in vivo.
Under Specific Aim 4, we will study the efficacy and safety of C-61 containing single dose TBI regimens at both sublethal (2 Gy) as well as clinically applied (7 Gy) total radiation dose levels in a syngeneic murine HSCT model of radiation-resistant BCL-1 murine B-lineage leukemia. We will evaluate the efficacy and safety of TBI at doses ranging from 2-10 Gy in combination with C-61 in BALB/c mice inoculated with 1x106 BCL-1 cells in the context of syngeneic BMT. We hypothesize that the addition of C-61 will not increase the non-hematologic toxicity of TBI, while markedly potentiating its anti-leukemic efficacy. We anticipate that the incorporation of C-61 into the pre-HSCT TBI regimens of patients with relapsed B-lineage ALL will improve their treatment response and survival outcome. The proposed research has the potential provide the foundation for the development of paradigm-shifting HSCT strategies that employ C-61 containing novel TBI regimens.

Public Health Relevance

Currently, the major challenge in the treatment of childhood leukemia is to cure patients who experience a recurrence of their cancer despite intensive chemotherapy. The purpose of the proposed research is the development of an effective treatment program against chemotherapy- and radiation therapy-resistant childhood leukemia employing a new anti-leukemia drug candidate. The successful completion of this research project may provide the foundation for therapeutic innovation against childhood leukemia.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Bernhard, Eric J
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Children's Hospital of Los Angeles
Los Angeles
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Uckun, Fatih M; Mitchell, Lloyd G; Qazi, Sanjive et al. (2015) Development of Polypeptide-based Nanoparticles for Non-viral Delivery of CD22 RNA Trans-splicing Molecule as a New Precision Medicine Candidate Against B-lineage ALL. EBioMedicine 2:649-59
Uckun, Fatih M; Ma, Hong; Cheng, Jianjun et al. (2015) CD22?E12 as a molecular target for RNAi therapy. Br J Haematol 169:401-14
Uckun, Fatih M; Qazi, Sanjive; Cheng, Jianjun (2015) Targeting leukemic stem cells with multifunctional bioactive polypeptide nanoparticles. Future Oncol 11:1149-52
Uckun, Fatih M; Myers, Dorothea E; Cheng, Jianjun et al. (2015) Liposomal Nanoparticles of a Spleen Tyrosine Kinase P-Site Inhibitor Amplify the Potency of Low Dose Total Body Irradiation Against Aggressive B-Precursor Leukemia and Yield Superior Survival Outcomes in Mice. EBioMedicine 2:554-62
Uckun, Fatih M; Myers, Dorothea E; Ma, Hong et al. (2015) Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand × Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-Resistant B-Precursor Acute Lymphoblastic Leukemia in Mice. EBioMedicine 2:306-316
Uckun, Fatih M; Myers, Dorothea E; Qazi, Sanjive et al. (2015) Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia. J Clin Invest 125:1006-18
Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M et al. (2015) IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer. ACS Nano 9:7976-91
Uckun, Fatih M; Qazi, Sanjive; Ma, Hong et al. (2015) CD22?E12 as a molecular target for corrective repair using RNA trans-splicing: anti-leukemic activity of a rationally designed RNA trans-splicing molecule. Integr Biol (Camb) 7:237-49
Cai, Kaimin; He, Xi; Song, Ziyuan et al. (2015) Dimeric drug polymeric nanoparticles with exceptionally high drug loading and quantitative loading efficiency. J Am Chem Soc 137:3458-61
Uckun, Fatih M; Qazi, Sanjive; Ma, Hong et al. (2014) A rationally designed nanoparticle for RNA interference therapy in B-lineage lymphoid malignancies. EBioMedicine 1:141-155

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