In this exploratory project, we are proposing to develop a new strategy to overcome radiation resistance of leukemic stem cells in B-lineage ALL using a novel recombinant biotherapeutic agent, namely CD19-Ligand, for selectively amplifying radiation-induced pro-apoptotic signaling. The long-term goal of the proposed research is to establish """"""""personalized"""""""" radiation therapy regimens against relapsed B-lineage ALL employing a recombinant biotherapeutic agent to selectively increase the anti-leukemic potency of ionizing radiation. We hypothesize that the treatment outcome of relapsed B-lineage ALL patients can be improved by using recombinant CD19-Ligand in combination with TBI in the context of HSCT.
Under Specific Aim 1, we will examine the effects of recombinant CD19-L on in vitro radiation resistance of radiation-resistant ALL cell lines as well as primary ALL cells from relapsed B-lineage ALL patients using quantitative flow cytometric apoptosis assays and clonogenic assays (Year 1 of the Project). We hypothesize that CD19-L will amplify radiation- induced pro-apoptotic BTK signals thereby markedly and selectively enhancing radiation-induced apoptosis of CD19+ B-lineage ALL cells as well as augmenting radiation-induced death of their clonogenic fraction. The radiation resistance of leukemic cells will be measured using our standard quantitative flow cytometric (CD19/Annexin V staining) and confocal (TUNEL) apoptosis assay platforms.
Under Specific Aim 2, we will examine the effects of the CD19-L on in vivo radiation resistance of leukemic stem cells in primary bone marrow specimens from relapsed B-lineage ALL patients using SCID mouse xenograft models of relapsed B- lineage ALL and sublethal TBI (Year 2 of the Project). We anticipate that the use of CD19-L before and concomitant with radiation will markedly enhance the anti-leukemic potency of TBI in the context of HSCT. Likewise, the sequential administration of TBI and post-TBI CD19-L is expected to be more effective than TBI alone. We will first perform mouse toxicity and pharmacokinetics experiments to determine non-toxic dose levels of CD19-L and then examine the effects of CD19-L on the anti-leukemic potency of sublethal TBI (2 Gy) against leukemic stem cells in primary bone marrow specimens from relapsed patients as well as radiation- resistant B-lineage ALL cell lines in a SCID mouse xenograft model system. Our working hypothesis is that CD19-L 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. We anticipate that the successful completion of this exploratory research project will provide the first preclinical proof-of-principle for a potentially paradigm-shifting therapeutic innovation against relapsed B-lineage ALL, whereby the radiation resistance of leukemic stem cells is overcome using recombinant CD19-L as a selective radiosensitizer that amplifies pro-apoptotic signaling after radiation.
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
|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; 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|
|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|
|Qazi, Sanjive; Ma, Hong; Uckun, Fatih M (2013) Absence of Genomic Ikaros/IKZF1 Deletions in Pediatric B-Precursor Acute Lymphoblastic Leukemia. Int J Mol Med Sci 3:72-82|
|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|
|Ozer, Zahide; Qazi, Sanjive; Ishkhanian, Rita et al. (2013) KU HAPLOINSUFFIENCY CAUSES A LYMPHOPROLIFERATIVE DISORDER OF IMMATURE T-CELL PRECURSORS DUE TO IKAROS MALFUNCTION. Int J Mol Med Sci 3:50-64|
|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|
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