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.
This study was designed to improve the efficacy of radiation therapy against radiation-resistant leukemia. We report that the potency of low dose radiation therapy against B-precursor acute lymphoblastic leukemia (BPL) can be markedly enhanced by combining radiation with a liposomal nanoparticle (LNP) formulation of the SYK-P-site inhibitor C61 ("C61-LNP"). C61-LNP plus low dose total body irradiation (TBI) was substantially more effective than TBI alone or C61-LNP alone in improving the event-free survival outcome NOD/SCID mice challenged with an otherwise invariably fatal dose of human ALL xenograft cells derived from relapsed BPL patients. C61-LNP plus low dose TBI also yielded progression-free survival, tumor-free survival and overall survival outcomes in CD22ΔE12 × BCR-ABL double transgenic mice with advanced stage, radiation-resistant BPL with lymphomatous features that were significantly superior to those of mice treated with TBI alone or C61-LNP alone.
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, USA ; Department of Pediatrics, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, USA ; Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, USA.
Fatih M
FM
Uckun
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, USA.
Dorothea E
DE
Myers
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign (UIUC), Urbana, IL 61801, USA.
Jianjun
J
Cheng
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles (CHLA), Los Angeles, CA 90027, USA ; Bioinformatics Program, Gustavus Adolphus College, 800 W College Avenue, St. Peter, MN 56082, USA.
Sanjive
S
Qazi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods*; D018572:Disease-Free Survival; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008081:Liposomes / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D053758:Nanoparticles; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000072377:Syk Kinase; D016896:Treatment Outcome; D014916:Whole-Body Irradiation; D023041:Xenograft Model Antitumor Assays
D047908:Intracellular Signaling Peptides and Proteins; D008081:Liposomes; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse
BPL, B-precursor acute lymphoblastic leukemia; Bone marrow transplantation; Cancer; LNP, liposomal nanoparticles; Leukemia; Personalized medicine; Precision medicine; Radiation resistance; SYK, spleen tyrosine kinase; Total body irradiation