Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia

Abstract

Key Points SYK is a suitable molecular target for nanotechnology-enabled therapy against ALL. Nanoscale liposomal formulation of SYK inhibitor C61 displayed a promising preclinical profile as an antileukemic drug candidate.

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

“…Total body irradiation (TBI)-based myeloablative pretransplant conditioning regimens are frequently used in hematopoietic stem cell transplantation (HSCT) for high-risk remission BPL (Bar et al, 2014; Bachanova et al, 2012; Kalaycio et al, 2011; Pulsipher et al, 2009; Balduzzi et al, 2014; Tracey et al, 2013; Locatelli et al, 2012; Mori et al, 2012; Gaynon et al, 2006; Marks et al, 2006). Although TBI-containing contemporary conditioning regimens are more effective than conditioning regimens without TBI (Kalaycio et al, 2011; Marks et al, 2006), relapse rates have remained high post-HSCT even after use of very intensive TBI-based conditioning regimens, especially in patients with a high minimal residual disease (MRD) burden (Uckun et al, 1993a; Pulsipher et al, 2009; Balduzzi et al, 2014; Bar et al, 2014; Bachanova et al, 2012), which is in agreement with our published data demonstrating that BPL cells are radiation-resistant (Uckun et al, 1993b; Uckun et al, 2010; Uckun et al, 2013; Uckun et al, 2015). New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed.…”

Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia

“…C61, a liposomal nanoparticle formulation of a SYK substrate-binding site inhibitor, has been developed as a nanomedicine candidate against poor prognosis and relapsed B-cell ALL by inducing apoptosis in radiation-resistant primary leukemic cells. 46,47 In the present study, a low concentration of bafilomycin A1 not only inhibited late-stage autophagy, specifically fusion between autophagosomes and lysosomes, but also inhibited autophagy at its early signaling by activating mTOR and attenuating the formation of the Beclin 1-Vps34 complex, a critical event needed for the induction of autophagy (Figure 2). Inhibition of autophagy can cause apoptosis.…”

Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia

“…Gene expression profiling, immunophenotyping using mAb, confocal imaging, immunoblotting using the ECL detection system (Amersham Pharmacia Biotech), and apoptosis assays were performed, as described in detail in previous publications (40,41,(44)(45)(46) and Supplemental Methods. For bioinformatics analyses of gene expression profiles, we used archived data sets on primary leukemia cells from matchedpair relapse versus diagnosis leukemia specimens from relapsed BPL patients as well as newly diagnosed BPL patients, including those with Philadelphia chromosome (Ph)/BCR-ABL fusion transcript-positive, t(1;19)/E2A-PBX1 fusion transcript-positive, or MLL-rearrangement (R)-positive disease, as detailed in Supplemental Methods.…”

“…Preclinical studies of CD19L-sTRAIL in rodents. The toxicity and PKs of CD19L-sTRAIL were studied in mice using previously published methods (46). The antileukemic activity of CD19L-sTRAIL was studied in a NOD/SCID mouse model of human BPL.…”