calixarenes and Glioblastoma

Brain tumor stem cells (BTSCs) and intratumoral heterogeneity represent major challenges in glioblastoma therapy. Here, we report that the LGALS1 gene, encoding the carbohydrate binding protein, galectin1, is a key regulator of BTSCs and glioblastoma resistance to therapy. Genetic deletion of LGALS1 alters BTSC gene expression profiles and results in downregulation of gene sets associated with the mesenchymal subtype of glioblastoma. Using a combination of pharmacological and genetic approaches, we establish that inhibition of LGALS1 signaling in BTSCs impairs self-renewal, suppresses tumorigenesis, prolongs lifespan, and improves glioblastoma response to ionizing radiation in preclinical animal models. Mechanistically, we show that LGALS1 is a direct transcriptional target of STAT3 with its expression robustly regulated by the ligand OSM. Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram the BTSC transcriptional landscape. Our data unravel an oncogenic signaling pathway by which the galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma.

Topics: Aged; Animals; Antineoplastic Agents; Brain Neoplasms; Calixarenes; Cell Line, Tumor; Cell Proliferation; Cell Self Renewal; ErbB Receptors; Galectin 1; Gene Expression Regulation, Neoplastic; Glioblastoma; Homeodomain Proteins; Humans; Male; Mice, SCID; Middle Aged; Mutation; Neoplastic Stem Cells; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; STAT3 Transcription Factor; Transcription, Genetic; Xenograft Model Antitumor Assays

OTX008 is a galectin-1-targeting compound, currently undergoing a phase I clinical trial. This study aimed at investigating OTX008 pharmacokinetics (PK) and antineoplastic activity.. Pharmacokinetics and activity of OTX008 were analyzed in the human ovarian carcinoma A2780-1A9 and glioblastoma U87MG xenografted in nude mice. In vitro, OTX008 was tested on tumor and endothelial cells.. After 5 mg/kg i.v., OTX008 achieved plasma Cmax of 14.39 μg/mL, distributed rapidly, and was eliminated with a half-life of 31.4 h. Tumor OTX008 Cmax (1.65 μg/g, 1.76 μM), achieved at 0.5 h, remained high at 24 h (0.516 μg/g, 0.55 μM) with AUC of 15.76 μg/g*h. OTX008 accumulated in the tumor after repeated administrations achieving a concentration of 2.3 μM, compatible with the concentrations active in vitro. OTX008 (5 mg/kg i.v., every other day for 3 weeks) inhibited the in vivo growth of A2780-1A9, whereas U87MG was not sensitive. In vitro, OTX008 affected endothelial cell proliferation, motility, invasiveness, and cord formation. Tumor cell proliferation was also inhibited, with differences in sensitivity among cell lines (IC50 from 1 to 190 μM). OTX008 potentiated the activity of the tyrosine kinase inhibitor sunitinib on A2780-1A9 in vivo and in vitro, where the combination showed synergistic (endothelial cells) and additive (A2780-1A9) antiproliferative activity, indicating that the combination targets both the tumor and vascular compartments.. OTX008-alone or in combination with sunitinib-has a favorable PK and antineoplastic activity on selected tumor models through the effects on both endothelial and tumor cells.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Calixarenes; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Endothelial Cells; Female; Galectin 1; Glioblastoma; Half-Life; Humans; Indoles; Inhibitory Concentration 50; Mice; Mice, Nude; Molecular Targeted Therapy; Ovarian Neoplasms; Pyrroles; Sunitinib; Tissue Distribution; Xenograft Model Antitumor Assays