Introduction: Brain gliomas have been extensively characterized by genomic and molecular marker analysis. These studies have underscored glioblastoma multiforme (GBM) heterogeneity, which may underlie failure of even the newest drugs to improve patient survival. For this reason, we turned to genetic modulation of glioma microenvironment using a novel nanobioconjugate.

Methods/Results: Clinical material from 107 GBM patients was analyzed, and tumors with overexpression of “malignant” tumor vascular basement membrane laminin-411 were found to have higher recurrence rate and shorter patient survival. In 92% of human GBM samples, overexpression of laminin-411 was associated with high expression of cancer stem cell (CSC) markers. To examine the interaction mechanisms between GBM cells and their extracellular matrix microenvironment, blood-brain barrier (BBB) passing nanobioconjugates based on poly(β-L-malic acid) (PMLA) were synthesized that specifically inhibit α4 and β1 chains of trimeric laminin-411. In vitro. Normal brain endothelial cells and astrocytes had higher expression of β1 integrin, Notch-1, and Notch ligands when seeded on “malignant” laminin-411 as compared with “normal” laminin-421. All these markers were downregulated in two GBM cell lines treated with antisense oligonucleotides against laminin α4 and β1 chains, suggesting regulation of Notch pathway by laminin-411 through integrin β1. In vivo. In GBM xenograft mouse models increased expression of laminin-411 correlated with overexpression of integrin β1 and Notch signaling pathway members. In two mouse models with intracranial human LN229 and U87MG GBMs, treatment with PMLA-based nanobioconjugate against tumor microenvironment protein laminin-411 led to significantly increased animal survival, associated with marked suppression of laminin-411- β1 integrin-Dll4-Notch axis and CSC markers CD133, Nestin, and c-Myc.

Conclusion: BBB crossing and brain tumor-targeted nanodrug therapy using laminin-411 suppression provided a unique tool to study mechanistic interactions between tumor microenvironment and signaling pathways, and showed promise for efficient GBM treatment affecting both the bulk of tumor cells and CSC.

Support: NIH grants U01 CA151815, R01 CA136841, R01 CA188743, R01 CA209921

Citation Format: Julia Y. Ljubimova. In vivo targeting of laminin-411-β1 integrin-Notch signaling pathway using nanobioconjugate alters glioma microenvironment for effective treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5938. doi:10.1158/1538-7445.AM2017-5938