Abstract 191: Double blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme

Abstract

Abstract Introduction: Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults, and is notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database. Methods and Results: The used nanobioconjugates are novel nanotherapeutics where all moieties are covalently connected to poly(β-L-malic acid) (PMLA). Our biodegradable and non-toxic nanodrugs bind to the receptors enriched on tumor vasculature and cross the BBB by transcytosis. They specifically bind to cancer cells and after internalization exit to the tumor cell cytoplasm using pH-sensitive endosomal disruption unit. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR were used. The knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment also markedly reduced the expression of programmed death-ligand 1 (PD-L1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused suppression of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which may inhibit the activity of key cellular kinases. Inhibition of either target was associated with downregulation of the other target as well, which may underlie efficacy of the dual nanobioconjugate that is directed against both CK2 and EGFR. Importantly, the single nanodrugs, and especially the dual nanodrug, markedly suppressed the expression of cancer stem cell markers c-Myc, CD133, and nestin, which could contribute to the efficacy of these nanodrugs. In both tumor models, the dually targeting nanobioconjugate significantly increased (up to 2-fold) animal survival compared with the control group. Conclusion: The versatile nanobioconjugates developed in this study, with the ability of anti-cancer drug delivery across biobarriers and inhibition of key tumor regulators, offer a promising nanotherapeutic approach to treat GBMs and to potentially prevent drug resistance and retard the brain tumor recurrence. Support: NIH grants U01 CA151815, R01 CA136841, R01 CA188743, R01 CA209921, R01 EY013431 Citation Format: Julia Y. Ljubimova. Double blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme [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 191. doi:10.1158/1538-7445.AM2017-191