Simultaneous blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also 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. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR at different levels were used. Simultaneous knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment also markedly reduced the expression of programmed death-ligand 1 (PDL1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused deactivation of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which may suppress the activity of key cellular kinases. Inhibition of either target was associated with downregulation of the other target as well, which may underlie the increased efficacy of the dual nanobioconjugate that is directed against both CK2 and EGFR. Importantly, in this study the single nanodrugs, and especially the dual nanodrug, markedly suppressed the expression of the cancer stem cell markers c-Myc, CD133, and nestin, which could contribute to the efficacy of the treatments. In both tumor models, the nanobioconjugates significantly increased (up to 2-fold) animal survival compared with the PBS-treated control group. The versatile nanobioconjugates developed in this study, with the abilities of anti-cancer drug delivery across biobarriers and the inhibition of key tumor regulators, offer a promising nanotherapeutic approach to treat GBMs and to potentially prevent drug resistance and retard the recurrence of brain tumors.

Blockade of a Laminin-411–Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk

“…U87MG or LN229 GBM cells were intracranially inoculated into athymic NCr-nu/nu mice obtained from Taconic as described (28). Mice were treated with PBS or nanobioconjugate P/PEG/LLL (40%)/AON (a4b1; 2.0%)/muTfR (0.15%)/huTfRch (0.15%) with AONs against laminin-411 chains and antibodies for blood-brain barrier (BBB; anti-murine TfR, muTfR) and tumor (chimeric anti-human TfR, huTfRch) targeting.…”

Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management

“…In HNSCC xenograft tumor models (lingual carcinoma, hypopharyngeal and laryngeal carcinoma), CK2 inhibitor (nano-capsules 2016). Inhibitors also decreased the activation of AKT, c-MYC, STAT-3, NF-κB, and the expression of EGFR, indicating that CK2 regulates various signaling pathways responsible for proliferation and survival (Zheng et al, 2013;Chou et al, 2016). In addition, silencing of CK2 alone or with EGFR increased tumor necrosis and mouse survival rate (Chou et al, 2016).…”

“…Inhibitors also decreased the activation of AKT, c-MYC, STAT-3, NF-κB, and the expression of EGFR, indicating that CK2 regulates various signaling pathways responsible for proliferation and survival (Zheng et al, 2013;Chou et al, 2016). In addition, silencing of CK2 alone or with EGFR increased tumor necrosis and mouse survival rate (Chou et al, 2016). Therefore, for patients with GBM who have undergone surgical resection plus radiotherapy combined with temozolomide adjuvant chemotherapy, the use of CK2 inhibitors may, to a certain extent, prevent tumor recurrence.…”

Covalent nano delivery systems for selective imaging and treatment of brain tumors

“…In one of such examples, our work successfully demonstrated BBB permeation in mice using a non-toxic, biodegradable nanobiopolymer, PMLA, as the nanocarrier for delivering GBM therapeutics (Fig. 9, [14, 19, 198]).…”

“…A novel mechanism of cross-talk between protein kinase CK2, an ubiquitous serine/threonine protein kinase, and wild and mutated variant vIII (EGFR/EGFRvIII) EGFR pathways is depicted. Reproduced from [198]. …”