Simultaneous blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme.
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 (PD-L1), 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, 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.
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Szu-Ting
ST
Chou
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Rameshwar
R
Patil
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Anna
A
Galstyan
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Pallavi R
PR
Gangalum
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA.
Webster K
WK
Cavenee
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA.
Frank B
FB
Furnari
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Vladimir A
VA
Ljubimov
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Alexandra
A
Chesnokova
Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Andrei A
AA
Kramerov
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Hui
H
Ding
Duke University School of Medicine, Department of Biostatistic and Bioinformatics Clinical Research Training Program ( CRTP ).
Vida
V
Falahatian
Johns Hopkins University, Baltimore, Maryland, USA.
Leila
L
Mashouf
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Irving
I
Fox
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Keith L
KL
Black
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Eggehard
E
Holler
Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Alexander V
AV
Ljubimov
Nanomedicine Research Center, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.|Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Julia Y
JY
Ljubimova
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008293:Malates / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D058726:Nanoconjugates / Q000737:chemistry / Q000627:therapeutic use*; D014411:Neoplastic Stem Cells; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D015398:Signal Transduction; D013499:Surface Properties
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008293:Malates; D058726:Nanoconjugates; D016376:Oligonucleotides, Antisense; D011108:Polymers; C410723:epidermal growth factor receptor VIII; C121060:poly(malic acid); D011092:Polyethylene Glycols; D066246:ErbB Receptors; D047390:Casein Kinase II
Blood-brain barrier delivery; Dual antisense oligonucleotide-dual antibody nanobioconjugate; EGFR/EGFRvIII; Glioblastoma multiforme; Protein kinase CK2