Abstract
Glioblastoma multiforme (GBM) is the most malignant primary adult brain tumor. The current standard of care is surgical resection, radiation, and chemotherapy treatment, which extends life in most cases. Unfortunately, tumor recurrence is nearly universal and patients with recurrent glioblastoma typically survive <1 year. Therefore, new therapies and therapeutic combinations need to be developed that can be quickly approved for use in patients. However, in order to gain approval, therapies need to be safe as well as effective. One possible means of attaining rapid approval is repurposing FDA approved compounds for GBM therapy. However, candidate compounds must be able to penetrate the blood-brain barrier (BBB) and therefore a selection process has to be implemented to identify such compounds that can eliminate GBM tumor expansion. We review here psychiatric and non-psychiatric compounds that may be effective in GBM, as well as potential drugs targeting cell death pathways. We also discuss the potential of data-driven computational approaches to identify compounds that induce cell death in GBM cells, enabled by large reference databases such as the Library of Integrated Network Cell Signatures (LINCS). Finally, we argue that identifying pathways dysregulated in GBM in a patient specific manner is essential for effective repurposing in GBM and other gliomas.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain tumor
Despite having an already established safe therapeutic index, many ongoing studies are investigating a dosing schedule and chemotherapy combination that will deliver the maximum effects in tumor cells (Triscott et al, 2012). These findings suggest the potential role of disulfiram to be repurposed for use in GBM, and potentially in pediatric brain tumors in the future
Gritti et al demonstrated that metformin can selectively target chloride intracellular channel-1 (CLIC1) in GBM and this inhibition leads to G1 arrest of glioblastoma stem cell (GSC)
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain tumor. *ALDH, acetaldehyde dehydrogenase; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPK, 5′-AMP-activated protein kinase; BBB, blood brain barrier; Bcl-2, B-cell lymphoma 2; CcO, cytochrome c oxidase; CLIC1, chloride intracellular channel-1; CNS, central nervous system; D2, dopamine 2; D-2HG, D-2-hydroxyglutaricacid; ERK1/2, extracellular regulated kinase 1/2; ETC, electron transport chain; FAK, focal adhesion kinase; GABAA, γ aminobutyric acid A; GBM, glioblastoma multiforme; GPCR, G-protein coupled receptor; GSC, glioma stem cell; HDAC, histone deacetylase; HMG-CoA, β-hydroxy-β-methylglutaryl coenzyme A; HNSCC, squamous cell carcinoma of head and neck; IDH, isocitrate dehydrogenases; IP3R, inositol 1,4,5-triphosphate receptor; JNK1/2, c-Jun N-terminal kinase 1⁄2; mAbs, monoclonal antibodies; MAPKs, mitogen-activated protein kinases; MGMT, O6-methylguanine-DNA methyltransferase; mTORC1, mammalian target of rapamycin complex 1; NSCLC, non-small-cell lung carcinoma; OL, oligodendrocyte; PARP, poly (ADP-ribose) polymerase; PCOS, polycystic ovarian syndrome; PD-L1, programmed death-ligand 1; PIK3CD, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta; PLK1, serine/threonine-protein kinase; Rb, retinoblastoma; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; SV2A, synaptic vesicle glycoprotein 2A; TKI, tyrosine kinase inhibitors; TMZ, temozolamide; TRAIL, TNF-related apoptosis-inducing ligand.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
