ReviewBreaching barriers in glioblastoma. Part I: Molecular pathways and novel treatment approaches
Graphical abstract
Section snippets
Clinical and epidemiological aspects
About 5–6 cases out of 100,000 people are diagnosed with primary malignant brain tumours per year, and 80% of them are malignant gliomas. (MGs) (Alifieris and Trafalis, 2015, Schwartzbaum et al., 2006, Stupp et al., 2010). Thus, the most common group of primary brain tumours are MGs, which include astrocytomas, oligodendrogliomas and ependymomas. The World Health Organization (WHO) subcategorized MGs into grade III/IV tumours (such as anaplastic oligoastrocytoma, anaplastic astrocytoma,
High treatment failure rates: mechanisms of therapy resistance
Once a tumour needs nutrients and oxygen from the blood to grow and spread, angiogenesis is a process that occurs frequently in tumour tissues. In the case of GBM, there is a high proliferative activity with infiltration into the surrounding tissues, since it is among the most highly vascularized tumours. These features of GBM do not allow a complete resection of the tumour through surgery, and radiotherapy alone is not always efficient due to the presence of tumour cells in the areas of
Novel approaches in the management of GBM
Despite multiple efforts over the past decades to develop new strategies to treat GBM, none of them led to a better prognostic or an enhanced quality of life for GBM patients, when compared to the current standard of care. The number of failed attempts is mainly due to well-known limitations in the treatment of GBM. These includes not only the inadequate drug delivery across the BBB and the possibility of damage to healthy brain tissues, but also the inter- and intra-tumour heterogeneity, which
Conclusions
Despite all the advances in oncology research, the management of patients with GBM remains one of the greatest challenges worldwide. The current standard of care in GBM, encompassing surgical resection with adjuvant radiotherapy and TMZ, remains the best option so far, although high rates of treatment failure cannot be ignored. Much is already known in what concerns the limitations imposed by the BBB, the inter- and intra-GBM heterogeneity and the drug-resistance nature of GBM cells to TMZ,
Acknowledgments
The authors acknowledge the FCT (Fundação para a Ciência e a Tecnologia, Portugal), for financial support through the Research Project n.° 016648 (Ref. PTDC/CTM-NAN/2658/2014), the project PEst-UID/NEU/04539/2013, and COMPETE (Ref. POCI-01-0145-FEDER-007440). The Coimbra Chemistry Centre is also supported by FCT, through the Project PEst-OE/QUI/UI0313/2014.
References (151)
- et al.
Glioblastoma multiforme: pathogenesis and treatment
Pharmacol. Ther.
(2015) - et al.
Convection-enhanced delivery of nanocarriers for the treatment of brain tumors
Biomaterials
(2009) - et al.
Autophagy is a therapeutic target in anticancer drug resistance
Biochim. Biophys. Acta
(2010) - et al.
HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity
Curr. Biol.: CB
(2007) - et al.
The cytoplasmic side of p53’s oncosuppressive activities
FEBS Lett.
(2014) - et al.
R132H mutation in IDH1 gene reduces proliferation, cell survival and invasion of human glioma by downregulating Wnt/beta-catenin signaling
Int. J. Biochem. Cell Biol.
(2016) - et al.
Angioarchitectural heterogeneity in human glioblastoma multiforme: a fractal-based histopathological assessment
Microvasc. Res.
(2011) - et al.
Tumor cells and neovasculature dual targeting delivery for glioblastoma treatment
Biomaterials
(2014) - et al.
Autophagy and apoptosis- what’s the connection?
Trends Cell Biol.
(2011) - et al.
Prediction of clinical outcome in glioblastoma using a biologically relevant nine-microRNA signature
Mol. Oncol.
(2015)
DNA repair mechanisms in dividing and non-dividing cells
DNA Repair
Nanocarriers for the treatment of glioblastoma multiforme: current state-of-the-art
J. Controlled Release
Potential of solid lipid nanoparticles in brain targeting
J. Controlled Release
Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: the promise of nanomedicine
Biochem. Biophys. Res. Commun.
Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma?
Lancet Oncol.
The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells
Cancer Lett.
EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling
Mol. Cell
PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy
J. Biol. Chem.
Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide
Drug Discov. Today
Carboplatin chemotherapy in patients with recurrent high-grade glioma
Clin. Oncol. (Royal College of Radiologists (Great Britain))
Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics
Semin. Cell Dev. Biol.
The cancer stem cell Niche: how essential is the Niche in regulating stemness of tumor cells?
Cell stem cell
Nanoparticles Novel vehicles in treatment of Glioblastoma
Biomed. Pharmacother. Biomedecine & pharmacotherapie
Glioblastoma multiforme: a review of where we have been and where we are going
Expert Opin. Investig. Drugs
Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species
Sci. Rep.
Glioblastoma: pathology
Mol. Mech. Markers
Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review
World J. Surg. Oncol.
The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence
Expert Rev. Neurother.
Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery
Expert Opin. Drug Deliv.
Temozolomide preferentially depletes cancer stem cells in glioblastoma
Cancer Res.
Minimal residual disease in cancer therapy – Small things make all the difference
Drug Resist. Updat.
Fast and high temperature hyperthermia coupled with radiotherapy as a possible new treatment for glioblastoma
J. Ther. Ultrasound
Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma
Cancer Chemother. Pharmacol.
Overview of current immunotherapeutic strategies for glioma
Immunotherapy
Emerging treatment strategies for glioblastoma multiforme
EMBO Mol. Med.
The hypoxic microenvironment: a determinant of cancer stem cell evolution, BioEssays: news and reviews in molecular
Cell. Dev. Biol.
Toxin-Based targeted therapy for malignant brain tumors
Clin. Dev. Immunol.
Assessment of drug resistance in anticancer therapy by nuclear imaging
Bionanotechnology and the future of glioma
Surg. Neurol. Int.
IDH1 and IDH2 mutations in gliomas
Curr. Neurol. Neurosci. Rep.
The role of galectin-1 in cancer progression, and synthetic multivalent systems for the study of galectin-1
Int. J. Mol. Sci.
Glioblastoma overview of disease and treatment
Clin. J. Oncol. Nurs.
Glioblastoma: background, standard treatment paradigms, and supportive care considerations
J. Law Med. Ethics
Natural polymeric nanoparticles for brain-targeting: implications on drug and gene delivery
Curr. Pharm. Des.
Complete inhibition of extranodal dissemination of lymphoma by edelfosine-loaded lipid nanoparticles
Nanomedicine
EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180
Oncogene
Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage
Autophagy
Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults
Cancer
Mechanism of thalidomide to enhance cytotoxicity of temozolomide in U251-MG glioma cells in vitro
Chin. Med. J. (Engl.)
Cited by (54)
Inhibiting autophagy flux and DNA repair of tumor cells to boost radiotherapy of orthotopic glioblastoma
2022, BiomaterialsCitation Excerpt :Thus, we conjecture that Au@CS NPs can influence the post-transcriptional process of tumor cells to reduce the level of Rad51 [38]. It has been known that the autophagy-lysosome system and the ubiquitin-proteasome system (UPS) are two main pathways for degrading damaged proteins and organelles [39]. Many studies have proven that SQSTM1/p62, an ubiquitin-binding protein, could act as the medium for degrading substrates via lysosomes and proteasomes [40].
Recent developments in drug delivery strategies for targeting DNA damage response in glioblastoma
2021, Life SciencesCitation Excerpt :Nevertheless, the improvements do not translate the considerable technological advances that have occurred in the biomedical areas in the past years. Several resistance mechanisms are related to the failure of current treatments against GBM, including the DNA repair mechanisms, the BBB and blood-brain tumor barrier (BBTB), and the glioma stem cells [10,12], which can be addressed to improve therapy outcomes. The role of DDR in carcinogenesis and tumor resistance is closely dependent on the timing of evaluation and DNA damage type.
Cytoskeletal proteins as glioblastoma biomarkers and targets for therapy: A systematic review
2021, Critical Reviews in Oncology/HematologyNose-to-brain delivery of disulfiram nanoemulsion in situ gel formulation for glioblastoma targeting therapy
2021, International Journal of PharmaceuticsBreaking barriers: exploring mechanisms behind opening the blood–brain barrier
2023, Fluids and Barriers of the CNSDissection of transcriptomic and epigenetic heterogeneity of grade 4 gliomas: implications for prognosis
2023, Acta Neuropathologica Communications