Review
Breaching barriers in glioblastoma. Part I: Molecular pathways and novel treatment approaches

https://doi.org/10.1016/j.ijpharm.2017.07.056Get rights and content

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumour, and the most aggressive in nature. The prognosis for patients with GBM remains poor, with a median survival time of only 1–2 years. The treatment failure relies on the development of resistance by tumour cells and the difficulty of ensuring that drugs effectively cross the dual blood brain barrier/blood brain tumour barrier.

The advanced molecular and genetic knowledge has allowed to identify the mechanisms responsible for temozolomide resistance, which represents the standard of care in GBM, along with surgical resection and radiotherapy. Such resistance has motivated the researchers to investigate new avenues for GBM treatment intended to improve patient survival.

In this review, we provide an overview of major obstacles to effective treatment of GBM, encompassing biological barriers, cancer stem cells, DNA repair mechanisms, deregulated signalling pathways and autophagy. New insights and potential therapy approaches for GBM are also discussed, emphasizing localized chemotherapy delivered directly to the brain, immunotherapy, gene therapy and nanoparticle-mediated brain drug delivery.

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)

  • T. Iyama et al.

    DNA repair mechanisms in dividing and non-dividing cells

    DNA Repair

    (2013)
  • R. Karim et al.

    Nanocarriers for the treatment of glioblastoma multiforme: current state-of-the-art

    J. Controlled Release

    (2016)
  • I.P. Kaur et al.

    Potential of solid lipid nanoparticles in brain targeting

    J. Controlled Release

    (2008)
  • S.S. Kim et al.

    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.

    (2015)
  • N.K. Kloosterhof et al.

    Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma?

    Lancet Oncol.

    (2011)
  • S.W. Lee et al.

    The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells

    Cancer Lett.

    (2015)
  • F. Liu et al.

    EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling

    Mol. Cell

    (2015)
  • L.D. Mayo et al.

    PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy

    J. Biol. Chem.

    (2002)
  • K. Messaoudi et al.

    Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide

    Drug Discov. Today

    (2015)
  • L.J. Murray et al.

    Carboplatin chemotherapy in patients with recurrent high-grade glioma

    Clin. Oncol. (Royal College of Radiologists (Great Britain))

    (2011)
  • P.K. Panda et al.

    Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

    Semin. Cell Dev. Biol.

    (2015)
  • V. Plaks et al.

    The cancer stem cell Niche: how essential is the Niche in regulating stemness of tumor cells?

    Cell stem cell

    (2015)
  • F. Pourgholi et al.

    Nanoparticles Novel vehicles in treatment of Glioblastoma

    Biomed. Pharmacother. Biomedecine & pharmacotherapie

    (2016)
  • C. Adamson et al.

    Glioblastoma multiforme: a review of where we have been and where we are going

    Expert Opin. Investig. Drugs

    (2009)
  • R. Alan Mitteer et al.

    Proton beam radiation induces DNA damage and cell apoptosis in glioma stem cells through reactive oxygen species

    Sci. Rep.

    (2015)
  • K. Aldape et al.

    Glioblastoma: pathology

    Mol. Mech. Markers

    (2015)
  • L.S. Ashby et al.

    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.

    (2016)
  • B. Auffinger et al.

    The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence

    Expert Rev. Neurother.

    (2015)
  • L. Battaglia et al.

    Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery

    Expert Opin. Drug Deliv.

    (2012)
  • D. Beier et al.

    Temozolomide preferentially depletes cancer stem cells in glioblastoma

    Cancer Res.

    (2008)
  • S. Blatter et al.

    Minimal residual disease in cancer therapy – Small things make all the difference

    Drug Resist. Updat.

    (2016)
  • G. Borasi et al.

    Fast and high temperature hyperthermia coupled with radiotherapy as a possible new treatment for glioblastoma

    J. Ther. Ultrasound

    (2016)
  • M. Bower et al.

    Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma

    Cancer Chemother. Pharmacol.

    (1997)
  • A.-A. Calinescu et al.

    Overview of current immunotherapeutic strategies for glioma

    Immunotherapy

    (2015)
  • S.K. Carlsson et al.

    Emerging treatment strategies for glioblastoma multiforme

    EMBO Mol. Med.

    (2014)
  • A. Carnero et al.

    The hypoxic microenvironment: a determinant of cancer stem cell evolution, BioEssays: news and reviews in molecular

    Cell. Dev. Biol.

    (2016)
  • V. Chandramohan et al.

    Toxin-Based targeted therapy for malignant brain tumors

    Clin. Dev. Immunol.

    (2012)
  • N. Charnley et al.

    Assessment of drug resistance in anticancer therapy by nuclear imaging

  • P.A. Chiarelli et al.

    Bionanotechnology and the future of glioma

    Surg. Neurol. Int.

    (2015)
  • ClinicalTrials.gov. https://clinicaltrials.gov. (Accessed on 17 July...
  • A. Cohen et al.

    IDH1 and IDH2 mutations in gliomas

    Curr. Neurol. Neurosci. Rep.

    (2013)
  • J.M. Cousin et al.

    The role of galectin-1 in cancer progression, and synthetic multivalent systems for the study of galectin-1

    Int. J. Mol. Sci.

    (2016)
  • M.E. Davis

    Glioblastoma overview of disease and treatment

    Clin. J. Oncol. Nurs.

    (2016)
  • S.V. Ellor et al.

    Glioblastoma: background, standard treatment paradigms, and supportive care considerations

    J. Law Med. Ethics

    (2014)
  • A.O. Elzoghby et al.

    Natural polymeric nanoparticles for brain-targeting: implications on drug and gene delivery

    Curr. Pharm. Des.

    (2016)
  • A. Estella-Hermoso de Mendoza et al.

    Complete inhibition of extranodal dissemination of lymphoma by edelfosine-loaded lipid nanoparticles

    Nanomedicine

    (2012)
  • H. Feng et al.

    EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180

    Oncogene

    (2014)
  • E.C. Filippi-Chiela et al.

    Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage

    Autophagy

    (2015)
  • H.A. Fine et al.

    Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults

    Cancer

    (1993)
  • S. Gao et al.

    Mechanism of thalidomide to enhance cytotoxicity of temozolomide in U251-MG glioma cells in vitro

    Chin. Med. J. (Engl.)

    (2009)
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