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Drug Repurposing to Circumvent Chemotherapy Resistance in Brain Tumours

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Resistance to Targeted Therapies Against Adult Brain Cancers

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

The incidence of primary brain tumours in the UK is steadily rising; prognosis for this devastating disease is dismal and not significantly improving. The relative failure for effective therapy may be attributed to heterogeneity with over 120 histological entities. Additionally, the biology is incredibly complex with numerous pathways and cascades working simultaneously or in harmonisation. Moreover, we find that as the tumour evolves, it commandeers alternative pathways for its survival. At its most aggressive form, glioblastoma produces guerrilla cells that trek into the normal brain parenchyma where they are protected by the intact blood-brain barrier (B-BB). The majority of drugs cannot cross the intact B-BB; the dosage required to cross the damaged area around the tumour would be toxic systemically. Effective therapy, therefore, has a number of hurdles against chemotherapy resistance. In this chapter we look at the tumour biology and conventional therapeutic resistance; we then look at the potential of using drugs originally used to treat other diseases. Indeed, repurposed drugs are drawing increasingly more interest, especially as after approximately ten years of development; the new drug failure rate of 25,000:1 costs the industry an astonishing fortune of around $2.6 billion per year. Here, we refer to UK regulations and doctor trepidation for prescribing outside of the drug’s licence—‘off-label’—and give examples of some of the repurposed agents which have gained attention within the laboratory and within our current legislation require additional clinical trials for marketing authorisation and prescription without fear of potential litigation.

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Abbreviations

ALDH:

Aldehyde dehydrogenase

CED:

Convection-enhanced delivery

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

GBM:

Glioblastoma

JAMs:

Junctional adhesion molecules

MDS:

Methylation-resistant DNA synthesis

MGMT:

Methylguanine-DNA methyltransferase

MMPs:

Matrix metalloproteinase

MMR:

Mismatch repair

mTORC2:

Rapamycin complex 2

PDGF:

Platelet-derived growth factor

PDK1:

3-phosphoinositide-dependent kinase

Pe :

Transendothelial permeability coefficient

PTEN:

Phosphatase and tensin homolog

TEER:

Transendothelial electrical resistance

UPR:

Unfolded protein response

VEGF:

Vascular endothelial growth factor

ZO-1, ZO-2 and ZO-3:

Zonula occludens proteins 1, 2 and 3

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Acknowledgement

The authors would like to thank Dr. Aditi Nadkarni for her advice and editing suggestions on this chapter.

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  1. Cellular and Molecular Neuro-oncology, Institute of Biomedical & Biomolecular Sciences, School of Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK

    Richard Hill, Samantha A. Murray, Zaynah Maherally, Samantha C. Higgins & Geoffrey J. Pilkington

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  2. Samantha A. Murray
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Correspondence to Geoffrey J. Pilkington .

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  1. Centre for Systems Medicine, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland

    Amanda Tivnan

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Hill, R., Murray, S.A., Maherally, Z., Higgins, S.C., Pilkington, G.J. (2016). Drug Repurposing to Circumvent Chemotherapy Resistance in Brain Tumours. In: Tivnan, A. (eds) Resistance to Targeted Therapies Against Adult Brain Cancers. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-46505-0_6

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