Drug Repurposing to Circumvent Chemotherapy Resistance in Brain Tumours

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.