Hypoxia-activated prodrugs to deliver targeted radiosensitisation to hypoxic oesophageal tumours


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Ishna Mistry1,Ewen DD Calder2,Stuart J Conway2,Ester M Hammond1
1Oxford Institute for Radiation Oncology,2Chemistry Research Laboratory, University of Oxford

Abstract

Background

Hypoxia (low oxygen) is associated with a more aggressive tumour phenotype and resistance to therapy. Significant levels of tumour hypoxia have been noted in oesophageal cancers and the 5-year survival rate remains low. Histone deacetylase (HDAC) inhibitors are a class of anti-cancer agents, which have shown promise in pre-clinical testing. Panobinostat has been shown to be a radiosensitiser in a number of cancer types but to our knowledge has not been tested in combination with radiation in oesophageal cancer. We hypothesised that panobinostat combined with radiation could be an effective therapy for oesophageal cancer and that targeting panobinostat to hypoxic tumour cells could reduce systematic toxicity and increase its efficacy.

Method

The average oxygen concentration in healthy tissues is significantly higher than that in untreated tumours, therefore hypoxia can be exploited as a feature of malignant tissue to develop targeted cancer therapeutics. Hypoxia-activated prodrugs (HAPs) are chemically protected inhibitors that are inactive in normoxic conditions, but undergo enzymatic reduction to the active compound in hypoxic cells.

Results

Here we demonstrate radiosensitisation of oesophageal cells with low doses of panobinostat. A nitroimidazole moiety was identified as an effective protecting group from a panel of HAPs of panobinostat. Colony-formation assays showed the prodrug did not affect cell survival in normoxic conditions, in contrast to unprotected panobinostat. Rapid, oxygen-dependent release of panobinostat from the nitroimdazole protected prodrug was demonstrated in vitro and in cells by HPLC/MS analysis. Optimisation of prodrug dose to deliver hypoxia-specific HDAC inhibition without normal cell toxicity is now underway.

Conclusion

We have identified panobinostat in combination with radiation as a novel therapy option for oesophageal cancer, and panobinostat as an ideal candidate to develop as a HAP. Further, we have designed, synthesised and validated a novel HAP of panobinostat. Using this compound, we aim to deliver targeted radiosensitisation to hypoxic oesophageal tumours.