Hypoxia as a target for drug combination therapy of liver cancer

Abstract

Oxygen is a requirement for almost all living organisms and adaptations to oxygen shortage are essential for surviving periods of oxygen deprivation, known as hypoxia. Cells have evolved a range of mechanisms which increase the supply of oxygen and facilitate metabolic alterations that enable the cell and the organism to maintain functionality under hypoxic conditions. Hypoxia is a hallmark of solid tumours and is associated with increased malignancy and mortality in hepatocellular carcinoma (HCC). Transarterial chemoembolisation therapy (TACE) using doxorubicin is the current standard of care for intermediate HCC, although response rates are poor. Drug eluting bead transarterial chemoembolisation (DEB-TACE) shows improved response rates over TACE. More recently, rapamycin has come under scrutiny as an effective therapy against HCC. Embolisation therapies have been shown to induce hypoxia in HCC, leading to the escape of hypoxia-adapted cancer cells from therapy. The principal transcription factor which orchestrates responses to hypoxia is hypoxia inducible factor 1 (HIF-1). Laboratory and clinical evidence support the hypothesis that HIF-1 activity contributes to cancer progression and increased mortality. Targeting HIF-1 therefore presents an opportunity for improving outcomes of cancer therapy.

Date of Award	20 Feb 2012
Original language	English
Awarding Institution	University of Brighton