Abstract SY34-03: Hypoxia-metabolic targets for drug development: Identification of targets and their validation
Authors: Stratford Ian J. 
Published: May 2019

The low oxygen status of solid tumours relative to normal tissues has been known for over 50 years. However, methods targeting or exploiting the presence of hypoxia in tumours, for therapeutic benefit, have generally met with little success. Initially, these methods included the use of hypoxic cell radiosensitizers and bioreductive drugs. In the light of current knowledge the reason for “failure” was not necessarily a flaw in the hypotheses being tested, but rather an inability to identify those patients most likely to respond to the modifying treatment. It is now known that tumours vary in their level and extent of hypoxia, with those tumours showing the least hypoxia (highest oxygen tension) being the most responsiveness to therapy. The discovery of the hypoxia-dependent transcription factor, HIF-1, and identification of its downstream gene targets revealed new avenues for targeting tumours. Expression of HIF-1, CAIX, and GLUT-1 have been used as molecular markers of hypoxia and there has been some success in their use as prognostic markers. Further, there has been recent development of a hypoxia metagene signature (Cancer Res. 2007, 67, 3441-9) that has shown prognostic significance in multiple cancers. Despite this progress in identifying molecular markers of hypoxia there has only been one well defined example of using this information for developing novel therapeutic targets; this is the identification and validation of lysyl oxidase (Nature 2006, 440, 1222-6).

Associated with hypoxia is an abnormal metabolic phenotype often characterized by high levels of lactate in human tumours. Monocarboxylate transporter-4 (mct-4) functions to transport lactate out of the cell preventing intra-cellular accumulation of lactate and therefore enabling sustained high glycolytic rates and maintenance of intra-cellular pH. We have demonstrated that mct-4 is a hypoxia/HIF-dependent gene and we evaluated its potential as a novel therapeutic target. Firstly, we evaluated whether expression of mct-4 protein in a panel of 155 oropharangeal tumours correlated with outcome of treatment with radiotherapy. Using a univariate analysis to assess high mct-4 expression (top 25% of scores) vs low mct-4 expression (lower 75%) we showed that mct-4 is a significant adverse prognostic factor in this series of biopsies. High mct-4 expression correlated with poor loco-regional control (p = 0.017), reduced cancer-specific survival (p = 0.02) and reduced overall survival (p = 0.055). In a multivariate analysis high mct-4 expression retained prognostic significance for poor loco-regional control (p = 0.007). We have therefore identified mct-4 as a potential target in head and neck cancer and we have gone on to validate its therapeutic significance by carrying out various gene knock-down studies in vitro and in vivo. Using siRNA to mct-4 we have shown that cells lacking mct-4 are substantially more radioresponsive under hypoxic conditions. Hence, not only is mct-4 expression an indicator of adverse outcome but it is also a target for the development of potential therapeutics (particularly when combined with radiotherapy).

Citation Format: Ian J. Stratford. Hypoxia-metabolic targets for drug development: Identification of targets and their validation [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY34-03