Abstract

Prognosis of HPV negative head and neck squamous cell carcinoma (HNSCC) patients remains poor despite surgical and medical advances and inadequacy of predictive and prognostic biomarkers in this type of cancer highlights one of the challenges to successful therapy. Statins, widely used for the treatment of hyperlipidaemia, have been shown to possess anti-tumour effects which were partly attributed to their ability to interfere with metabolic pathways essential in the survival of cancer cells. Here, we have investigated the effect of statins on the metabolic modulation of HNSCC cancers with a vision to predict a personalised anticancer therapy. Although, treatment of tumour-bearing mice with simvastatin did not affect tumour growth, pre-treatment for 2 weeks prior to tumour injection, inhibited tumour growth resulting in strongly increased survival. This was associated with increased expression of the monocarboxylate transporter 1 (MCT1) and a significant reduction in tumour lactate content, suggesting a possible reliance of these tumours on oxidative phosphorylation for survival. Since MCT1 is responsible for the uptake of mitochondrial fuels into the cells, we reasoned that inhibiting it would be beneficial. Interestingly, combination of simvastatin with AZD3965 (MCT1 inhibitor) led to further tumour growth delay as compared to monotherapies, without signs of toxicity. In clinical biopsies, prediagnostic statin therapy was associated with a significantly higher MCT1 expression and was not of prognostic value following conventional chemo-radiotherapy. These findings provide a rationale to investigate the clinical effectiveness of MCT1 inhibition in patients with HNSCC who have been taking lipophilic statins prior to diagnosis.

Details

Title
Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters
Author
Mehibel, Manal 1 ; Ortiz-Martinez, Fernando 1 ; Voelxen, Nadine 2 ; Boyers, Amy 1 ; Chadwick, Amy 3   VIAFID ORCID Logo  ; Telfer, Brian A 1 ; Mueller-Klieser, Wolfgang 2 ; West, Catharine M 4 ; Critchlow, Susan E 5 ; Williams, Kaye J 6 ; Stratford, Ian J 1 

 Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK 
 Institute of Pathophysiology, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany 
 Faculty of Biology, Division of Molecular & Clinical Cancer Sciences, Medicine and Health, University of Manchester, Manchester, UK 
 Translational Radiation Biology, University of Manchester, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom 
 iMED Oncology, AstraZeneca, Cambridge, UK 
 Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK; CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester, Cambridge, UK 
Pages
1-12
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2133412178
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.