MSACL 2019 EU Abstract

Exploratory Metabolomics of Urine and Plasma to Identify Novel Pharmacodynamic Biomarkers in a Phase I Clinical Trial of AZD3965

Alexandros P Siskos(1), CH Lau(1), S. Halford(2), P. Jones(2), S. Hirschberg(2), G. Veal(3), G. Payne(4), M. Chenard-Poirier(4), U. Banerji(5), S. Wedge(3), E. Aboagye(1), R. Plummer(3), Hector Keun(1)
(1)Division of Cancer, Imperial College London - ECMC centre, London, Uk (2)Cancer Research UK Angel Building, London/GB (3)Newcastle University, Newcastle upon, NE2 4HH, Tyne/GB (4)Institute of Cancer Research ICR, London/GB (5)Drug Development Unit, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB

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Alexandros Siskos (Presenter) Imperial College London

Presenter Bio: 2011 – present: Research Associate in Metabolic phenotyping and environmental toxicology at Imperial College London, Department of Surgery and Cancer.

2017 - present: Translational biomarkers research scientist (metabolomics) at Imperial College London – ECMC (Experimental Cancer Medicine Centres).

2007 – 2011: Research Fellow at the Biomedical Research Foundation, Academy of Athens, Division of Pharmacology.

Ph.D. in Biological Chemistry, King’s College London

Relevant Financial Disclosures (within past 24 months) No relevant financial relationship(s) to disclose. Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

INTRODUCTION: A key metabolic alteration in tumour cells is increased dependency on glycolysis, resulting in the production of lactate which is transported out of cells by monocarboxylate transporters (MCT1 & MCT4) which are therefore a therapeutic target in cancer. Current literature suggests that inhibition of MCT1 in preclinical models can constrain cancer cell growth in tumours with low MCT4 expression. To date the systemic pharmacodynamic effects of the small-molecule non-competitive inhibitor of MCT1, AZD3965, the agent of study in this first-in-class (FIC) trial CRUKD12/004, have not been fully characterised. Preclinical metabolomics studies conducted at Imperial College London indicated that AZD3965 exposure caused increases in lactate, ketone bodies (also MCT1 substrates) and citrate in blood plasma and urine independently of tumour burden and tumour expression of MCT1, and also caused decreases in fatty acids in blood plasma.

OBJECTIVES: To investigate whether blood and urine levels of key metabolic markers are modified by AZD3965 treatment with the aim to provide pharmacodynamic biomarkers of efficiency, understand mechanisms of toxicity and define toxicity biomarkers.

METHODS: For the exploratory metabolomics study, we used NMR spectroscopy of urine and plasma samples from 34 patients from the trial to specifically monitor lactate and other ketone bodies and in addition a metabolomics screen using a well-validated LC-MS/MS protocol (Biocrates AbsoluteIDQ p180 kit) on plasma.

RESULTS: Metabolomics screen of plasma and urine appears to correlate with AZD3965 exposure and especially total urinary excretion of lactate and ketone bodies offers proof of target engagement. This effect is not mirrored in plasma suggesting that this may be primarily a renal effect. Observed systemic metabolic effects of AZD3965 exposure appear to lessen with repeated dosing, suggesting a rapid adaptive response. Metabolomics profile offers insides in understanding the mechanisms of drug toxicity and the potential to define metabolic biomarkers to identify individuals which are more likely susceptible to adverse drug toxicity.

CONCLUSIONS: The present metabolic profiling study provided biomarkers of drug exposure, proof of target engagement and understanding of the mechanism of drug toxicity. These results contributed to the successful completion of the Part 1 of the trial and the subsequent Part 2 is currently underway.