Download Accepted version - Queen Mary University of London

Title:
Metabolomic analysis of pegylated arginine deiminase treatment in patients
with malignant pleural mesothelioma.
Authors:
Essam Ahmed Ghazaly, Phuong Luong, Magdalena ChmielewskaKassassir, Lucyna Wozniak, John S. Bomalaski, John G. Gribben, Peter
Wojciech Szlosarek; Centre for Haemato-Oncology, Barts Cancer Institute,
Queen Mary University of London, London, United Kingdom; Centre for
Molecular Oncology, Barts Cancer Institute, Queen Mary University of
London, London, United Kingdom; Medical University of Lodz, Lodz,
Poland; Polaris Pharmaceuticals, San Diego, CA
Abstract:
Background: Arginine is a key amino acid for tumorigenesis modulating a
diverse array of metabolic pathways, from synthesis of proteins, NO and
polyamines to nucleotide turnover and mTOR signalling. Tumors deficient
in the urea cycle enzyme, argininosuccinate synthetase 1 (ASS1), are
especially sensitive to deprivation of exogenous arginine using the drug
pegylated arginine deiminase (ADI-PEG20, Polaris Group, US). Previously,
we have reported the metabolic changes induced by ADI treatment in a
panel of ASS1-deficient bladder cancer and malignant pleural
mesothelioma (MPM) cell lines. Here, we examined the metabolic effects in
plasma of patients with MPM treated with ADI [ClinicalTrials.gov
NCT01279967].
Methods: MPM plasma samples (29 patients treated with ADI-PEG20 and
6 control patients over a 9 wk period) were analysed by ultra performance
liquid chromatography-mass spectrometry (UPLC-MS) for untargeted
identification and quantitation of the metabolomic changes. The top
metabolic changes were then assessed by targeted UPLC-MS/MS.
Results: ADI-PEG20 induced marked changes in plasma, which clearly
discriminated treated from untreated patients using partial least squares
discriminant analysis (PLS-DA), a multivariate statistical approach. As
expected, the plasma [arginine] decreased (126±15µM wk 0 vs 3.2±2.5 µM
wk3) with a reciprocal increase in the plasma [citrulline] (56±6µM wk 0 vs
879±113 µM wk3) in ADI-PEG20 treated patients only. In addition, ADIPEG20 treatment triggered the following novel plasma metabolite changes:
increased [thymine] (3.0±0.4 µM week 0 vs 11.5±1.5 µM wk 3), [carnitine]
(43±5 µM week 0 vs 96±7 µM wk 3) and [proline] (147±18 µM wk 0 vs
246±37 µM wk 3), while decreasing [isoleucine] (53±11 µM week 0 vs 17±4
µM wk 3). A 2-fold increase in plasma [glutamine] and [glutamate] was
detected in non-responder patients as assessed by PET-CT, reaching a
maximum by wk 5 of ADI-PEG20 treatment.
Conclusions: This study has identified several metabolic changes in
plasma that may be employed as potential biomarkers for optimizing the
efficacy of ADI-PEG20 in the treatment of MPM and other argininedependent cancers. Clinical trial information: NCT01279967.
Citation:
EA Ghazaly, P Luong, M Chmielewska-Kassassir, L Wozniak, JS Bomalaski, JG Gribben, PW
Szlosarek. “Metabolomic analysis of pegylated arginine deiminase treatment in patients with
malignant pleural mesothelioma”.
Journal of Clinical Oncology, Vol 32, No 15_suppl (May 20 Supplement), 2014: 7587
2014 ASCO Annual Meeting Abstracts
Link to published version:
http://meeting.ascopubs.org/cgi/content/abstract/32/15_suppl/7587