Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients.

Emanuela Di Gregorio,Giuseppe Corona,Emilio Minatel,Gianmaria Miolo,Elena Muraro,Alberto Revelant,Michela Cangemi,Agostino Steffan,Asia Saorin,Marco Trovò

doi:10.3390/cancers13030508

Emanuela Di Gregorio, Giuseppe Corona + Show 8 more

Open Access

https://doi.org/10.3390/cancers13030508

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Abstract

Simple SummaryRadical hemithoracic radiotherapy represents a promising new advance in the field of radiation oncology and encouraging results have been achieved in the treatment of malignant pleural mesothelioma patients. This study showed that this radiotherapy modality produces significant changes in serum metabolomics profile mainly affecting arginine and polyamine biosynthesis pathways. Interestingly, individual metabolomics alterations were found associated with the clinical overall survival outcome of the radiotherapy treatment. These results highlight metabolomics profile analysis as a powerful prognostic tool useful to better understand the mechanisms underlying the interpatients variability and to identify patients who may receive the best benefit from this specific radiotherapy treatment.Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.

Highlights

Malignant pleural mesothelioma (MPM) is a rare primary carcinoma originating from the pleural cavity, strongly linked to asbestos exposure [1]
Despite the relevant overall survival gain, the clinical outcome of the radical hemithoracic radiotherapy (RHRT) was very heterogeneous among patients and there is an urgent need for prognostic biomarkers to guide clinical decision-making and to tailor the RHRT treatment
The knowledge of the molecular mechanisms involved in tumour and normal tissue response to RT has retained an important footstep to improve the efficacy of the treatment through the identification of specific molecular signatures useful to recognize patients who may achieve the best benefit from RT

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a rare primary carcinoma originating from the pleural cavity, strongly linked to asbestos exposure [1]. In MPM patients, this new RT modality referred as radical hemithoracic radiotherapy (RHRT) is delivered with a curative intent. Despite the relevant overall survival gain, the clinical outcome of the RHRT was very heterogeneous among patients and there is an urgent need for prognostic biomarkers to guide clinical decision-making and to tailor the RHRT treatment. The knowledge of the molecular mechanisms involved in tumour and normal tissue response to RT has retained an important footstep to improve the efficacy of the treatment through the identification of specific molecular signatures useful to recognize patients who may achieve the best benefit from RT. In order to get more insight into the role of RHRT in the treatment of MPM patients, we investigated the host response to this specific treatment evaluating the systemic metabolic changes by the application of metabolomics and searched for potential new prognostic biomarkers

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