In Vivo Imaging of Tumor Metabolism and Acidosis by Combining PET and MRI-CEST pH Imaging.

Dario L Longo,Paola Bardini,Antonietta Bartoli,Silvio Aime,Markus Schwaiger,Lorena Consolino,Francesca Arena

doi:10.1158/0008-5472.can-16-0825

Abstract

The vast majority of cancers exhibit increased glucose uptake and glycolysis regardless of oxygen availability. This metabolic shift leads to an enhanced production of lactic acid that decreases extracellular pH (pHe), a hallmark of the tumor microenvironment. In this way, dysregulated tumor pHe and upregulated glucose metabolism are linked tightly and their relative assessment may be useful to gain understanding of the underlying biology. Here we investigated noninvasively the in vivo correlation between tumor 18F-FDG uptake and extracellular pH values in a murine model of HER2+ breast cancer. Tumor extracellular pH and perfusion were assessed by acquiring MRI-CEST (chemical exchange saturation transfer) images on a 3T scanner after intravenous administration of a pH-responsive contrast agent (iopamidol). Static PET images were recorded immediately after MRI acquisitions to quantify the extent of 18F-FDG uptake. We demonstrated the occurrence of tumor pHe changes that report on acidification of the interstitial fluid caused by an accelerated glycolysis. Combined PET and MRI-CEST images reported complementary spatial information of the altered glucose metabolism. Notably, a significant inverse correlation was found between extracellular tumor pH and 18F-FDG uptake, as a high 18F-FDG uptake corresponds to lower extracellular pH values. These results show how merging the information from 18F-FDG-uptake and extracellular pH measurements can improve characterization of the tumor microenvironment. Cancer Res; 76(22); 6463-70. ©2016 AACR.

Highlights

Solid tumors are characterized by a highly heterogeneous and acidic microenvironment
We show that the combination of 18F-FDG PET uptake and iopamidol-based magnetic resonance imaging (MRI)-chemical exchange saturation transfer (CEST) pH mapping can provide new insights for an improved characterization of tumor metabolism and microenvironment
As our project aims at exploring routes to transfer preclinical results to clinical applications, it was deemed of interest to work at 3T that is the magnetic field strength of the currently available PET-MRI scanners

Summary

Introduction

Solid tumors are characterized by a highly heterogeneous and acidic microenvironment. The combination of poor vascular perfusion, regional hypoxia, and high rates of glucose metabolism are responsible for generating extracellular acidosis in solid tumors [1]. For energy production, tumor cells rely mostly on the conversion of glucose into lactate rather than mitochondrial oxidation, even in the presence of well-oxygenated conditions This metabolic switch toward a glycolytic phenotype occurs early in cancers, during the avascular phase, promoting the adaptation of the tumor cells to an acidic microenvironment. Tumor acidosis has been linked to multidrug resistance due to the neutralization of weak base chemotherapeutic drugs, which makes the drugs less efficient to cross the

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