Development of tools for monitoring the tumor microenvironment by MR techniques:

Bruxelles Woluwe

Since several years, we are continuously developing innovative MR technologies to characterize the tumor hemodynamics and its different components: oxygenation of the tissue, perfusion and oxygen delivery, oxygen consumption.
We pioneered developments in EPR oximetry with the characterization of paramagnetic materials possessing favorable features for oximetry. Thanks to these developments, EPR oximetry is routinely used in the laboratory for studying the temporal evolution of tumor pO2. The technique is unique in a sense that it monitors oxygenation inside a tissue non-invasively and repeatidly from the same site over the time. In a translational approach, we also developed biocompatible forms of these systems. One clinical EPR system (second in the world) has been installed in the laboratory by the end of 2014. This sytem will allow to carry out clinical EPR oximetry studies in oncology and diabetology. We have been also interested in developing new ways to measure oxygen using MRI, namely by using fluorine 19F relaxometry in order to map tumor oxygenation. More recently, we developed and patented a technology called MOBILE (Mapping of Oxygen By Imaging Lipid relaxation Enhancement). This technique is based on the change in relaxation of the proton lipids induced by the oxygen which is paramagnetic and acts as an endogenous oxygen sensor. By using special MRI sequences that measure the relaxation of lipids, it is possible to generate parametric maps of the tissue oxygenation. This method is presently under qualification in pre-clinical models and in cancer patients (head and neck cancer, gliomas).

Figure 1. Typical maps of global R₁ and R₁ of lipids obtained on the same mice at baseline, and after hyperoxic and hypoxic challenges performed with carbogen and CA4, respectively. For this tumor, actual values of pO₂ was 6.1 mm Hg at baseline increased to 9.0 mm Hg during the carbogen breathing, and decreased to 5.1 mm Hg 3 hours after CA4 administration.

We are also focusing on the spontaneous fluctuations of tumor oxygenation (tumor acute hypoxia phenomenon or perfusion-limited hypoxia) with new methodologies to provide map of oxygen fluctuations inside the tumors. Regarding hemodynamics, we are characterizing the tumor perfusion and permeability with Dynamic Contrast-Enhanced (DCE) – MRI. On the other hand, we have developed and are continuously developing new methodologies to measure in vivo the tumor oxygen consumption. In more recent studies, we focused on the tumor metabolism which is a target of new therapeutic strategies. More specifically, ongoing studies are focusing on the non-invasive measurement of the extracellular pH, on the characterization of Warburg/oxidative tumor phenotypes and on the link between tumor cell metabolism and cell proliferation.
Besides the applications of MRI in tumors, we are actively developing new applications of in vivo EPR. In this field, we evaluated the capabilities of EPR imaging to provide maps of melanomas. We are also involved in an international collaboration using EPR as a tool in retrospective dosimetry by measuring the free radicals that are generated in teeth and in bones after irradiation. We are also developing new spin traps for measuring mitochondrial superoxide.