Abstract CN01-02: Detecting tumor responses to treatment using magnetic resonance imaging and spectroscopy
Authors: Brindle Kevin M. 
Published: May 2019

Abstract
Patients with similar tumor types can have markedly different responses to the same therapy. The development of novel targeted cancer therapies could benefit significantly, therefore, from the introduction imaging methods that allow an early assessment of treatment response in individual patients. These would allow an oncologist to rapidly assess the effectiveness of a new therapy. Ineffective treatments could be abandoned at an early stage and more effective treatments selected (1, 2).
There has been considerable interest in the development of non-invasive and clinically applicable magnetic resonance-based methods for detecting the early responses of tumors to therapy. A primary focus has been on the development of methods for detecting tumor cell death (3), since the level of tumor cell death following drug treatment has been shown, in clinical studies of some tumor types to be a good predictive indicator for treatment outcome (4, 5). Thus by monitoring tumor cell death we may get an indication of whether a particular drug is working very early during treatment, possibly within 24–48 hours, and long before there is any evidence of tumor shrinkage.
We have been developing a targeted contrast agent that allows detection of apoptotic cells by MRI. We showed that the C2A domain of the protein synaptotagmin would bind to the phosphatidylserine (PS) that appears on the surface of apoptotic cells. When conjugated to small paramagnetic iron oxide (SPIO) particles this protein allowed MRI detection of apoptotic cells, both in vitro and in vivo, in a tumor treated with chemotherapeutic drugs (6). A similar approach has also been used with the PS-binding protein, annexin V (7, 8). More recently we have developed Gd3+-based versions of this C2 agent, which give positive contrast and are therefore easier to detect, and which are smaller and thus more readily enter the tumor interstitium (9–11).
Altered water diffusion appears to be a promising tool for detecting successful treatment response in tumors. Zhao et al. demonstrated an increase in the apparent diffusion coefficient (ADC) of tissue water following successful chemotherapy in murine tumors prior to any visible reduction in tumor volume, suggesting that changes in water diffusion can potentially serve as an early biomarker of therapeutic efficacy (12). The increased ADC appears to be due to a therapy-induced loss of tumor cellularity. The technique is “label-free” and relatively sensitive and has already shown promise in the clinic (13).
Detecting tumor cell death through changes in tumor cell metabolism has been challenging due to the lack of sensitivity of MRS measurements. However sensitivity in the NMR experiment can be increased dramatically using nuclear spin hyperpolarization techniques (14). The polarized compound, typically a 13C-labeled cellular metabolite, can be injected into the biological system and observed for the life time of the polarization (typically 1–2 minutes) (15–18). The massive gain in sensitivity means that we can now image the location of the hyperpolarized 13C-labeled molecule in the body and its metabolic interconversion with other metabolites, in the absence of any background signal.
We have shown that exchange of hyperpolarized 13C label between the carboxyl groups of lactate and pyruvate, in the reaction catalyzed by the enzyme lactate dehydrogenase, could be imaged in tumors and that this flux was decreased in treated tumors undergoing drug-induced cell death (19). Similar experiments have also been performed in a prostate tumor model (20,21). We have suggested that this technique could be used in the future for response monitoring in the clinic, in much the same way as 18FDG has been used with PET, and indeed have compared the two techniques for detecting treatment response in a murine lymphoma model (22). We have also shown that we can monitor the conversion of hyperpolarized (5-13C)glutamine to glutamate in human hepatoma cells in vitro. Since glutaminase activity has been correlated with the rate of cellular proliferation, measurements of its activity in vivo could be used to detect the early responses of tumors to cytotoxic and cytostatic drugs, as has been done with 3′- deoxy-3′-(18F)fluorothymidine (FLT) and PET (23). More recently we have shown that we can detect treatment response using hyperpolarized (1,4-13C)fumarate. Fumarate, a tricarboxylic acid cycle intermediate, is hydrated to produce malate in the reaction catalyzed by the enzyme fumarase or fumarate hydratase. In viable cells plasma membrane transport is so slow that little or no labeled malate is detected within the lifetime of the polarization. However, in drug-treated cells undergoing necrosis, where there is loss of this membrane permeability barrier, there is a marked increased in the rate of labeled malate production and thus the technique can be used to monitor necrotic cell death (submitted for publication).
In conclusion, there are several markers of cell death that can be detected using non-invasive MR imaging and spectroscopic methods. Diffusion-weighted imaging is relatively sensitive and has already translated to the clinic. Measurements of changes in cellular metabolism, using hyperpolarized 13C-labeled metabolites, show great promise and should translate to the clinic in the future. These methods are of particular value in oncology, where they could be used in drug development to obtain an early indication of efficacy and subsequently in the clinic, where they could be used to guide the treatment of individual patients (“personalized medicine”).
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN01-02.