Research Highlights

Learn how Cubresa’s customers are using the power of NuPET technology to enhance their research in a variety of application areas.

PET/MRI evaluation of white matter inflammation in a co-morbid rat model of ischemic stroke and Alzheimer’s disease (and others)

Jonathan Thiessen, Ph.D., Matthew S. Fox, Ph.D., Jonathan Thiessen, Ph.D. Director, PET/MRI Program, Lawson Health Research Institute Assistant Professor, Depts. of Medical Biophysics and Medical Imaging, Western University, Matthew S. Fox, Ph.D. Preclinical Imaging Physicist, Lawson Health Research Institute Research Associate, Dept. of Physics, Western University, .

By helping to advance hybrid PET/MRI and multi-parametric diagnostic imaging tools, we hope to give new insight into the early biomarkers of disease and improve diagnosis and therapy in patients. Projects at a glance: PET/MRI evaluation of white matter inflammation in a co-morbid rat model of ischemic stroke and Alzheimer’s disease One in three individuals over 60 will either experience a stroke, develop dementia or experience both. In addition, the number of Alzheimer’s disease (AD) cases is expected to triple in the next 40 years. When AD and stroke exist together, cognitive impairment increases. White matter inflammation may be the mediator for this interaction. We are using a PET tracer sensitive to the presence of activated microglia ([18F]FEPPA) to measure neuroinflammation longitudinally together with MRI and CT perfusion in a co-morbid rat model of ischemic stroke and Alzheimer’s disease. We are also working to implement a new PET tracer sensitive to synaptic density ([11C]UCB-J). Changes in MRI and PET biomarkers following a stroke have been measured separately and by disparate research labs. Our study represents a unique and comprehensive assessment of brain structure and function using quantitative MRI, dual PET tracers sensitive to neuroinflammation and synaptic density, and behavioural studies assessing motor and executive function. Simultaneous PET/MRI will help us understand when and where white matter inflammation occurs, it’s impact on white matter integrity and synaptic density, and help predict its role in cognitive impairment following a stroke. PET/MRI of altered glucose metabolism and its byproducts in a rat model of glioma Gliomas are a type of brain tumour characterized, in part, by high energy demands. This increased tumour metabolism can be imaged with radiolabelled glucose ([18F]FDG) using positron emission tomography (PET). Although [18F]FDG-PET is a powerful tool for assessing the metabolic activity of tumour cells, it is less effective in the brain, where the surrounding brain tissue also exhibits increased metabolism. In order to better visualize brain tumours and predict their progression, we are investigating magnetic resonance imaging (MRI) methods that can measure brain tumour metabolism and its byproducts without the use of radioactive PET tracers. Specifically, we are using a brain tumour model to investigate two distinct aspects of brain tumour growth: 1. One byproduct of increased tumour metabolism is a change in acidity, known as tumour acidosis. We are investigating an MRI method known as chemical exchange saturation transfer (CEST) that is sensitive to changes in tumour acidosis. Our experiment will use both FDG-PET to measure the rate of glucose metabolism and MRI to measure the amount of tumour acidosis in a C6 rat model of glioma. Based on previous results, we expect to see an increase in tumour acidosis that corresponds to the metabolic activity of the tumour as well as changes outside of the main tumour that may help identify the spread of tumour cells (AKA tumour proliferation). 2. The body’s immune system responds to the presence of tumour cells by sending immune cells to the site of injury. This is known as the inflammatory response. In turn, inflammatory cells take up glucose and may conceal the true extent of metabolically active tumor cells measured with FDG-PET. Inflammation may also contribute to the proliferation of tumour cells in the brain. We are able to measure active inflammatory cells with another PET tracer, [18F]FEPPA. We are using CEST-MRI to measure chemicals related to the inflammatory response in conjunction with [18F]FEPPA-PET. MRI measurements sensitive to inflammation will allow us to create a more complete picture of the tumour and measure treatment response with simultaneous PET and MRI systems (PET/MRI). This project is unique in its combination of information from two distinct and powerful imaging methods: PET and MRI. With the help of gold-standard PET measurements of glucose metabolism and inflammation, we are developing comparable MRI methods that will help classify the aggressiveness of brain tumours and guide the design of new therapies. Eventually, we aim to translate this work to our clinical PET/MRI located in the same research facility to help improve patient outcomes. Carotid artery image derived input functions and kinetic modeling using simultaneous PET/MRI Arterial input functions are often needed in order to perform kinetic modelling of dynamic PET data. Blood sampling in small animal models is challenging due to the availability of total blood volume and ethically permitted sampling volumes in longitudinal studies. Image derived input functions may eliminate the need for invasive blood sampling. Our goal here is to validate a carotid artery image-derived input function (cIDIF) compared to gold standard left ventricle image-derived input functions and arterial blood sampling. Utility of the cIDIF extends to imaging small animal models on PET and PET/MRI systems (e.g., Cubresa NuPET) having short axial FOVs and may extend to clinical imaging where a single bed position scan covers only a head-sized region. Simultaneous x-nuclei PET/MRI The power of multi-parametric and multi-modal imaging for the study and diagnosis of diseases has fueled research in combining modalities, resulting in imaging techniques with higher sensitivity for disease. Advancements in technology have already made possible the combination of simultaneous PET and MRI. Bringing multi-modal and multi-parametric imaging techniques together enables simultaneous imaging, natural co-localization and potential improvement in patient comfort. This arm of our program serves to incorporate several non-proton MRI techniques (e.g. 23Na, 19F and 129Xe) for pre-clinical and clinical simultaneous PET/MRI, enabling improved vision into human disease diagnosis and treatment management.

The application of simultaneous PET/MRI in preclinical cancer research, focusing on the study of novel cancer immunotherapies.

Kim Brewer, PhD, Assistant Professor - Department of Diagnostic Radiology, Dalhousie University, Research Scientist – Biomedical Translational Imaging Centre (BIOTIC), IWK Health Centre/Nova Scotia Health Authority, .

Our research program is investigating the application of simultaneous PET/MRI in preclinical cancer research, focusing on the study of novel cancer immunotherapies. PET/MRI allows for advanced localization of both primary tumors and metastases, particularly in more complex models that are difficult to monitor without imaging, such as ovarian cancer and glioblastoma. Some of our specific ongoing research includes:

1. Evaluating combination immunotherapy in ovarian cancer – Our goal is to better understand the effects of individual immunotherapies and how these effects change in response to combination. We are using quantitative MRI cell tracking to monitor the migration and recruitment of cytotoxic T cells and dendritic cells to tumors and lymph nodes while also using [F18]FDG PET to monitor metabolic changes.

2. Developing novel PET probes for multi-parametric imaging of cancer immunotherapies – Simultaneous PET/MRI offers valuable opportunities for using novel PET probes specific to immune cells in combination with MRI specific probes and complementary MRI contrast mechanisms, particularly apoptosis as measured by a caspase-sensitive Gadolinium probe. We are working on evaluating novel [89Zr] probes that are specific to activated T cells to evaluate how different immunotherapies can affect the recruitment and migration of these cells.

3. Developing novel PET/MRI radiomic biomarkers for glioblastoma – To maximize the effect of immunotherapies, it is crucial that we develop better imaging biomarkers, both for early diagnosis and therapeutic efficacy. Simultaneous PET/MRI allows for the acquisition of several different types of image contrast and molecular indications (depending on probes used). The rapidly expanding field of radiomics seeks to move past the use of simple image analysis by incorporating larger, more comprehensive parameters encoded within images. We are developing novel radiomic biomarkers for immunotherapies and glioblastoma, one of the deadliest and hardest to treat cancers. These biomarkers as based on traditional forms of image contrast (T1, T2, DCE, [18F]FDG), as well as cutting edge techniques such as magnetic resonance fingerprinting and novel PET probes (such as a [89Zr] B cell probe).

Our research program is investigating three developments of simultaneous PET/MRI with pre-clinical tumor models.

Marty Pagel, Ph.D., Professor, Department of Cancer Systems Imaging, UT MD Anderson Cancer Center.

(1) Improving tumor diagnoses based on imaging metabolism with PET/MRI: Our goal is to improve cancer diagnoses using tumor acidosis as a noninvasive, longitudinal biomarker for cancer imaging. Glycolytic metabolism is upregulated in many solid tumors, known as the Warburg effect, which increases lactic acid production and causes acidosis of the tumor microenvironment. Other pathologies such as fibrosis, inflammation, and infection produce little or no tissue acidosis. Therefore, imaging extracellular pH (pHe) can differentiate cancer from non-cancerous pathologies. In addition, [F18]FDG PET can be used to differentiate tumors from infections; [F18]FET PET has been used to differentiate tumors from inflammation; Ga68 agents are currently under development that can evaluate tissue fibrosis. The combination of PET with acidoCEST MRI has strong potential to further improve tumor diagnoses.

(2) Improving cancer immunotherapy based on imaging tumor metabolism with PET/MRI: Extracellular acidosis in the tumor microenvironment causes resistance to immunotherapy. We are evaluating acidosis neutralization treatments that inhibits extracellular acidosis and reduces resistance to immunotherapy. To support these evaluations, we are using our innovative imaging method, acidoCEST MRI, to monitor tumor acidosis during acidosis neutralizing treatments with immunotherapy. To further improve our imaging evaluations, we will perform simultaneous PET/MRI studies with mouse tumor models to compare acidoCEST MRI with FDG PET, where FDG PET can evaluate tumor viability. This combination will be used to determine if acidosis neutralization only changes tumor pHe without affecting tumor viability, or if acidosis neutralization changes tumor pHe and also contributes an anti-cancer effect. Together, simultaneous PET/MRI provides a key technology for imaging tumor metabolism that can improve cancer immunotherapy.

(3) Improving assessments of tumor acidosis with new PET/MRI contrast agents: Our goal is to quantitatively measure extracellular pH (pHe) in the tumor microenvironment to assess tumor acidosis. These assessments can be used to improve evaluations of solid tumors, and to aid in predicting the response to immunotherapy before the treatment is initiated. To meet this goal, we are developing PET/MRI contrast agents that can quantitatively measure pHe, and apply these agents during simultaneous PET/MRI studies in mouse models of human cancers. Dynamic changes in the relaxation-based MR image contrast are sensitive to tumor pHe as well as the concentration of the agent in tumor tissue, while the PET image can be used to measure the concentration of the agent in the tumor. Therefore, the PET results can be used to account for the effect of concentration on MR image contrast, which can improve the quantitative measurement of tumor pHe. Our deliverable is a fundamentally new class of contrast agents for molecular imaging with PET/MRI. As a longer term goal, our PET/MRI contrast agents have outstanding potential for clinical translation, which will provide a transformative “game changing technology” for clinical PET/MRI.

 

Tracking CAR T cell therapies with PET/MRI

Amer Najjar, Ph.D., Assistant Professor, Department of Pediatrics, UT MD Anderson Cancer Center.

The combined Cubresa PET/MRI system has been a crucial tool in advancing our understanding of adoptive cell therapy of brain tumors. These studies exploit the sensitivity of PET to define the spatial distribution of adoptively transferred immune cells and the specificity of MRI to delineate brain tumors and their responses to therapy. Over the last few months, we have utilized the Cubresa PET/MRI system to study the trafficking of adoptively transferred T cells expressing chimeric antigen receptors (CAR T cells) in a mouse glioma model. One of most important and clinically relevant parameters in this disease model is determination of the optimal route of CAR T cell infusion and understanding their trafficking and persistence post-infusion. To this end, combined PET/MRI has provided critical spatio-temporal information revealing the position of Zr-89 labeled CAR T cells within the brain following intratumoral and intraventricular delivery. MRI also delineates brain tumors and provides an assessment of response to therapy, as inferred by anatomical changes within the malignancy and co-localization of adoptively CAR T cells.

We have also utilized the PET/MRI system to evaluate PET tracers for leptomeningeal disease. Specific accumulation of metabolic PET radiotracers within the meninges of the brain is confirmed by co-registration with anatomical MRI of the brain. Future studies will expand the use of PET/MRI to NK and CAR T cell therapy models of other solid tumors such as osteosarcoma. These studies will similarly utilize PET to image adoptively transferred Zr89-labeled immune cells and MRI to delineate tumor tissue and assess responses to cell therapy. Other studies will utilize this tool in mouse models of brain metastases to assess the capacity of PET radiotracers in diagnosing and monitoring responses to therapy.

Evaluations of oxidative phosphorylation and glycolysis metabolism in tumors using PET/MRI

Sanhita Sinharay, Ph.D., Instructor, Department of Cancer Systems Imaging, UT MD Anderson Cancer Center.

Tumor cells often show high uptake of glucose, which is used to feed the metabolic pathways of oxidative phosphorylation and glycolysis. Although glycolysis is often upregulated in tumor cells relative to normal tissues (known as the Warburg effect), oxidative phosphorylation may be upregulated or downregulated in tumors relative to normal tissues. Furthermore, the relative rates of oxidative phosphorylation vs. glycolysis within a tumor is often unknown. Importantly, different anti-cancer treatments that directly target or indirectly affect tumor metabolism change the rates of oxidative phosphorylation and glycolysis to different extents. Therefore, a method is needed to simultaneously interrogate oxidative phosphorylation and glycolysis in a tumor, to provide a more comprehensive assessment of tumor metabolism, and changes in metabolism caused by treatments.

We propose to use simultaneous PET/MRI to address this need. Translocator Protein (TSPO) is expressed on membranes of active mitochondria, and therefore TSPO expression is an excellent biomarker of upregulated oxidative phosphorylation in tumor cells. [F18]GE-180 is a new PET tracer that binds TSPO and has shown promise in differentiating tumors with high vs. low metabolic activities, presumably due to high vs. low levels of oxidative phosphorylation. Also, lactic acid is produced and secreted into the extracellular tumor microenvironment at the endpoint of glycolysis, and therefore extracellular acidosis is an excellent biomarker of glycolytic rate. AcidoCEST MRI is can measure tumor acidosis, which can be used to assess the level of tumor glycolysis. We are developing simultaneous PET/MRI to perform [F18]GE-180 PET in an attempt

Combining [F18]FAZA PET and DCE MRI to evaluate anti-cancer drug treatments

Seth Gammon, Ph.D., Assistant Professor, Department of Cancer Systems Imaging, UT MD Anderson Cancer Center.

Historically we have sequentially utilized PET/CT and then MRI in both our existing projects and emerging projects. First we are utilizing PET/CT then MRI to validate new PET reporters of inflammation. While these experiments are possible and one can reasonably compare volume of interest based analysis, precise co-registration is difficult and does not leverage the true power of multiple MRI acquisitions to study interesting co-variants such as soft tissue composition, flow, diffusion, and perfusion in the regions of inflammation in the same mice at the same time. We are also interested in studying and will utilize sequential [F18]FAZA PET/CT then DCE MRI to study the effects of specific gen knockouts in the context of syngeneic tumor models both with and without immunotherapy. This projects are ideal for simultaneous PET/MRI, so that we can study both the flow based input function and the net oxygenation on a voxel wise basis, and determine how specific genes and molecularly targeted therapeutics might modulate these parameters. In the future I hope to migrate both of these projects to the simultaneous PET/MRI system to take advantage of simultaneous, multimodal imaging.

Pratip Bhattacharya, Ph.D., Associate Professor, Department of Cancer Systems Imaging, UT MD Anderson Cancer Center

Pratip Bhattacharya, Ph.D., Associate Professor, Department of Cancer Systems Imaging, UT MD Anderson Cancer Center.

Dysregulated cell metabolism is a key driver for lethal prostate cancer (PCa) and resistance to therapy. Androgen receptor (AR) signaling regulated by androgen ligands is one of the critical pathways for PCa pathogenesis, aggressiveness and progression. We have performed a comprehensive metabolic imaging and metabolomics study on Androgen Receptor dependent (AR+) and AR independent (AR-) patient derived xenograft (PDX) tumors employing 13C-pyruvate hyperpolarized magnetic resonance imaging (HP-MRI), 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), 1H Nuclear Magnetic resonance (NMR) and mass spectrometry for assessment of antiandrogen drug, Enzalutamide. Metabolic imaging using 13C-pyruvate HP MRI may be able to clinically predict efficacy and monitor metabolic disruptive agents in individual PCa patients. Hyperpolarized Metabolic MRI may be superior to PET to image cancer metabolism.  Ideally we would like to perform this experiment using a simultaneous PET/MRI scanner for imaging tumor models that will enable us to perform this side-by-side comparison directly.