Investigating Metabolism by MRI
AIRC researchers are world leaders in using magnetic resonance techniques to investigate metabolism in cancer, diabetes, obesity, heart and liver disease, and other disorders. These studies promise to give clinicians stunning new insights into these diseases, as well as noninvasive diagnostic tests that can replace many surgical biopsies and do not involve the use of ionizing radiation such as radioactive tracers or X-rays.
In their cancer studies, their aim is not only to develop clinical tests to find and measure the aggressiveness of cancers, but also to pinpoint vulnerable targets for cancer therapies.
A major aim of AIRC is to understand how cancers power their malignant growth by accelerating the energy-producing metabolic pathways of the cell. These pathways are the cell's biochemical disassembly/assembly lines. They break down energy-containing molecules to extract energy to power the cell, and they build molecules needed for cell structure and function. The glycolytic pathway breaks down energy-containing glucose to pyruvate, in the process extracting chemical energy in the form of the molecule ATP to power the cell. This pyruvate can enter the tricarboxylic acid (TCA) cycle in the cell's power plants, the mitochondria, which extract more energy.
Understanding the metabolic engine that drives cancers means measuring the flux through metabolic pathways in cancer, that is, the flow of molecules through the enzyme-catalyzed steps of the pathways. To do such metabolic imaging, AIRC researchers administer tracer-tagged compounds that are natural components of metabolic pathways and map how cancer cells metabolize those compounds.
One widely used atom in tracer studies is the heavier non-radioactive isotope of carbon, 13C (whose nucleus contains one more neutron than the common 12C). AIRC researchers enhance the MRI signal from such compounds by "supercharging" their spin polarization, the amount of spin alignment in a magnetic field. In this process, called hyperpolarization, they freeze a sample of a 13C-containing molecule with a polarizing agent, then subject it to a high magnetic field to align the spin of its atomic nuclei by bombarding the sample with microwaves. The polarizing agent absorbs energy and transfers it to the 13C-containing molecule, thereby hyperpolarizing it. A hyperpolarized 13C-containing molecule emits an MRI signal that is enhanced up to 50,000 times that of the background, making it far more detectable in MRI scans.
Many Medical Applications
Among such studies, AIRC researchers are using hyperpolarized 13C pyruvate to study flux through metabolic pathways in cancer cells (Matthew Merritt, Neil Rofsky, Dean Sherry,) and heart muscle (Sherry, Craig Malloy). In normal heart muscle, hyperpolarized 13C pyruvate is rapidly metabolized in the TCA cycle to bicarbonate. So, an MRI scan showing the distribution of hyperpolarized 13C bicarbonate could provide a map of normal heart muscle, also revealing the presence of tissue damaged by a heart attack.
In studies involving diabetes and obesity, AIRC researchers use 13C pyruvate and other tracers in the cell to explore how the glucose-producing pathway, gluconeogenesis, is controlled (Merritt, Shawn Burgess). Gluconeogenesis, in essence the reverse of glycolysis, is the process by which the liver and kidneys synthesize glucose from smaller molecules in order to maintain blood glucose levels, for example, during fasting. The researchers are analyzing gluconeogenesis in rats and mice genetically engineered to have defects in metabolism, to explore how these animals can aid understanding of the malfunctioning machinery of obesity and diabetes and improve their treatment.
In other studies, AIRC researchers add 13C glucose tracer to cells to analyze the abnormal metabolic pathways of brain tumors (Malloy). They are also using hyperpolarized 13C benzaldehyde to study the activity of an enzyme called aldehyde dehydrogenase in cancer cells (Sherry). This study is important because researchers believe that the activity of this enzyme is characteristically high in cancer stem cells, believed to be the origin of cancer malignancy.
They are also studying the use of hyperpolarized 13C gluconolactone (Sherry) to follow flux through the pentose phosphate pathway – an offshoot of the glycolytic pathway that generates energy and precursor molecules for DNA and some amino acid building blocks of proteins. These studies are important because cancer researchers believe the pentose phosphate pathway is overactivated in cancers. Such measurements could offer a quantitative, noninvasive measure of tumor grade or malignancy.
Revealing Tracer Molecules
In other studies, AIRC researchers are synthesizing tracer molecules that mimic glucose (Sherry), to offer molecular tracers that could reveal tumors in MRI scans. While these glucose-mimics would resemble glucose, and thus would be taken up more avidly by cancer cells, they would be engineered to resist breakdown by the glycolytic pathway. Because tumors need massive amounts of glucose, these tracers would concentrate in tumors, marking them in MRI scans.
AIRC researchers are also designing MRI-enhancing contrast agents for molecular imaging of cancer (Sherry). Such agents are chemicals that influence MRI-relevant properties of water in a target tissue such as a tumor, to create higher contrast between the tissue and the surrounding water. The researchers are engineering chemical complexes that selectively attach to molecules in tumors, to enhance contrast in the tumor images. Such imaging could offer new diagnostic information about tumors and enable oncologists to assess the effectiveness of cancer therapies.
Besides using hyperpolarized tracers, AIRC researchers are also engineering ways to "tweak" the parameters of magnetic resonance spectroscopy (MRS) to reveal metabolic processes. For example, they are developing MRS techniques to analyze how muscle metabolizes carbohydrates and fat (Jimin Ren, Sherry, Malloy). Their objective is to understand not only how normal muscle functions, but the pathologies of such diseases as diabetes, metabolic syndrome, and mitochondrial myopathies. Metabolic syndrome is a set of obesity-related abnormalities, including high blood pressure, insulin resistance, and abnormally high lipid levels, that increase risk of cardiovascular disease and diabetes. Mitochondrial myopathies are metabolic disorders of the cell's mitochondria.
AIRC researchers are also designing MRS techniques to trace the intricate metabolic pathways by which the liver metabolizes fat (Jeffrey Browning, Burgess). Their objective is to understand nonalcoholic fatty liver disease, particularly why some people develop progressive inflammatory disease and others do not. Fatty liver disease, which is associated with obesity, insulin resistance, and metabolic syndrome, is a burgeoning problem affecting nearly 71 million individuals in the U.S. alone. Currently, lack of basic understanding of the pathology of fatty liver disease severely hinders progress in developing treatments.
New Visualization Techniques
Besides developing MRI techniques to analyze metabolic pathways, AIRC researchers are also designing new MRI visualization techniques to reveal organ structures. These research efforts including mapping the structures of the brain to produce highly detailed brain atlases (Hao Huang), and imaging the lung to better diagnose emphysema, fibrosis, pulmonary embolism, pulmonary hypertension, and lung cancer (Masaya Takahashi). Such lung imaging will enable assessment of response of these disorders to drugs and other treatments.
In addition to inventing new MRI technology, AIRC researchers are also synthesizing new nuclear imaging probes for positron emission tomography (PET) and single photon emission computed tomography (SPECT) (Xiankai Sun). In PET, a biologically active tracer is injected into the body and its tissue concentration mapped by detecting pairs of gamma rays that arise from tracer-emitted positrons annihilating with electrons. The analytical technique SPECT involves detecting gamma rays directly emitted by a radioactive tracer. In both techniques, mapping emissions enables the construction of images showing real-time tracer distribution in vivo.
These new imaging probes are based on versatile molecular scaffolds that carry a PET or SPECT radiolabel, onto which could be attached a variety of biomolecules of interest that target a particular cell or biological process. Among the imaging probes the researchers are developing are those that could reveal prostate cancer metastases and that target pancreatic beta-cells, to enable monitoring of the progression of diabetes and its treatment.