Researchers at UCLA are developing a new molecular imaging probe called FAC that may one day help physicians evaluate autoimmune diseases and therapies, as well as certain cancers.
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If a physician orders a positron emission tomography (PET) imaging probe today, the chances are that it will be some variant of fluorodeoxyglucose (FDG). While FDG probes are effective for a host of molecular imaging applications—from oncology to cardiology—they are less successful in revealing the body’s immune response to disease and therapies.
Realizing the existing PET probe toolbox could be expanded, researchers at the University of California Los Angeles set out to find new PET probes that could better image the immune system’s response to autoimmune diseases and therapies. The early result of their research is an experimental probe, called FAC, which has been proven to be safe and effective in animal studies. The researchers have recently published the results of their study in Nature Medicine.
If current human trials are successful, FAC will eventually give clinicians and researchers a dynamic diagnostic and prognostic tool for showing how the body’s lymphocytes respond to cancers, autoimmune diseases, and specific therapies.
Beyond FDG
Lead UCLA author of the Nature Medicine study, Caius Radu, MD, assistant professor, Department of Molecular and Medical Pharmacology at UCLA and the Crump Institute for Molecular Imaging, stressed that they were not trying to replace FDG. Rather, they are seeking a new type of PET probe that would target lymphocytes.
“The question that we tried to answer was, can we develop a PET imaging probe that can enable us to localize T lymphocytes in the body? We were particularly interested in immune activation, so we were looking more toward a probe that could light up activated T cells,” he said. Owen Witte, MD, investigator at the Howard Hughes Medical Institute and professor of microbiology at UCLA, is another FAC researcher who believed there could be a more effective way to image the immune system’s response to cancer, cancer therapies, and other inflammatory diseases, such as rheumatoid arthritis.
“When we looked into particular diseases and situations, such as the immune response to cancer, we could find some applicability of using FDG to measure both the immune system as well as the cancer that was attacking, but it really didn’t have enough specificity,” Witte said. “The challenge in front of us was to try to develop new probes based on other pathways and chemical structures, which might better tell us what the immune system was doing.”
The UCLA scientists focused on developing a PET probe that could enter the cell using the DNA salvage pathway rather than the DNA de novo pathway that is used by glucose-based FDG.
“When our cells divide, they have to make new DNA,” Witte said. “Sometimes they make it in the de novo pathway from building blocks starting as small as glucose getting metabolized and built up into the precursors of nucleic acid. But during, for example, an active immune response, there’s not only a lot of cell proliferation, but also a lot of cell death. The contents of those dying cells include a lot of DNA, which gets chopped into the precursors of DNA, and then there are special mechanisms for the remaining viable cells to draw that precursor pool back into the cells and build DNA from the salvage pathway.”
Radu added: “These two pathways, for reasons that are still unknown, appear to be active [in response] to different diseases in different cell types. It looks like lymphocytes, especially activated lymphocytes, rely much more on the salvage pathway than other cells.”
Consequently, the UCLA researchers began screening existing compounds that synthesize DNA using the salvage pathway and would have the potential of adding a radiolabel.
Fortunately, there were a few known compounds that met their criteria. Eventually, the UCLA scientists focused on the well-known cancer chemotherapy drug, gemcitabine, from Eli Lilly, Indianapolis, which they believed could be modified and labeled with a radioisotope.
“It looked really good, but there were some chemistry constraints [with gemcitabine],” Radu said. “Not every small molecule can be labeled with fluorine-18 for PET imaging. The other problem is that the half-life of that radioisotope is only 2 hours. If there are too many chemical synthesis steps, then you really go way beyond that 2-hour half-life and you don’t have enough radioactivity at the end. So, the second part of this process was to try to tweak the structure of gemcitabine and come up with a compound that retains its ability to accumulate and proliferate in T cells, but also becomes amenable to labeling with F-18 for PET imaging.”
It took about a year, but eventually Radu and his colleagues developed FAC (an abbreviation for [18F]fluoroarabinofuranosyl cytosine).
FAC’s Clinical Potential
The initial purpose of FAC was to visualize and localize the activated lymphocytes. Physicians would then be able to measure the patient’s autoimmune response and perhaps change treatment decisions based on an FAC PET study.
“Suppose you’re managing a patient [who has] an autoimmune disease with an increase in the cellularity and activation of the immune system,” Witte said. “For example, rheumatoid arthritis and certain types of organ-specific autoimmunity where lymphocytes and other inflammatory cells invade the organ and damage the tissue. Our goal is to visualize that process, and then if a physician is using a drug to treat the autoimmunity, such as corticosteroids or some of the other agents, we would hope to be able to use such probes to visualize that response to those therapies.”
Thus, patients with diseases such as autoimmune hepatitis, multiple sclerosis, or autoimmune diseases where cells attack the kidney, brain, etc, could benefit from FAC studies—as well as those with cancers.
FAC may also have a unique cancer application. Since FAC would follow the same biochemical pathway as gemcitabine, an FAC PET study could be used to pre-evaluate patients specifically for gemcitabine.
Such an FAC study could reveal whether that particular chemotherapy would even reach the target or show how much of the drug ends up in the targeted tumors. If the tumors were subsequently found to have relatively little uptake of the FAC, those patients would be spared perhaps months of toxic and ineffective chemotherapy.
Furthermore, FAC could help chemotherapy researchers understand why some patients do or do not respond to gemcitabine-based therapy, because they can now trace the FAC being metabolized in the same way.
Although FAC could be used to diagnose some cancers and other diseases, Radu hesitates to say that it would be considered a direct competitor to FDG, but rather a complementary probe.
“It could be used for diagnosis, but FDG can pick up the majority of cancers with few exceptions, so it’s very difficult to match FDG from this point of view,” he said. “But what FDG cannot do is give information about certain molecular targets that are important for different drugs. So, I don’t think FAC will be used for diagnosis, but more to get the molecular signature that can be relevant to how a drug will work or not.”
Witte added: “Particularly for my interests, [FAC] sees places where the immune system is activated in response to tumors and in response to autoimmune stimuli. So, our hope is that this will become a probe that is useful for the diagnosis and management for patients with autoimmune diseases or in cases where the cellular immune system is attacking cancer.”
Next Steps
With animal studies showing FAC’s potential, the researchers have begun to test FAC in humans for a variety of clinical applications, though these experiments are in their early stages and have not been published.
In addition to performing human studies, the UCLA researchers are honing FAC’s structure to make it more effective. They are also taking the lessons they learned from developing FAC and applying them to discovering new innovative PET imaging probes.
Another area of interest is analyzing the immune system as it reacts to certain conditions in an individual.
“The immune system is distributed throughout the whole body and it’s in various states of activation,” Witte explained. “For example, if you get a cut on your arm, the lymph nodes in your armpit are responding to that infection and becoming swollen and activated, while the lymph nodes on the other side of your body might be normal. So, there’s a lot of asymmetry in the immune system, depending on what the disease process is: infection, cancer, autoimmunity, etc. And one of the nice things about these types of probes is that they’ll give you this distribution on an individual basis. So, we’re evaluating the individual variability [of the immune system], person to person, under normal conditions or various pathological conditions.”
While FAC may one day have broad potential for many conditions and molecular research, Radu said that they will focus on one or two immune disorders and on several cancers at first. However, it is still too early to say which diseases they will be targeting until they have enough human data.
Of course, the goal is for FAC to become a human probe in the clinic. As to when that will become reality, Radu is optimistic that it could be within the next several years, but Witte is more cautious.
“I’ve been doing fundamental and applied research for years, and I’ve learned that you never can guess the time line,” Witte said. “But the one thing I know for sure is that these compounds can move very quickly from analysis in animals to analysis in people, and we’re already beginning that process. So, I don’t think it’s unrealistic that if the probe shows the right behavior and gives us useful information that can’t be obtained with existing probes or other techniques, you would see this moving into the clinic within a 5-year period of time.”
Tor Valenza is a staff writer for Axis Imaging News. For more information, contact .
