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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center


Cancer: An Inside View

August 7, 2008

Thomas Yankeelov, Ph.D.By Melissa Marino (from the Spring 08 Momentum)

For most of human history, cancer remained largely hidden from view. Unless the tumor could be felt (breast cancer) or seen (skin cancer), this imperceptible intruder lurked quietly inside the body until its spread ultimately led to the death of the patient.

With the discovery of radiation and X-rays in the late 1800s, cancer began to come out of the shadows. For more than 50 years, X-rays remained one of the only noninvasive ways to see inside the body.

Today there are many ways to track down this hidden killer, including X-ray, CT, MRI, ultrasound, and nuclear medicine modalities like PET.

While these imaging methods are indispensable to cancer diagnosis, treatment and follow-up, making true progress against this disease will require more refined, detailed views of cancer. Researchers in the Vanderbilt-Ingram Cancer Center and Vanderbilt University Institute of Imaging Science (VUIIS) are working together to develop more sensitive and informative imaging technologies that not only provide the location and size of tumors, but reveal the inner biology and behavior of cancer.

Sizing up cancer imaging
Imaging plays an integral role at all stages of cancer care. “We use imaging for cancer in a few different settings,” says Dennis Hallahan, M.D., Ingram Professor of Cancer Research and professor and chair of Radiation Oncology at Vanderbilt-Ingram Cancer Center.

One of the most common uses for imaging is in screening for cancer, for example, traditional mammography screening for breast cancer. When cancer is suspected, imaging is used to find where the cancer is located in the body.

Beyond diagnosis, imaging plays an important role in determining how advanced the disease is. This process, called staging, Hallahan explains, “tells us the best way to manage the disease. For example, if a patient has metastatic disease, they’re probably not going to undergo surgery.”

Imaging can also help physicians and researchers evaluate a patient’s response to therapy and monitor for cancer recurrence. This use is particularly important for measuring the effectiveness of new therapeutics.

While standard imaging modalities have been central to improving diagnosis and cancer care, the measurements they give are crude estimates of cancer response.

“Historically, the things imaging is used for…are all based on morphology – sizes and shapes and volumes of the tumor,” says Thomas Yankeelov, Ph.D., Cancer Center member and director of Cancer Imaging at VUIIS. To monitor tumor response to therapy, for example, the size of the tumor after treatment is compared to tumor size before treatment based on a CT or MRI scan. But these measurements are only recorded for the two longest dimensions.

“That’s very limiting because every object in the known universe has three dimensions,” he says. “You can imagine, if (the tumor) is shifting, you may not even necessarily be measuring the same two dimensions before and after treatment.”

Yankeelov notes that only recently has the refinement of existing technologies – like CT and MRI – made it possible to obtain 3-D views of tumors and to determine their volume, a better indicator of long-term response than the “longest dimension” criteria.

Using these criteria, changes in tumor size can usually only be detected after several weeks or months of treatment – a delay that can waste valuable time on ineffective treatments. Since the earliest responses to a cancer treatment occur on a much smaller (cellular) scale, the next generation of imaging methods will have to move beyond these rough physical parameters and probe the invisible realm – the biology of the tumor.

“What we’re trying to do now is to figure out what are the next generation of imaging devices and how should they be used in the clinic,” says Yankeelov. “We’re trying to be more quantitative in characterizing tumors. Instead of just measuring the tumor’s longest dimension, we want to know the volume, the tumor’s metabolic rate, the blood flow, hypoxia distribution, etc.”
Some of these features can be determined invasively with biopsies, says Yankeelov. But repeated biopsies are not practical in the clinic, and biopsies, by their nature, sample only a small portion of the tumor.

“We want to figure out how we can make those measurements with imaging, so that we can do it longitudinally and over time without having to cut into people,” Yankeelov says. Bringing these methods into the clinic for use in humans, however, first requires thorough studies in animals.

Animal models of cancer – especially genetically engineered mice – are central to bringing new imaging techniques to the clinic.

The VUIIS recently received a five-year, $2.2 million grant from the National Cancer Institute (NCI) to apply new imaging techniques for studying cancer in small laboratory animals. This funding helped establish VUIIS as one of only 12 Centers for Small Animal Imaging in the nation.

The center houses scaled-down and more refined versions of all of the major medical imaging devices – including CT, MRI, PET, SPECT and ultrasound. Some other imaging methods, like optical imaging, are so far used mostly in preclinical (animal) research, with a few specialized clinical applications.

“All of them have a lot more flexibility than what you might find in the clinic,” says Yankeelov. And they all provide different information about the tumor.

“There’s no one imaging method that will answer all questions – they all have different strengths and weaknesses.”

Researchers often use different combinations of imaging methods to study cancer. But matching up the data from one imaging method to data from another is a major technical obstacle. To facilitate this process for use in small animal research, VUIIS members, whose expertise range from biology to physics and mathematics, have been developing procedures to help facilitate this process, called “registration.”

Yankeelov, a mathematician by training, is building mathematical models that synthesize data from multiple modalities, “so that you can truly have a comprehensive imaging characterization of tumor response.”

The problem of registration can be overcome by combining two different imaging modalities into a single apparatus. This allows researchers to simultaneously obtain a tumor’s physical measurements as well as information about the molecular processes going on in the tumor. Already, combined imaging is making an impact on cancer diagnosis and treatment in humans.

“Combined imaging is going to be big,” says John Gore, Ph.D., director of the VUIIS and Cancer Center member. “These hybrid instruments will be able to give you information simultaneously. You’ll be able to get physiological measurements, anatomical measurements, as well as molecular imaging information.”

For example, PET-CT, which is already in clinical use, has been one of the great advances in cancer imaging. The PET scan detects glucose metabolism, which tells the physician whether a growth within the body is cancerous or not (malignant growths metabolize more glucose than benign tumors). CT provides detailed information about the size, shape and location of the tumor but cannot differentiate malignant lesions from normal or benign lesions as accurately as PET. Gore predicts that more types of combination imaging are on the horizon from MRI-PET to SPECT-CT.

Vanderbilt researchers are continuing to refine the existing platform of MRI for cancer monitoring. One advancement, called dynamic contrast-enhanced MRI (DCE-MRI), is already being tested in women to determine the effectiveness of targeted therapies in shrinking breast tumors.

DCE-MRI is a “general technique to look at blood flow and vessel permeability in tumors,” explains Yankeelov, who conducted his graduate studies on the technology. “It’s well known that a tumor can’t survive on its own after it gets to be about a cubic millimeter. It has to vascularize (grow new blood vessels), in this well-known process called angiogenesis.”

“Angiogenesis inhibitors” make up a large segment of recently developed targeted therapies, but their clinical effectiveness needs to be monitored over the long-term. DCE-MRI may be a way to observe if these drugs – which include Avastin and Sutent – are having their intended effect of preventing angiogenesis.

Vessel development inside a tumor is “very chaotic,” says Yankeelov. These vessels are not normal – they are leaky and unstructured. “DCE-MRI is a way to probe that leakiness to see how tumors respond to these anti-angiogenesis drugs, and do it non-invasively over time,” he says. “It’s a very useful tool. But it’s not a magic tool that tells you everything you need to know about a tumor.” It will, he says, need to be combined with other measures of cellular proliferation and other molecular features of the tumor.

Going molecular
Molecular imaging, or imaging based on advancements in basic molecular and cellular biology and genetics, is one of the most exciting and promising new avenues for imaging.

VUIIS and Cancer Center scientists are working to develop novel molecular imaging methods, including molecular probes that can reveal aspects of tumor behavior.

“Part of the thrust in cancer imaging now is, can you target treatment knowing more about the tumor?” says Gore. “Characterizing the tumor more completely is important especially for first-line medicine. And that’s one thing that imaging will be able to do quite well.”

Molecular, functional and metabolic imaging has the potential to reveal physiologic, cellular and molecular processes related to disease. These include glucose metabolism, blood flow, oxygen use, cell proliferation rate, and alterations in gene expression and intracellular signaling pathways that influence tumor behavior.

Such techniques may find uses in early diagnosis by detecting changes happening at the cellular or molecular level that appear before the onset of symptoms.

Recently, Cancer Center member Robert Coffey, M.D., and Vanderbilt chemistry professor Darryl Bornhop, Ph.D., reported their development of novel fluorescent ligands of the peripheral benzodiazepine receptor (PBR), a membrane protein whose expression is increased in colon, prostate and breast cancer. Using this ligand, which was tagged with a fluorescent (light-emitting) compound, the researchers were able to detect early stage colon tumors in mice genetically predisposed to developing colon cancer. The probe also accurately distinguished the tumors from inflammation – key to developing a sensitive and specific screening test for cancer.

“The ability to follow molecular events in vivo represents a paradigm shift for medical science,” they wrote in their April 2007 paper reporting these results. “A critically important goal of molecular imaging studies is to detect spontaneously arising tumors in the context of the host/tumor microenvironment.”

This particular molecular imaging tool will facilitate rapid cancer screening in animal models. But the researchers are also working to adapt the technology for human use by labeling the probes with radioactive compounds for use in existing clinical platforms, like SPECT and PET, with the long-term goal of improving the early diagnosis and therapy monitoring in colon cancer.

“Additionally,” they wrote, “we expect these agents to be useful for noninvasive monitoring of therapeutic efficacy that should be useful in improving clinical outcomes.”

Molecular-based imaging may also allow physicians to determine, based on the tumor’s molecular characteristics, which targeted treatments would be most likely to work in a particular patient.

For example, Gore asks, “why take an agent targeting estrogen receptors if the tumor doesn’t have estrogen receptors?” With molecular imaging, one could potentially “tag” probes that bind to particular receptors to see if a patient’s tumor expresses those receptors, and thus be likely to respond to drugs targeted to those receptors.

Perhaps the most promising application of molecular cancer imaging will be monitoring cancer response to therapy. These new methods are now possible because of advancements in understanding the biology of cancer.

“The big push in the last few years has been to develop better methods for assessing whether drugs are hitting their targets, and judging whether patients are doing well,” says Gore. “Our understanding of cancer biology will help us develop biomarkers of cancer response to treatment.”

Already, several Vanderbilt researchers are making progress in this area.

In November 2007, a multidisciplinary team of investigators including Gore, Hallahan, and Andrej Lyshchik, M.D., Ph.D., a Radiology resident, reported that “molecular ultrasonography” – ultrasound technology targeted to specific molecules – may enable in vivo imaging of biomarkers in tumor blood vessels, which could be used to evaluate early tumor responses to anti-angiogenic drugs.

In a mouse breast cancer model, they investigated the use of high-frequency ultrasound coupled with a contrast agent targeted to the vascular endothelial growth factor receptor 2 (VEGFR2), a receptor that is highly expressed in new tumor blood vessels and is a major target for several angiogenesis inhibitors.

They showed that the intensity of the ultrasound signal in the tumors correlated with the expression of VEGFR2, as confirmed by immunoblotting and histologic evaluation.

This technology, contrast-enhanced high-frequency ultrasonography, they wrote, “has several important advantages over other molecular modalities for in vivo imaging of angiogenesis.” It is portable, readily available, and is the only imaging modality that can provide real-time imaging. Ultrasound also is generally less expensive than nuclear imaging and MRI. In addition to adapting technologies for molecular imaging, Vanderbilt researchers are also identifying novel molecular probes that may help individualize cancer treatments and speed up development of new cancer therapies.

Hallahan and colleagues recently developed a technique that may be able to determine a cancer treatment’s effectiveness within days of starting treatment instead of the weeks or months it currently takes.

“It currently takes two to three months of cancer therapy before we can determine whether the therapy has been effective for a patient,” says Hallahan. “If we can get that answer within one to two days, we can switch that patient to an alternative regimen very quickly.”

From a panel of billions of protein fragments, or peptides, Hallahan and colleagues identified one that specifically bound to tumors dying in response to a targeted therapy. To this peptide, they attached a light-emitting molecule and injected these labeled peptides into mice that had been implanted with human tumors.

Using specialized imaging cameras that detect light in the near-infrared range (invisible to the human eye), the investigators saw that tumors responding to therapy were “brighter” than non-responding tumors. The peptide detected response in a wide range of tumors – brain, lung, colon, prostate and breast – within two days of initiating treatment.

“The key word here is ‘days,’” Hallahan says. “This will allow us to minimize the duration of treatments with ineffective regimens in cancer patients.”

The next step will be to move the technology into humans. The imaging technique used in mice (near-infrared) is not sensitive enough to penetrate deeply into human tissues, so the researchers are adapting the technology to an imaging modality commonly used in humans, like PET.

Hallahan predicts that the peptide may enter clinical trials within 18 months. If the probe works as well in humans as it does in mice, he says, such molecular imaging methods could help accelerate the development of new chemotherapeutic drugs.
“In the pharmaceutical industry, we’ll have a patient on a drug for months before we can re-evaluate the size of the tumor,” Hallahan said. “If we can get that answer within a couple of days, it will speed cancer drug development in the early phases of clinical trials.”

This new frontier of molecular imaging holds much promise, but also faces major obstacles – not the least of which is funding. “Funding is a real problem,” Hallahan notes. Federal sources of funding focus primarily on discovery research, but support for translating these discoveries into humans is scarce. Commercial interest is also limited since each kind of test may only be applicable in a small number of patients.

“There’s really a minimal amount of funding for that,” he says. “We have to make that road a little easier from discovery to application.”

Despite the roadblocks, Vanderbilt researchers will keep pursuing new avenues for viewing cancer’s march through the body.

“Imaging is a very useful tool,” Gore says. “You know exactly where you’re looking, how big it is. Imaging has a really persuasive message.” bullet