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For other articles and previous issues click here. January 24, 2005 New
Tracers — Beyond FDG Researchers are working on new radioactive tracers designed to reveal how fast a tumor is growing, how much oxygen it is using, whether it is resistant to drugs, and how much blood supply it has. The goal is helping physicians individualize more optimal treatments for each cancer patient. Until recently, PET scans have been primarily used to find cancer cells in the body. The most widely used radiopharmaceutical available today for identifying cancer cells is FDG (fluoro-2-deoxy-D-glucose). Because cancer cells use more of the glucose radiopharmaceutical than normal cells, PET imaging with FDG allows physicians to accurately identify tumors based on metabolic activity. Today, physicians often use PET with CT to reveal the precise location of abnormal tissue masses and whether those masses are cancerous. Now, however, researchers are taking the concept of imaging cellular activity a step further to improve cancer diagnosis and treatment. They are developing new radioactive tracers that reveal how fast a tumor is growing, how much oxygen it is using, whether it is resistant to drugs, and how much blood supply it has. The hope is that by someday providing all that information, physicians will be able to individualize more precise and thus optimal treatments for each cancer patient, says David A. Mankoff, MD, PhD, an associate professor of radiology in the nuclear medicine division at the University of Washington in Seattle who is researching a number of new tracers and applications. Numerous Studies “Within two to five years,” Sullivan says, “we hope to have a much larger body of evidence about how these agents can help in choosing the most appropriate treatment and monitoring patient response.” PET has also made headlines in recent years because of its potential to assist in diagnosing Alzheimer’s disease in living patients. New PET tracers are also under development that could allow physicians to not only diagnose Alzheimer’s disease but also, as in cancer, monitor and even direct treatment. One new PET tracer for breast and other hormone-sensitive cancers under development is fluorine-18 (F-18) fluoroestradiol (FES). It may be used to predict which patients with advanced breast cancer will be resistant to and which will do well with hormonal therapy. FES is an estrogen analog that binds to estrogen receptors (ERs) in ER-positive breast cancer, says Mankoff, whose group has been studying the tracer extensively for several years. “We know from earlier studies that only those tumors that express hormone receptors respond to hormonal therapy,” Mankoff says. However, more recent studies have shown that ER expression in recurrent or metastatic disease may not be the same as in the primary tumor. ERs The information from the PET imaging studies with FES could be particularly important as some hormone-blocking drugs called aromatase inhibitors have proven effective, with modest side effects, in treating both early- and late-stage breast cancers, Mankoff says. If validated in larger trials, “one might use FES PET to make clinical treatment decisions. For example, if a PET study using FES found that the patient had lost her estrogen receptors, a nonhormonal therapy might be indicated,” he says. Sullivan says research involving FES and ERs is also underway at the Washington University School of Medicine in St. Louis, while research involving PET and androgen receptors in men with progressive prostate cancer is underway at Memorial Sloan-Kettering Cancer Center in New York. Researchers at Sloan-Kettering have been comparing conventional imaging methods for prostate cancer, including bone scan and CT, with PET with FDG and PET with the androgen receptor binding agent [18F] fluoro-dihydro-testosterone. Prostate Cancer Another probe, fluorine-labeled thymidine (FLT), will soon enter NCI-funded clinical trials to measure how fast cancer cells are replicating. When used before treatment and soon after treatment begins, the probe may help determine the extent to which a tumor’s growth is being slowed, Sullivan says. FLT has shown promise as an in vivo means of providing important information about cellular proliferation that could improve cancer therapy response monitoring using PET imaging. In December 2004, the Cancer Imaging Program of the NCI submitted an Investigational New Drug Application for FLT to the FDA. The submission is a product of a collaboration between GE Healthcare and the NCI under a Clinical Trials Agreement. [F-18]-FLT has the ability to detect changes in cellular proliferation or growth. “Cellular proliferation—uncontrolled growth—is a hallmark of cancer, and this tracer is very nicely tailored to that,” Mankoff says. “That’s why over the last few years, there has been quite a bit of excitement over PET cellular proliferation imaging using thymidine analogs such as FLT. There has been a fair amount of work coming out in the literature lately from a variety of different groups, including our center, looking at FLT as a cell proliferation tracer.” PET studies with FLT may allow oncologists to personalize treatments because if a tumor is responding to treatment, “one of the very first things that is going to happen is that the cancer cells are going to stop dividing,” Mankoff explains. With FLT, “we might expect to see changes in cell proliferation occurring much earlier and to a much greater extent than with other methods of measuring response, even FDG PET.” The phase 1 and 2 clinical trials that will initially be performed focuses on the clinical utility of FLT as a PET tracer in helping distinguish between radiation necrosis—the unprogrammed death of cells—and malignant brain tumors. The phase 1 trial should start in February, Sullivan says. Eventually, it could be expanded to cancers other than of the brain. Assessing Therapy • F-18 fluoromisonidazole (FMISO). FMISO detects hypoxia—the absence of oxygen—and predicts its effect on radiotherapies and chemotherapies. The cellular response to hypoxia leads to a number of changes that can raise the cancer’s resistance to therapy. Joseph Rajendran, MD, an assistant professor of nuclear medicine at the University of Washington, recently presented results showing that FMISO uptake, as a measure of tumor hypoxia, predicts survival in head and neck cancer patients. Similar results, using a different PET hypoxia tracer, have been published by the group at Washington University, St. Louis, for cervical cancer. “You’d think that lack of oxygen would hurt the tumor,” Mankoff says. “But, paradoxically, the tumor’s response to hypoxia makes it more resistant to radiotherapy and certain forms of chemotherapy.” • Annexin V. Annexin V has exhibited the ability to track apoptosis, or programmed cell death, which increases in response to successful cancer therapy. Imaging apoptosis would provide another early measure of cell death in response to therapy, Mankoff says. • F-18 labeled choline analogs. Lipid synthesis rates are highly elevated in proliferating cancer cells. Fatty acid and phospholipid precursors such as choline are avidly taken up by cancer cells to support the higher synthetic rates. Researchers at Indiana University School of Medicine in Indianapolis and Duke University Medical Center in Durham, N.C., are developing F-18 labeled choline analogs as cancer imaging agents. The choline analogs are characterized chemically and biochemically by choline metabolizing enzymes. The new radiotracers are evaluated for diagnostic efficacy in patients with prostate cancer, breast cancer, and brain tumors. Tracing Angiogenesis The NCI has started a new program to speed the time to clinical trials and thus the development of new PET tracers. It had issued a request for proposals and selected from among the applicants four centers that serve as Centers of Excellence in PET imaging and tracer development. The four are the University of Washington, Johns Hopkins University in Baltimore, Virginia Commonwealth University Medical Center in Richmond, and Massachusetts General Hospital in Boston. It was a highly competitive process, Sullivan says. Those chosen had to show that they had the equipment and staff to conduct clinical trials, the ability to write protocols, and the population of cancer patients that a new tracer study would require. Having the sites under contract saves time because the applications for clinical trials do not have to go through grant applications and peer review, which can take a couple of years. “The centers have the infrastructure already in place and they’ve agreed to do it in advance,” Sullivan says. He does not expect that the Centers of Excellence will ever replace the traditional grant-related pathways to clinical trials, but to be an additional, effective mechanism. New PET tracers are also showing increasing promise in improving existing capabilities for early detection and treatment of Alzheimer’s disease. It was determined that the distinguishing factor between Alzheimer’s disease and other dementias is the formation of a protein substance called beta-amyloid, or amyloid plaque, believed to contribute to the death of brain cells. Over the last 10 years, researchers at the University of Pittsburgh School of Medicine have created a compound, dubbed Pittsburgh Compound-B (PIB), that allows physicians to use PET to image the amount of amyloid in the brains of patients living with Alzheimer’s. Previously, the scientific community could view and study amyloid plaques only in postmortem brain tissue. Attacking Alzheimer’s “We’re working with a number of pharmaceutical companies through GE Healthcare, which has been licensed to do clinical trials and evaluate amyloid compounds,” Mathis says. “They’re entering clinical trials and identifying patients who would benefit.” PIB may allow physicians to study the very roots of Alzheimer’s disease by assessing the extent of amyloid deposits in people years before symptoms appear. As treatments are developed, the technique may be used to image those whose genetic makeup leads to their family members developing Alzheimer’s at an early age—often in their 40s. The goal is to be able to perform PET scans of at-risk patients before they develop any signs of the disease, follow them during and after therapy, and “hopefully see that the amyloid in their brains is a lot less after treatment than before they started,” Mathis says. Others around the world are doing similar research with PIB. — Beth W. Orenstein of Northampton, Pa., is a regular contributor to Radiology Today. |
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