Highly targeted radiopharmaceuticals in development coupled with advances in PET/CT and SPECT/CT look to bring more personalized diagnosis and treatment.
Molecular imaging has entered a dramatic paradigm-shifting phase of development that many experts agree will revolutionize the way that healthcare is delivered.
While current imaging techniques are being refined with enhancements to equipment such as hybrid PET/CT scanners and the introduction of SPECT/CT this year, the basic science and pre-clinical activities in molecular imaging centers is guiding the direction that healthcare will assume during the next decade.
CURRENT STATE OF MOLECULAR IMAGING
By current definition, molecular imaging involves intravenous injection of a radiopharmaceutical that emits a tracer captured by either a gamma camera (single photon emission computed tomography) or positron emission tomography (PET) system. The contrast agent FDG (fluorodeoxyglucose) has been used with PET for many years, and although it reveals glucose uptake and has proven useful in the diagnosis of cancer, it is not as capable of targeting specific lesions as some of the newer radiopharmaceuticals under development. SPECT uses radiotracers that are less costly to produce and because gamma cameras are not as expensive as PET units, the overall expenses associated with SPECT imaging has added to its appeal.
Carl Hoh, MD, associate professor of radiology at the University of California at San Diego, explains that PET has proven to be a valuable clinical tool for the past seven to eight years, but that the field is moving into developing radiopharmaceuticals that are more specific in their targeting abilities. He suggests that these agents are several years away from widespread use, because it will take that long for full assessment of safety and clinical utility.
Although nuclear medicine scans have produced remarkable images of metabolic activity, the primary drawback of their utility has always been the lack of anatomic data to pinpoint location of the identified lesion. In response to that challenge, Siemens Medical Solutions, GE Healthcare and Philips Medical Systems developed hybrid PET/CT systems and other OEMs have developed software fusion packages to co-register CT and PET as well as facilitate co-registration of images from a variety of modalities.
At the June meeting of the Society of Nuclear Medicine, Philips debuted the Precedence SPECT/CT hybrid scanner that features a diagnostic-quality CT component. At that same meeting, Siemens introduced TruePoint SPECT-CT technology on the Symbia product family that incorporates the e.cam SPECT imaging technology with a diagnostic multislice CT capability as well. While these units provide attenuation correction as well as pinpoint accurate anatomic data coupled with current radiopharmaceuticals, their true significance may be revealed as new specific targeting molecular agents are developed.
Some confusion has arisen as the definition of molecular imaging has evolved. Some people use the term molecular imaging simply as a description of imaging molecules. Any contrast agent is actually comprised of thousands (if not millions) of small molecules, and nuclear medicine scans image its affinity for certain processes in the body, such as increased metabolic rate observed in FDG-PET scans. But today's definition involves development of a targeted molecule that is designed to reach a specific lesion, bind and interact with cells and permit imaging that reveals the reaction.
Alexander Tokman, the general manager of global molecular imaging and radiopharmacy for GE Healthcare, describes the evolving medical paradigm as moving from a "see and treat" focus where symptoms of a disease are diagnosed, and treatment applied, to a "predict and prevent" mode where the molecular basis of human development is assessed to determine risks of diseases to facilitate earlier intervention before a person becomes symptomatic.
"Molecular imaging is focused on the techniques and technologies of interrogating molecular and cellular events in the context of the whole body," says David Piwnica-Worms, MD, PhD, president of the Society for Molecular Imaging and professor of radiology, molecular biology and pharmacology at Washington University in St. Louis, where he also serves as director of their molecular imaging center. "It's a scientific discipline that embraces everything from biochemistry to cell assays and cell cultures as steps to imaging in vivo." Small animal imaging paves the way to clinical applications.
He continues, "The focus is to look at endogenous [inside] genes and proteinsâ?¦ that are present in normal health and disease. These can be interrogated with injectable agents to look at a receptor expression, a transporter function or enzyme activity somewhere in the body." So the long-term goal would be to use molecular probes to observe, at a molecular level, disease processes in oncology, neurology or cardiovascular disorders within the living body.
Although several such agents are well under investigation, there is a new thrust to the research that involves use of reporter strategies to look at biologic events in vivo. Piwnica-Worms explains that these techniques involve use of a genetically encoded reporter to illuminate the area of interest. For example, scientists take firefly luciferace, (the enzyme that makes fireflies glow), and cell biologists engineer it into cells where they program it to interact with certain proteins within other specific cells. Once the probe is injected, it seeks out the specific target cell, binds with the protein, and releases the firefly luciferace, which is then observed with external imaging devices.
Besides the obvious advantages of these techniques in improving diagnostic information, the future directions for this technology include attaching chemotherapeutic or radiotherapeutic agents to the probes and using them to deliver treatment directly to the tumor or other site requiring intervention. This approach would eliminate the side effects and morbidity of current treatments, while delivering dose-dense therapeutics to the lesion of interest. Further, using post-therapy imaging techniques within a couple of days is useful in the assessment of treatment effectiveness.
David Rollo, MD, PhD, chief medical officer for Philips, explains that one of the benefits of using a SPECT/CT system, is that as more and more imaging agents are approved, the quantification of molecular activity is enabled, providing more specificity to the imaging procedure.
COLLABORATIVE VENTURES: THE DRIVING FORCE
Because the new directions for molecular imaging require enormous resources, several large university settings have embarked on massive collaborative efforts with a number of imaging OEMs and other partners to pursue these exciting advancements.The Center for Molecular Imaging Research (CMIR) at Massachusetts General Hospital and Harvard University that was founded in 1994 by Ralph Weissleder, MD, PhD, has entered a collaborative partnership with Siemens.
Mohammed Naraghi, MD, PhD, senior vice president of global business development for Siemens Medical Solutions, explains that because these new directions in molecular imaging activities are highly complex, Siemens believes that a wholistic approach becomes mandatory. The three pillars to support this work include the development of IT solutions to enable integrative approaches, discovery of new agents and radiopharmaceuticals and innovative design of new imaging instrumentation. In their collaborative effort with the CMIR, they anticipate addressing these three aspects of molecular imaging advancement.
Umar Mahmood, MD, PhD, assistant professor of radiology at Harvard, and director of the CMIR Mouse Imaging Program, explains that their staff of 80 includes chemists who are involved in making molecular probes, molecular biologists who are making new cell lines, and many other specialized scientific researchers. The center engages in research from the basic sciences to clinical applications.
He describes one MR agent developed in the Center that appears to improve the specificity and sensitivity to 90 percent for detecting cancer that has spread from the prostate to lymph nodes. Prior imaging techniques for these assessments resulted in only a 60 percent accuracy rate. Another human trial in progress includes methodology to image inflammatory processes that precede the onset of type-one diabetes.
"We work extensively in 'smart probes,' which are agents that change their physical property after target interaction," explains Mahmood. "For example, we have fluorescent probes that become more fluorescent by tenfold or one hundredfold after a specific enzyme interaction." Some of these enzymes are expressed in pre-cancerous colonic adenomas, so the goal is to eventually improve endoscopic diagnostic techniques based on this technology.
In speaking about their collaboration with Siemens, Mahmood explains that although their scientists have a wide array of areas of expertise, the Center has been able to draw on Siemens experience in IT, among other competencies, to facilitate their work.
One of the tools developed as a result of the collaboration is the MIPortal, which is an information technology platform designed to provide molecular imaging research laboratories access to archiving and processing of data, both image and non-image based. Using this tool, links from DICOM and non-DICOM modalities can be integrated with the IT platform and information such as High Throughput Screening (HTS) in genomics (the study of genes) and proteomics (the study of proteins, their expressions and interaction in the body). The goal of this tool is to more quickly translate research results into the clinical environment.
Stanford University in California has made a significant investment in both the basic science and clinical aspects of molecular imaging, and uses GE equipment for some of their activities. The Molecular Imaging Program at Stanford (MIPS) established as an inter-disciplinary program in 2003 and is in the process of developing their infrastructure to pursue their primary interests in oncology and cardiovascular disease, and will move in the future into an emphasis in neurosciences, including Alzheimer's disease, epilepsy and Parkinson's disease.
Sam Gambhir, MD, PhD, director of MIPS, serves as the head of nuclear medicine and a professor of radiology at Stanford University. "The strengths here are that we have the ability to take some agent to a target that might be relevant to, for example cancer, and then work to develop molecular imaging probes against that target, validate those in small animal models using technology such as microPET and optical technologies," says Gambhir. From those initial steps, they have the capability of moving into phase I clinical trials and transfer the new techniques to the clinical realm more easily.
"As this field expands, there should be much more synergy and collaboration between companies and universities," says Gambhir. "Hopefully, with help from GE, more probes will be discovered and become available commercially."
At M.D. Anderson Cancer Center in Houston (Texas), the research effort is focused on developing a variety of imaging approaches to visualize processes underlying the development, maintenance and progression of cancer. Juri Gelovani, MD, PhD, professor of radiology and neurology and chairman of the department of experimental diagnostic imaging, explains that they are working on an agent that images various hyperactive epidermal growth factor receptor variants. Being able to visualize in three dimensions over time, such as before and after treatment, the level of activity provides valuable information. The total number of receptors could be very high, but not active.
"Assessing response to therapy early on, during the initiation of therapy, within 24 to 48 hours as opposed to waiting weeks or months to detect tumor shrinkage if that indeed occurs is important," says Gelovani. They are working to develop methods to image apoptosis or programmed cell death, or tumor proliferation by imaging DNA synthesis with DNA-specific imaging agents.Gelovani says researchers at M.D. Anderson use a wide array of imaging modalities to accomplish their work in collaboration with GE Healthcare. "We are imaging apoptosis with radio-labeled annexinV, we're imaging neoangiogenesis [early development of new blood vessels] with anti-integrin peptides, such as cyclo-RDG and others. By the end of the year, we'll have several studies underway," he says.
While a great amount of the work to develop new imaging approaches is being accomplished in major medical centers, some exciting probes are being discovered in smaller institutions as well.
NEW IMAGING PROBES
John Babich, president and CSO of Molecular Insight, a Cambridge, Mass.-based company, is involved with a technique for studying myocardial perfusion in symptomatic patients who present in the emergency department.
"BMIPP is a radiopharmaceutical which is labeled with Iodine123, which is a gamma-emitting isotope similar in its quality to Technitium99m, which is the workhorse of nuclear medicine," explains Babich.
As a fatty acid analog, BMIPP takes advantage of the physiologic function of heart muscle that utilizes fatty acids in conjunction with oxygen as the primary energy source. If the oxygen supply is disrupted, for example as a result of a coronary artery blockage, the heart muscle switches to carbohydrate metabolism, a scenario which remains persistent for up to several days later, even if treatment has altered or re-opened the vessel and normalized blood flow.
"This is all happening on the molecular levelâ?¦we're not looking at blood flow," explains Babich. "This kind of fingerprint that has been left on the heart is something we can see even if it's been 30 hours since the ischemic event."
To take advantage of this series of events, Molecular Insight is working to develop the BMIPP agent to be used as a SPECT-based study in the emergency department to determine next steps for treatment of the patients who may have experienced a heart attack. The primary advantage this technique offers is the ability to image ischemia without a stress test, a procedure that is contraindicated in patients with chest pain. BMIPP is able to demonstrate ischemia up to 30 hours after an event, while current imaging agents must be used within two hours after the onset of chest pain.
"We've had about 24 patients who have completed our phase II clinical trial, and we've seen patients with normal troponins, normal EKGs and who have glaring abnormalities on BMIPP and who go on to be stented," Babich says. They plan to enroll 120 patients by the end of the year.
Kereos Inc. in St. Louis, Mo., is collaborating with Philips to develop an MRI agent that detects extremely small tumors (one to two millimeters in size) using an angiogenic marker, alphav beta3, to transport a large gadolinium concentration to the tumor site.
"Like PET, it's specific for active tumors because angiogenesis does not occur if the tumor is dead, or with a benign cyst or hemangioma on the liver," says Robert Beardsley, PhD, Kereos' president and CEO. It only lights up on those lesions that are actively promoting angiogenesis, like tumors. They anticipate future work to attach chemotherapeutics that are naturally lipophilic (likes fat) to deliver treatment to tumors.
In addition to this oncology application, Kereos scientists are working on a targeting ligand that takes high concentrations of gadolinium to the fibrin, a protein formed during normal blood clotting, that accumulates in the cracks and tears of unstable plaque inside cardiac arteries. This application may eventually replace invasive coronary angiography. But several more years of research are necessary to refine the details.
CONCLUSION
While nuclear medicine has proven to be a valuable imaging technique in a number of clinical applications, its effectiveness is on the cusp of significantly changing the way medicine is practiced. Through the use of specific targeting agents, increases in diagnostic capabilities are only the beginning. Experts agree that they anticipate these techniques will provide the basis for non-invasive treatment of serious health problems in the future.