Medicine is taking on an increasingly molecular character. For evidence, look no further than the pharmacy: many new-generation therapeutic drugs are designed with highly specific molecular targeting capabilities and delivery mechanisms.
Of significant importance, the biomarkers deposited by these drugs can be observed using readily available imaging technology. Thus are radiologists and nuclear medicine physicians in the enviable position of being equipped to both measure drug efficacy and, at far earlier stages than ever, detect disease.
However, not many imaging professionals today work on the molecular level. Before long, though, it will be commonplace practice. Ralph Weissleder, MD, PhD, believes this unswervingly. Weissleder is director of the Center for Molecular Imaging Research (CMIR) at Massachusetts General Hospital in downtown Boston, with satellite facilities at the Charlestown Navy Yard and at the newly created Broad Institute on the campus of the Massachusetts Institute of Technology in Cambridge.
 Ralph Weissleder, MD, PhD, directs the Center for Molecular Imaging Research at Massachusetts General Hospital, Boston. |
Given the unstoppable growing importance of molecular medicine, Weissleder contends that community-based radiologists will find it profitable to begin educating themselves now about molecular targeting, molecular therapeutics and the role of imaging in both regards. To stimulate thinking in that direction, Decisions in Axis Imaging News talked at length with Weissleder about the state of molecular imaging and today’s new or little-known contrast agents that could well become tomorrow’s household names.
We first asked Weissleder to explain how a radiologist found his way into a sun-splashed laboratory, surrounded by chemists, immunologists, geneticists, and mice. He explained that the Center for Molecular Imaging Research, which he created a decade ago, is one of the largest enterprises of its kind in the country, with 80 researchers working under one roof. He is proud of what CMIR has accomplished. Among other things, it can claim credit for developing a number of molecular-oriented technologic advances involving optical, nuclear, and MR imaging. Weissleder, previously a basic biology investigator, told Axis Imaging News he launched the center as a response to a perceived deepening need for molecular imaging advancement. In so doing, he brought together scientists from various other fields who, cumulatively, possess the keys to this kingdom.
IMAGING ECONOMICS: Let’s talk first about “smart” contrast agents. Just what is meant by the designation of smart?
WEISSLEDER: To begin, you need to understand that smart MRI agents come in basically two forms: targeted agents and activatable agents. The former are directed to a specific molecular target—thus, when you image, the information directly reflects how much of the molecular target is present. The latter is a substrate for a specific enzyme, ie, it becomes detectable after enzyme conversion, and here imaging relates to the enzyme activity—for instance, in a tumor.
IMAGING ECONOMICS: Can you offer a few examples?
WEISSLEDER: Currently, there are numerous targeted agents in the pipeline and moving toward clinical development. Many are based on magnetic nanoparticles or small molecules and target cancer. These agents will facilitate or enable the detection of early cancers or cancer-related processes such as angiogenesis. Examples include agents capable of imaging V-CAM-1 or aV-B 3 or E-Selectin or tumor markers such as her2/neu.
IMAGING ECONOMICS: Is cancer detection the only promising clinical application?
WEISSLEDER: No, even though much of the current research and development is being funded through the National Cancer Institute. It is important to point out that most researchers in the field develop generic tools, which can then be used for diverse disease processes. For example, we had developed certain nanoparticle preparation for cancer imaging several years ago and now they are used for imaging in diabetes, rheumatoid arthritis, cardiovascular disease, and more.
IMAGING ECONOMICS: Can we improve on the specificity of the contrast agents without compromising their sensitivity?
WEISSLEDER: Most of the molecular agents currently under development are designed for very high sensitivity and specificity. Having both high sensitivity and specificity is possible because of very sophisticated design methods previously unavailable, such as combinatorial chemistries and high-throughput screening approaches—very similar to what a drug company would do in the course of developing a new therapeutic. These processes allow one to dial in, up front, the degree of sensitivity and specificity desired.
GLOSSARY |
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Angiogenesis. The formation of new blood vessels, indicative of tumor growth. Cathepsin. One of a number of enzymes of the hydrolase class that catalyze the hydrolysis of peptide bonds. E-Selectin. Cell adhesion molecule and CD antigen that mediates neutrophil, monocyte, and memory T-cell adhesion to cytokine-activated endothelial cells. (www.Online-Medical-Dictionary.org) HER2/neu (human epidermal growth factor receptor 2). A gene that helps control how cells grow, divide, and repair themselves; important in the control of abnormal or defective cells that could become cancerous. (www.breastcancer.org) Hypoxia. The reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. Kinase. Phosphotransferases and diphosphotranferases of the transferase class that catalyze the transfer of a high-energy phosphate group from a donor compound to an acceptor compound. Macromolecule. A very large molecule having a polymeric chain structure. Metalloproteases. Endopeptidases which use a metal, normally zinc, in the catalytic mechanism. This group of enzymes is inactivated by metal chelators. (www.Online-Medical-Dictionary.org) Nanoparticles. A molecule or other particle of an extremely minute size. Near-infrared fluorescence imaging (NIRF). Imaging of photons in the near-infrared range, typically 600-1100 nm. (www.art.ca) Optical imaging. In vivo imaging of fluorescent molecular probes using ultraviolet to near infrared light. Peptide. Any member of a class of compounds of low molecular weight that yield two or more amino acids on hydrolysis. Polymer. A compound formed by the joining of smaller molecules. Protease. Any of various enzymes, including the endopeptidases and exopeptidases, that catalyze the hydrolytic breakdown of proteins into peptides or amino acids. VCAM-1 (Vascular Cell Adhesion Molecule). Cytokine-induced cell adhesion molecule present on activated endothelial cells, tissue macrophages, dendritic cells, bone marrow fibroblasts, myoblasts, and myotubes. Important for the recruitment of leukocytes to sites of inflammation. (www.Online-Medical-Dictionary.org) |
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—M. Tharp |
IMAGING ECONOMICS: The FDA’s processes for approving molecular imaging agents—much criticism there, and from many voices. What are the prospects of changing things for the better on that front?
WEISSLEDER: Talks are being held, effort is being made, between the NIH and the FDA to improve the situation. Over the last couple of years, the changes we did see were driven by the PET community, which sought a lowering of the hurdles for approval of PET imaging agents on the rationale that, since these were merely tracer compounds, the risk to patients would be minimal. How well that rationale will translate to other imaging modalities—MRI and optical imaging—in the eyes of the FDA is yet to be known.
IMAGING ECONOMICS: What is the biggest challenge for MRI contrast agents with regard to the FDA approval process?
WEISSLEDER: Time. Currently, it takes 13 years on average to satisfy FDA requirements and bring a new agent to market. In actuality, it should take no more than 3 to 5 years. The other eight represent wasted time. There are various stages at which time is wasted, in the development process, during clinical trials, raising money, and data analysis. In just this last year, for example, a gadolinium agent and a magnetic nanoparticle have faced regulatory hurdles.
IMAGING ECONOMICS: What role do taxpayer dollars play in the development of new MRI molecular imaging agents?
WEISSLEDER: A very important one. The NIH, for instance, has been extremely supportive in advancing the field of molecular imaging by putting money into research programs and also by creating links to other government agencies—the FDA among them.
IMAGING ECONOMICS: What about the private sector? What role does it play?
WEISSLEDER: The private sector plays an equally important role—a role that will only increase in importance in the future. Many smaller companies drive the research field while mergers and acquisitions between large companies shape the field. [Recent mergers] create a powerhouse involved in the production of both imaging systems and imaging agents, with sufficient capital to be able to take developments into the clinic.
IMAGING ECONOMICS: When an imaging equipment manufacturer and an agent-producing drug company pair in that fashion, which one drives the process of molecular imaging innovation?
WEISSLEDER: They both will. Traditionally, it has been very difficult to advance technology, equipment, agents, and biology when the two organizations responsible for each aren’t talking to one another. As unrelated companies, each has different incentives and rationales for going forward. So, by putting the development of the imaging technology and the agent technology under a single roof, you align the incentives and rationales, which I believe will allow the field to advance in a much more robust way. Also, such companies will have tremendous marketplace advantages because they are in a position to be able to ensure the speed of development—unlike unrelated companies that must depend on strategic partnerships to move things forward.
IMAGING ECONOMICS: What effect is the widespread availability of PET scanners having on industry investment in positron-based molecular imaging-based agents?
WEISSLEDER: It’s true that there has been a significant proliferation of PET scanners, and that is due to the genuine need for that type of imaging, as reflected by the frequency of requests for it from referring clinicians. The three major equipment manufacturers are all investing in combined PET-CT imaging systems to capture that growing market. However, I don’t believe it can be said with any certainty that the installation of these scanners into clinical practices will drive the development of research agents. For example, there are numerous orphan drugs that in 10 or 20 years time have not further advanced despite the abundance of PET scanners.
IMAGING ECONOMICS: Over the next 5 years, what optical methods and agents do you expect to see coming into clinical practice?
WEISSLEDER: There is a whole array of them that are different, highly complementary to what is currently being done in the typical radiology/imaging department. Optical imaging opens up new approaches including intraoperative imaging, catheter-based sensing, optical tomography, and endoscopic imaging.
IMAGING ECONOMICS: Of the various new imaging agents, which do you predict will migrate into the clinic, and what will be their uses?
WEISSLEDER: The molecular imaging agents we’re using here at CMIR include near-infrared fluorescent probes, protected graft copolymers—or macromolecules, if you will—enzyme-sensing imaging agents, chelating peptides, cell trackers for adoptive immunotherapy, and kinase imaging agents. If ultimately proven effective, they will all migrate into the clinic because they represent technology platforms, rather than just one specific agent. The near-infrared fluorescent probes—which are based to some degree on protected graft copolymers, or macromolecules—are about a year away from going into the clinic. Some versions perform enzyme sensing, such as determining levels of cathepsins and matrix metalloproteases. These are involved in a wide range of diseases and change early after therapy. Targeted nanoparticles are also being developed for clinical use.
IMAGING ECONOMICS: In the molecular imaging world, which modalities are going to be universally recognized as the workhorses of the field?
WEISSLEDER: PET and, right behind it, optical imaging modalities. Then, of course, SPECT and MRI. One modality that probably won’t have much of a future in molecular imaging is x-ray, other than for purposes of displaying molecular information onto a CT scan. At least in the United States, ultrasound will play a lesser role because of its more limited use in the clinic.
IMAGING ECONOMICS: What sorts of clinical trials are at present in progress at your Center for Molecular Imaging Research?
WEISSLEDER: Currently, we have five active clinical trials in which patients are being recruited. Additionally, there are 13 other clinical trials in planning. Together with two other major medical centers, we are part of an NIH-sponsored national network dedicated to the testing of all new molecular imaging agents being developed—in its pipeline right now are another 10 or 15 agents that will be tested over the next several years.
IMAGING ECONOMICS: The five clinical trials, specifically. What are you looking at and hoping to ascertain?
WEISSLEDER: Most of these utilize magnetic nanoparticles for MR imaging, either to image and quantitate angiogenesis during treatment with angiogenesis inhibitors such as anti-VEGF antibodies or Avastin, but also for purposes of detecting nodal metastasis during cancer staging and even to identify patients who are at risk of developing diabetes. These trials have been under way for quite some time now. To whet your appetite with regard to findings, I can disclose that the nodal detection sensitivity for finding cancers in lymph nodes increases from around 60% for traditional imaging—either MRI or CT—to way over 95% for imaging with the new agents. Moreover, we’re confirming that one can measure angiogenesis and other processes in vivo.
IMAGING ECONOMICS: How about with the 13 clinical trials you’re planning?
WEISSLEDER: These involve mainly PET agents. We’re going to be looking at them in the context of cancer, since the chief funding source is the National Cancer Institute.
IMAGING ECONOMICS: What are the possible applications for all this when it comes to everyday radiology out in the community?
WEISSLEDER: Ultimately, it will translate into additional imaging tests, by either MRI, nuclear, optical, or even interventional imaging techniques. If you look at medicine these days, you see it’s becoming more and more molecularly oriented; most of the therapeutic drugs currently given have very specific molecular targets and mechanisms, and it’s very likely there will be imaging tests for those to look at the imaging biomarkers down the line and thus measure drug efficacy as well as to detect diseases much earlier. So, it’s relatively important for radiologists to educate themselves about what these targets are, what the molecular therapeutics are, and how imaging can help in measuring their therapeutic efficacy.
IMAGING ECONOMICS: In radiation oncology, as one specific example, what impact might all of this have?
WEISSLEDER: A tremendous impact. First of all, some of these methodologies really identify where cancer is in the body better than anatomic methods alone, and thus better define the radiation portal one is given. The second major impact is in intensity modulated radiation therapy—IMRT—where, by knowing precisely where the cancer is in a given patient, one can actually minimize the side effects while maximizing the therapeutic effect on the cancers, the tumor kill. The third major impact is developing methodologies to look at tumor hypoxia and other modulators to improve the tumor kill for imaging.
IMAGING ECONOMICS: Many of the community-based radiologists who will be the beneficiaries of all this molecular R&D will probably be thinking that it’s nothing to get excited about just yet because it may be years and years before these advances are placed in their hands for everyday use. What’s your answer to those who think that way?
WEISSLEDER: To some degree, they are right. It does take time for these technologies to become mainstream. If you look at PET imaging by itself, it has been around for 20 years, but it is not until the last year or two that it has really advanced to a stage where it is being used in more widespread fashion. What needs to happen with molecular imaging to bring it into the mainstream is the availability of higher resolution imaging tools, and to enhance the clinical usefulness of these systems with the addition of molecular information. All I can say is some of these advances will happen and will become mainstream much sooner than people expect. For example, the optical imaging agents will be in clinical trials next year, and that by itself will open up a whole new opportunity in the ways we look at disease. In particular, vulnerable plaque imaging—identifying regions in inflammatory coronary arteries so we can know precisely which segments need to be stented.
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IMAGING ECONOMICS: Twenty-five years from now, what will radiology in general look like when molecular imaging is as common as a chest x-ray today?
WEISSLEDER: There is a good rate of attrition down the line, so some imaging we currently offer will likely go away. If you look at IVPs 5 years ago, everyone in the country was doing those; now hardly anyone does them because CT imaging has gotten so fast and so good that just about everyone has gone over to it. It’s very clear that most of the current imaging technologies will be available at much higher spatial and temporal resolution, at lower radiation doses. There will also be the emergence of combined anatomic and molecular imaging toolssuch as PET-CT, SPECT-CT, optical-CT, and maybe even MRI-PET—to look at disease processes.
IMAGING ECONOMICS: Is there anything that today’s younger radiologists, the ones who’ll still be practicing a quarter century from now, ought to be doing today to properly prepare themselves for the molecular future?
WEISSLEDER: I would recommend they annually visit the RSNA, Society of Molecular Imaging, and Society of Nuclear Medicine meetings where these emerging technologies are being showcased. One good example is a combined meeting that the RSNA and SMI are putting on next year in Hawaii specifically for practicing radiologists to bring them up to speed on what’s currently on the horizon and how this will impact their practices. At this point, it doesn’t seem likely they’ll need to obtain any kind of recertification, although there is some curriculum development taking place through some of the radiology organizations.
Rich Smith is a contributing writer for Decisions in Axis Imaging News.
