In fact, molecular imaging can be particularly impactful in cardiovascular drug development because, unlike in cancer medicine, tissue is not routinely obtained from humans and imaging may be able to provide a virtual biopsy of drug effects on the heart or vascular tissues. Figure 2. Schematic illustrating preclinical research stages leading to investigational new drug IND application and clinical stages leading to new drug application NDA , and potential roles of molecular imaging for discrete stages. Left y axis schematically depicts the number of candidate new molecular entities that at screening stage top and each subsequent stage to culminate in a single NDA.
Methods for assessing specific cellular or molecular processes have been developed for all forms of noninvasive imaging used in cardiovascular medicine and science. The development of in vivo molecular imaging techniques has been predicated on the ability to provide unique quantitative spatial and temporal information that can be used for a variety of purposes in patients and in preclinical models of disease. For drug development, molecular imaging has been used to 1 identify new druggable targets, 2 evaluate biodistribution and appropriate dosing strategies, 3 test efficacy and off-target effects, 4 to select appropriate patient cohorts for initial testing, and 5 to serve as a surrogate end point in preclinical and clinical studies.
The role of molecular imaging is likely to increase given trends in academia and industry to focus more on humans or nonrodent animal models that more clearly resemble humans for the early stages of drug development. From a technical standpoint, molecular imaging relies on one of several strategies.
A commonly used approach is to engineer contrast agents that are selectively retained by the biological process of interest. Contrast agents for radionuclide imaging, magnetic resonance imaging MRI , ultrasound, optical imaging and computed tomography have all been modified eg, conjugation of a targeting ligand to alter their kinetics and be used for molecular imaging.
A critical factor in the evaluation of the relative value of the different contrast imaging approaches is the biodistribution of the contrast agents eg, diffusible versus confinement to the vascular compartment. Another approach for molecular imaging is to design contrast agents that leverage natural processes for uptake or retention. Examples of this strategy include uptake of 18 F-fluorodeoxyglucose FDG during PET imaging to detect processes with increased energy expenditure, such as advanced atherosclerosis or sarcoidosis, or the detection of inflammation through opsonization and uptake of particle-based contrast agents which are recognized as foreign by immune cells, and may even reveal specific monocyte subtypes in atherosclerosis.
Application of Positron Emission Tomography in Drug Development
This strategy is most commonly used in optical imaging by development of fluorophores that produce either a change in photon emission or a spectral shift after interaction with a pathogenic pathway, such as protease activity or abnormal redox state. Selection of the most appropriate targeting approach and the most appropriate imaging modality to use within the scope of drug development is based on similar considerations as when applying the technology in the clinical realm Figure 3.
It is worth noting that experience in cancer molecular imaging indicates that an imaging modality used to assess preapproval drug efficacy is more likely to be adopted by clinicians for patient selection or for assessing therapeutic response. Technical deliberations include need for high sensitivity, spatial resolution, temporal resolution, target specificity, and biodistribution of contrast agent, when applicable, which determines likelihood for accessing the biological process of interest.
Some of the biggest technical concerns are to assure that a signal reflects tissue phenotype rather than primarily reflecting blood flow, vascular permeability, or other variables that can influence tracer uptake. Practical considerations for both academia and pharma include cost, availability, and safety. Figure 3. Imaging technology characteristics commonly considered when selecting an approach for molecular imaging in science and in medicine. The identification of molecular pathways previously unknown to be involved in the pathophysiology of a disease is often a catalyst for the development of new treatments.
Information on newly recognized pathways, proteins, or genes allows for the generation of lead candidates for therapy which can be tested by a variety of molecular biology approaches, most commonly in the form of automated high-throughput or focused compound screening processes. Noninvasive in vivo molecular imaging has been tasked in the research setting to create new insight into pathobiology in a wide range of disease categories. This application of molecular imaging has helped identify new druggable targets.
In addition to simply uncovering pathophysiology, the opportunity to temporally evaluate a disease-related process noninvasively can provide critical knowledge of how a drug can be used to its greatest effect or when it is likely to be of little benefit. Moreover, molecular imaging is often paired with more conventional forms of cardiovascular noninvasive imaging to match a molecular phenotype to standard measurements of anatomy, flow, or function.
In the field of atherosclerosis biology, most molecular imaging studies have simply demonstrated feasibility of assessing a pathological process that is already well characterized. Yet, there are examples where molecular imaging has aided in the discovery of a modifiable disease-related process. Molecular imaging of phosphatidylserine expression on the outer leaflet of the cell membrane with annexin-V probes has been used to detect macrophage apoptosis in unstable plaques but also has been used to demonstrate that this process can occur from nonapoptotic ischemic pathways.
They have provided evidence that altering the balance of monocyte cell type may be a therapeutic target in certain conditions, such as atherosclerosis and left ventricular remodeling. Figure 4. Molecular imaging studies examining pathobiology of atherosclerosis. The full characterization of on-target effects and completion of proof-of-mechanism studies are critical steps in drug development. It is a logical assumption that any molecular imaging technique that has been used to uncover modifiable disease-related biology can also be used to noninvasively quantify response to therapy.
More commonly, pathophysiology that is not discovered through molecular imaging has also been targeted for evaluation of new therapeutic agents in preclinical models and in even in human proof-of-concept trials.
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The investment in molecular imaging for preclinical in vivo testing of candidate efficacy and off-target effects has been justified in situations where it provides incremental benefit. Conventional forms of noninvasive cardiovascular imaging without recourse to molecular imaging protocols provides information on morphology or function including but not limited to 1 plaque size, volume, and content in atherosclerosis; 2 left ventricular volumes, systolic function, diastolic properties, and scar area in heart failure; 3 myocardial perfusion imaging and metabolism in ischemic heart disease.
In this context, the rationale for using molecular imaging is often based on its ability to assess modification of a specific targeted biological pathway early before a structural or functional outcome to select the most appropriate of several candidate agents. Aligning with the concept of precision medicine, molecular imaging can be used in diseases that have wide phenotypic variation to predict benefit based on the specific molecular or cellular characteristics or the stage of disease.
Imaging data can also provide valuable insight when new therapies fail by demonstrating lack of effect on the intended biological pathway, thereby avoiding an incorrect assumption that a certain pathway is not a suitable for therapeutic targeting. In atherosclerosis drug development, probably the most recognized use of molecular imaging that has been applied is 18 F-FDG imaging with PET.
Figure 5. Molecular imaging of angiogenesis. C , Imaging of therapeutic angiogenesis with multipotential adult progenitor cells MAPC in a murine model of hind limb ischemia illustrating rapid clearance of cells by optical imaging of luciferase-transfected MAPCs, ultrasound images B-mode and P-selectin—targeted imaging of endothelial adhesion molecule expression in a MAPC-treated hind limb, and quantitative data from CX 3 CR-1 molecular imaging to detect sustained increased recruitment of proangiogenic monocytes in MAPC-treated over control conditions.
Illustration that a molecular imaging readout is altered by a therapy already known to be effective in a disease state is often used as a step toward clinical translation of a new diagnostic. These types of studies are also useful when considering whether a molecular imaging technique is suitable for assessing preclinical efficacy of a new drug.
The application of molecular imaging to obtain unique information not provided by anatomic or functional imaging on the efficacy of new therapies is slowly increasing. In atherosclerotic disease, molecular imaging has provided valuable information for demonstrating efficacy and in some circumstances optimal dosing for investigational agents, such as new potent antioxidants eg, nicotinamide adenine dinucleotide phosphate-oxidase-2 modifiers , high-density lipoprotein mimetics, and matrix metalloproteinase inhibitors.
The notion that new therapies may be able to prevent atherosclerosis altogether hinges on the ability to identify subjects at exceptionally high risk for accelerated disease at a early stage. It is unlikely that existing risk assessment paradigms will suffice because they are most commonly used to estimate year risk and are heavily influenced by age, leading to a likely underestimation of lifetime risk in young individuals. Molecular imaging has also been used to provide important proof-of-mechanism information on new therapies that act through vascular remodeling.
For example, in vivo optical imaging of a luciferase reporter under the control of a Tie-2 reporter has been used to temporally and spatially assess the transformation to a more endothelial phenotype of mesenchymal stem cells injected in mice with myocardial infarction. In summary, some of the examples discussed above illustrate how molecular imaging has been used as a readout for the intended or on-target drug effects. With the maturation, further validation, and increased penetration of these techniques in research laboratories, it is highly likely that molecular imaging will play an increasing role in the early evaluation of candidate new molecular entities.
Pharmokinetic and pharmacodynamic profiling is a critical process in understanding drug dosing, toxicity, and likelihood for therapeutic success. Noninvasive imaging has played a role in this process and has been vital in the conduct of many FDA phase 0 exploratory microdosing studies designed to expedite drug approval. In particular, radionuclide imaging with PET and single photon emission tomography has been useful for temporally evaluating whole-body biodistribution of therapeutic candidates that can be labeled without changing their properties and administered by intravenous route.
Another strategy for imaging drug biodistribution is to use imaging agents that are activated or produce signal in the presence of a drug or by a specific interaction of 2 proteins. This strategy, which has been reviewed elsewhere, 56 often involves 2 separate molecular moieties or a split protein each of which are labeled with an optical reporter system so that in the presence of a therapeutic agent, there is a change in confirmation and rearrangement of the reporters to produce a light signal.
The use of pharmacokinetic imaging of radiolabeled drug candidates has been most impactful in situations where drug uptake at a specific site is desired or when access of drugs to target is in question. This application is particularly important for the assessment of macromolecular biological therapies that are used not only in cancer but other conditions where site-targeted uptake is important.
Use of a common agent with diagnostic and therapeutic properties has been helpful in understanding not only whether selective cancer targeting has been effective but also for predicting therapeutic response and explaining variation in response. For example, a recent trial in patients with metastatic human epiderman growth factor receptor-2 HER-2 —positive breast cancer used 89 Zr-labled trastuzamab PET imaging together with FDG PET to document that poor clinical response could be expected in those with low trastuzamab uptake despite positive biopsy results Figure 6B.
Figure 6. Imaging to understand drug biodistribution. In cardiovascular drug development, we are not aware of any situations where molecular imaging has been critical for understanding pharmacokinetics for drugs that currently approved. However, molecular imaging has the potential to confirm the penetration and retention of drugs targeted to atherosclerotic plaques, thrombus, and ischemic myocardium.
In particular, major advances have been made in combining a therapeutic and diagnostic agent into a single nanoparticle moiety, commonly referred to as theranostics and which have been reviewed elsewhere. Another area where molecular imaging has been used extensively to study biodistribution has been to study stem cell therapy. Strategies for labeling and detecting stem cells have been developed for essentially all forms of noninvasive imaging. Optical, radionuclide, and MRI have all revealed that the residence time of viable adult mesenchymal and bone marrow—derived stem cells is usually temporary, lasting days to weeks, 32 , 55 , 65 — 68 thereby supporting the notion that these cells act primarily through paracrine signaling of endogenous cells.
Imaging has also been useful for understanding the failure or unpredictability of cell therapy. For example, PET detection of mesenchymal stem cells has been critical for establishing the concept that the beneficial effects of cell therapy on left ventricular remodeling or angiogenesis are most pronounced when tissue retention of labeled cells is high. The use biomarkers as surrogate end points in clinical trials has been a topic of lively debate for decades. Both pharma and the regulatory agencies that oversee drug approval have accepted the concept that biomarkers, including imaging biomarkers, have an important role for accelerating and reducing cost of the drug development and approval process.
The only biomarker that has been consistently accepted for cardiovascular disease drug approval by the FDA has been serum cholesterol levels. The application of molecular imaging as a potential biomarker in clinical trials hinges on several requirements.
The technique must be quantitative and provide temporal information. High sensitivity for detecting the targeted molecular process is advantageous although equally important is a complete understanding of how specific the target is to the pathway of interest. For example, for tracers with high first-pass retention, tissue uptake is not simply dependent on-target molecule expression but is also influenced by the relative blood flow. This issue is of critical importance when temporally assessing angiogenesis where changes in perfusion over time must be accounted for when registering tracer intensity.
The most common molecular imaging technique that has been used as an end point in cardiovascular clinical trials is 18 F-FDG PET to assess atherosclerotic disease activity. This approach has been used to assess the effects of many different inflammation-targeted therapeutics that have been reviewed elsewhere. The situation is different in cancer medicine.
Clinical trials in breast cancer, gastrointestinal stromal tumors, lung cancer, etc, have definitively shown that changes in primary and metastatic tumor activity on 18 F-FDG PET precedes changes in anatomic tumor burden. Aside from its use as surrogate end point, molecular imaging has the potential to select appropriate cohorts for initial testing of new drugs in clinical trials.
Gewalt S. Magnetic resonance histology for morphologic phenotyping. Imaging 16, — Magnetic resonance microscopy of chemically-induced liver foci. Sills R. Applications of magnetic resonance microscopy. Nakamura K. Mieda T. Suto N. Matsuura S. Hirai H. Mesenchymal stem cells as a potential therapeutic tool for spinocerebellar ataxia.
Cerebellum 14, — Nyska A. Schiffenbauer Y. Brami C. Ramot Y. Histopathology of biodegradable polymers: Challenges in interpretation and the use of a novel compact MRI for biocompatibility evaluation. Skolnick M. Ziv G. Gulkarov A.
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Correlation of injection site damage and serum creatine kinase activity in turkeys following intramuscular and subcutaneous administration of norfloxacin nicotinate. Avian Pathol. Moon C. Kim H. Park J. Lee J. Chang I. Kim K. Kim S. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl. Rosenstock M. Klinger E.
Bursztyn D. Shinar D. Comparative long-term preclinical safety evaluation of two glatiramoid compounds glatiramer Acetate, Copaxone R , and TV, protiramer in rats and monkeys. Amouyal N. Ezov N. Steiner M.
Izrael M. Lavon N. Hasson A. Revel M. Neurotoxicology 59, 27— Touitou D. Levin G. Ickowicz D.
Positron Emission Tomography in Drug Development and Drug Evaluation
Zada M. Abbas R. Yankelson L. Domb A. Interspecies differences in reaction to a biodegradable subcutaneous tissue filler: Severe inflammatory granulomatous reaction in the Sinclair minipig. Schmid A. Schmitz J. Mannheim J. Maier F. Fuchs K. Wehrl H. Pichler B. Imaging Biol. Taketa Y. Shiotani M.
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Tsuru Y. Kotani S. Osada Y. Fukushima T. Inomata A. Hosokawa S. Application of a compact magnetic resonance imaging system for toxicologic pathology: Evaluation of lithium-pilocarpine-induced rat brain lesions. The NCI-COP also plays an active role in organizing consortia on specific topics to advance its role in guiding comparative oncology studies, with a focus on fostering transparent discussions of the opportunities and limitations of the comparative approach within the cancer drug development community.
This comparative approach to cancer research may be particularly beneficial for encouraging the translation of candidate therapies that yield promising results in vitro and in mouse models. Investigator-driven research and discovery of potentially effective therapies at the bench frequently stall before advancement into the clinical pipeline simply because the intellectual property surrounding these discoveries is not licensed to a pharmaceutical or biotech company, and they are thus never evaluated in people. The simultaneous study of the same agents in pets thus provides an important and clinically relevant interface between investigator-driven translational research and commercial clinical development.
One Health, an ancient concept recently embraced by the US Centers for Disease Control and Prevention, is based on the idea that animal and human health are intimately linked and that disease processes in humans and other animals are very similar. In the spirit of this approach, interdisciplinary collaboration among researchers, veterinarians, and human health-care workers should improve our understanding of basic pathological processes across species and accelerate clinical discovery in both medical and veterinary arenas.
Timothy M. Woese Institute for Genomic Biology. Amy K. A selective list of comparative oncology programs and their integral roles in supporting allied human cancer research initiatives.