A typical molecular imaging probe, such as a fluorescently labeled antibody, is introduced into a subject (animal, patient) and washed out over time. Contrast is achieved by maximizing the amount of signal at the target while minimizing that remaining associated with nonspecific tissue. A host of factors, from uptake, metabolism, and clearance of the probe to interference by endogenous factors (e.g., autofluorescence) to sensitivity and selectivity of the probe to timing of the imaging, can impact the achievable signal to noise ratio (called tumor to background ratio or TBR in oncology).
Most currently available probes are “always on”—that is, they continuously emit signal (or in the case of fluorescently labeled probes, they always fluoresce in response to excitation). The targeting moiety should direct most of it to the organ, cell, or receptor of interest, yet TBR often remains an issue.
What if a probe only emitted a signal when associated with its target? asked Hisataka Kobayashi, M.D., Ph.D., chief scientist in the National Cancer Institute's molecular imaging program. Dr. Kobayashi has been working on “activatable” probes that respond to biological processes. In one example, quenched fluorophores are conjugated to tumor-specific antibodies. Once bound, the probe is internalized where it can be activated by the acidic environment of the endolysosome.
Although fluorescent imaging is typically limited to very shallow depths, it can be used to guide open surgery—for example, in the brain—and most parts of the body (except the heart and brain) can be reached by using endoscopy as well. “We can go almost anywhere through the GI or urinary tract, or peritoneal or plural spaces,” Dr. Kobayashi pointed out.
He also uses different wavelength fluorophores and other different energy probes, to simultaneously query several discrete entities. In addition, MRI, nuclear, PET/CT, and optical can also be multiplexed to generate more information from the body, the radiologist added, “to detect things much better than the single modality.”
Dr. Gelovani, who also leads the development of molecular imaging agents at the Center for Advanced Biomedical Imaging Research at the University of Texas' MD Anderson Cancer Center, wants to see molecular imaging used more as a means of early detection of cancers, as well as a way to stratify patients based on unique mutations or genomic or phenotypic abnormalities.
Take, for example, small-cell lung carcinoma patients whose tumor is dependent on a mutation that locks the tyrosine kinase part of the epidermal growth factor receptor (EGFR) into a particular dominant active configuration. Such patients respond positively to therapy with EGFR inhibitors.
“We have explored the chemical space of that configuration and developed a particular molecular imaging agent that would have selectivity for that particular activating mutation and irreversibly bind to that dominant active EGFR kinase,” said Dr. Gelovani.
“Therefore, we can now enable imaging of patients noninvasively using PET/CT to predict the responsiveness or resistance of primary and metastatic tumor lesions in individual patients. We are really getting closer to that notion of individualized therapy.”
Molecular imaging can seek out its target wherever it lies, is quantitative, and (because it's noninvasive) can serially query the same target. A biopsy, on the other hand, only reveals a mutation where it is sought, which because of the tumor heterogeneity often does not represent the rest of the tumor and metastatic tumor lesions. In contrast, molecular imaging can aid the characterization of tumors in the whole body at once.
Do It My Way
Yet, not all scans—not even all PET scans—are created equal, and this has implications for the interpretation of clinical trials. “The problem is not so much that the drug is different, but that each center does the scan in its own particular way. Their equipment is calibrated in their own way, and radiologists interpret the study in his or her own way,” observed Peter Conti, M.D., Ph.D., co-chair of the Society of Nuclear Medicine's Clinical Trials Network (CTN).
At the same time, drug companies may be pretty naïve as to how to structure the protocols, the University of Southern California professor continued. “So there's a tug of war between the right way to do it as per the radiologists and the right way to do it as per the drug company,” leaving the FDA with the problem of not being able to compare the studies.
Basic parameters need to be optimized and standardized. “We can argue about which way may be better than the other, but we have to agree at least on some baseline,” Dr. Conti said. From there, it's a matter of education and training.
Progress, he said, has been good. Manufacturers are trying to come up with common analytical methods so that data is transparent as to which device was used to generate it. More than 300 imaging sites worldwide have begun the process to join the CTN imaging registry, and over 100 have been qualified. More than 60 scanners have been fully validated.