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Development of cancer therapeutics could benefit from new fluorescence imaging technique
Martinos Center investigators Bill Rice (left) and Anand Kumar (right) have reported a fluorescence imaging technique that could accelerate the discovery of new cancer drugs.
Being able to track tumor metastasis over time would be an important step forward in drug discovery of cancer therapeutics. It would allow researchers to monitor the response to therapy over time in the same tumor, which today is possible in only a very limited way. But existing imaging technologies that might allow this either are prohibitively expensive or lack the necessary sensitivity.
Now, investigators in the Optical Molecular Imaging Lab at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital have described a fluorescence imaging technique that enables detection of deep-seated cancers in mouse models with high sensitivity. The technique, which they describe in a paper published this month in Cancer Research, could provide an important new tool in the fight against the disease.
Currently used methods in pharmaceutical research mostly rely on post-mortem histology and thus cannot track the same tumor over time. Commercially available fluorescence imaging technologies enable imaging of living subjects, but these technologies are limited to seeing cancers that either are very large or are located just beneath the skin.
This is because of the substantial background autofluorescence from healthy tissue, said Anand T.N. Kumar, an Assistant Professor at the Martinos Center and principal investigator of the Cancer Research study. “Thus, even though the cells can be labeled with highly specific fluorescent markers such as fluorescent proteins, the signal from the protein is often overwhelmed by the background signal.”
To address this issue, Kumar and colleagues – including first author William Rice, also of the Martinos Center, and collaborators Daria Shcherbakova and Vladislav Verkhusha, both of Albert Einstein College of Medicine – brought to bear two important innovations.
First was the incorporation of fluorescence lifetime – the length of time a fluorophore spends in its excited state before emitting a photon and returning to the ground state. Tissue autofluorescence and the fluorescence from particular “reporter” proteins used widely for cell labelling in biology exhibit different lifetimes. In the Cancer Research study, the researchers were able to capitalize on these lifetime differences to distinguish between protein-labeled cancer cells and the healthy tissue.
The second innovation was the use of a novel version of fluorescence proteins – called near-infrared fluorescent proteins, or iRFPs – that absorb in the near-infrared (as opposed to the visible) spectral range. These iRFPs were invented by Dr. Verkhusha, a co-author of this paper and Professor at the Albert Einstein College of Medicine in New York. Because they have lower tissue absorption than visible fluorescent proteins, iRFPs allow deeper tissue imaging.
By combining these innovations, the researchers were able to “see” cancers even when there were considerably fewer cells than they could previously detect. Only one other optical imaging technology – bioluminescence – provides this kind of sensitivity, Kumar said. Fluorescence imaging offers several advantages over this technology, including greater flexibility in longitudinal studies, studies performed in the same subject over time.
Development of the technique continues. The researchers are now working to validate it for longitudinal imaging of tumor growth and metastasis in mouse models and for tracking the response of the tumors to therapy. They are also exploring the simultaneous use of proteins with different fluorescence lifetimes. This approach, dubbed lifetime multiplexing, could contribute still further to advances in the study of biological processes.
Overall, they said, the fluorescence imaging technique shows tremendous promise for drug discovery.
“With further validation, the technology will allow cancer biologists and pharmaceutical scientists to explore early metastasis and design targeted therapies in more realistic scenarios,” Kumar said. “Since optical imaging is more affordable, more portable and less complex than either PET or MRI, it will ultimately offer a new tool to accelerate the discovery of cancer therapeutics.”