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Aug 1, 2013 (Vol. 33, No. 14)

Molecular Imaging Driving Development

  • Click Image To Enlarge +
    A detailed evaluation of treatment response shows an axial FATSAT T1W MRI image (A) of a mouse tumor (red outline) and corresponding speckled transformation of the pixels within the region of interest (B). For a human tumor treated with exper-imental therapy (C & D), the shape and amplitude of the histogram curve has little difference on precontrast CT scans but a different shape and amplitude with contrast following therapy suggesting a favorable treatment response and change in tumor morphology. [Imaging Endpoints]

    Elsewhere, studies being conducted at Imaging Endpoints are focused on facilitating effective clinical trial design, based on the bidirectional translational approach involving clinician feedback and preclinical response, said Ronald L. Korn, M.D., Ph.D., the firm’s founder and CEO.

    Dr. Korn said that despite successful preclinical studies, drugs often show dose-related toxicity. He referred to his experience studying vascular disrupting drugs, which were effective in patients with metastasis, but still showed potentially damaging effects on red blood cells.

    “We then found the most appropriate preclinical model to test the hypothesis— an MRI using a special contrast agent that measures oxidation, to screen the preclinical agent, which showed the oxidizing effects of this agent,” he explained.

    Dr. Korn also cited his experience with stromal disrupting agents, which were promising in early preclinical testing. “We used MRI perfusion imaging to test its mechanism of action,” he said. Interestingly enough, “we also noticed that PET scans were going cold in preclinical phase, but were more appropriate for human testing,” Dr. Korn added.

    Working in collaboration with scientists at TexRAD, Dr. Korn and colleagues at Imaging Endpoints used advanced imaging technology and software to extract information from standard medical images, to observe the heterogeneity and morphology of lesions. Quantifying treatment-related changes through texture analysis helps in the detection and measurement of tumor complexity. The resulting images correlate with the underlying biological processes such as blood flow or hypoxia, as well as tumor microarchitecture.

    “Once we know the clinical drivers, we communicate with our preclinical colleagues to identify the drug’s mechanism of action on specific signaling pathways,” Dr. Korn explained. The results also enable linkage with genomic and proteomic data.

    Dr. Korn’s team is currently developing noninvasive tests to measure mutational status in lung cancer and using advanced imaging tools to distinguish K-ras from wild-type mutations in colorectal cancer, as well as ER+ from ER- breast cancer.

    Imaging has yet to be fully integrated into drug discovery and development, but when applied successfully, it can unearth tremendous insights into the biology and effectiveness of a drug, probing important issues like driver mutations and tumor heterogeneity.

  • The World’s Brightest Luminescent Protein

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    Luminescence (left) and fluorescence (right) imaging of HeLa cells expressing Nano-lantern targeted to cytoplasm, mitochondria, and histone H2B. The reference fluorescence signal was captured by exciting Venus with light at 490 nm. Scale bars, 50 mm. [Photometrics]

    An Osaka University professor has taken up a common challenge with optogenetic imaging: How do you use light to both control and analyze the activity of individual neurons while avoiding interference between the two?

    Fluorescent indicators offer a means to analyze what happens inside the cell after optogenetic manipulation. But because of their common dependence on light, problems can arise when optogenetics and fluorescent indicators are used together in the same cell at the same time. The excitation light that’s used to “see” the signal from the indicator might misactivate what’s under optogenetic control. For instance, the blue light that excites a fluorescent-based calcium indicator may also activate an optogenetically controlled photosensitive receptor.

    To address this problem, Osaka University’s Takeharu Nagai set out to develop an optogenetically compatible indicator that does not require light illumination. His strategy was to re-engineer a chemiluminescent probe—which produces its own light through a chemical reaction but is too weak for use in optogenetic studies—to make it as bright as a fluorescent probe.

    As reported in a recent issue of Nature Communications, Dr. Nagai’s lab fused a luminescent protein from a sea pansy with another fluorescent protein. The result is the “Nano-lantern,” the world’s brightest luminescent protein, with a brightness and spatial resolution on par with fluorescence.

    To test the protein in an optogenetics scheme, Dr. Nagai’s group modified it into a calcium sensor and co-expressed it with a light-sensitive photoreceptor in rat neurons. To visualize Nano-lantern signals, they turned to Photometrics’ Evolve 512 EMCCD camera.

    First, though, they had to solve an imaging problem: The light used to stimulate optogenetic processes is so strong, it can “contaminate” the camera and lead to unacceptable background noise. To reduce the noise, they conducted light stimulation and erased the charges during the camera’s “dead-time,” a feature that is easily accessible in the Evolve. Using these techniques, they were able to track photoreceptor excitation by imaging the Ca2+ increase as reported by the Nano-lantern Ca2+ indicator.

    With the arrival of the Nano-lantern, imaging can now be performed in the absence of external light, enabling analysis of events that cascade from optogenetically controlled proteins.

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