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David Piston, Ph.D., says the new In Vivo Imaging Center will help stimulate molecule-based cancer imaging research. (photo by Dana Johnson)

Multi-discipline cancer imaging effort launched

BY: LEIGH MACMILLAN

8/25/2000 - Vanderbilt University is among the first group of institutions to receive an In Vivo Imaging Center planning grant from the National Cancer Institute.

The grants are part of an NCI initiative to stimulate molecule-based cancer imaging research from inception to use in patient care, by facilitating the interaction of scientists from a variety of disciplines.

The Vanderbilt In Vivo Imaging Center (VIVID) is unique among the twelve new centers in its focus on optical imaging, said David W. Piston, Ph.D., associate professor of Molecular Physiology and Biophysics, director of the W. M. Keck Free Electron Laser (FEL) Center, and the principal investigator for the VIVID grant.

“The goal of our new center is to develop optical imaging methods that are departures from the old standard technologies like MRI and PET,” Piston said. “Projects funded by the NCI grant will move from the test tube to the cell to the whole animal.”

The three-year NCI planning grant will support the organization of VIVID and the initiation of multidisciplinary development projects. These projects will form the basis for a full center grant application after the initial three-year period.

The sample projects featured in Vanderbilt’s VIVID application focused on the role of angiogenesis — new blood vessel growth — in tumor development and metastasis.

The ability to image molecules involved in blood vessel development at the time of diagnosis could contribute to the design of therapies tailored to the individual tumor and patient.

The VIVID center is organized around core facilities that will promote the development of new imaging techniques — an in vitro optical imaging core, an in vivo optical imaging core, and a monochromatic X-ray imaging core — all housed at the FEL Center. A fourth core — the MRI/ultrasound/CT core — will be used to compare new methods with the established gold standards of in vivo imaging.

At a recent symposium, the directors of the core facilities introduced investigators to the technologies available and encouraged broad, multidisciplinary approaches to developing new molecular and cellular imaging techniques for the in vivo setting. Projects are expected to interact collaboratively with the VIVID core labs.

Piston directs the In Vitro Imaging Core, which supports spectroscopy of purified molecules and cell suspensions and microscopy of cells and tissues. The core is working to adapt a technique called two-photon microscopy to in vivo studies. Piston envisions placing an anesthetized mouse directly on the microscope stage and focusing the microscope objectives on the skin or, through minimally invasive incisions, on organs to actually look at molecules in a living animal.

The approach requires that the animal produce a molecule such as green fluorescent protein (GFP), which emits fluorescent light when it is excited by the microscope’s laser. Mice can be genetically engineered to produce GFP, and such mice are increasingly available for studying the processes that occur during tumor development, Piston said.

The In Vivo Optical Imaging Core, directed by E. Duco Jansen, Ph.D., assistant professor of Biomedical Engineering, offers fiber-optic based and direct illumination techniques, including optical coherence tomography (OCT). OCT is the optical equivalent of ultrasound, using light instead of sound waves. The light scattered back from the sample is detected with very high spatial resolution (clear images of microscopic structures).

The In Vivo Core is developing luminescence methods to image genes being turned on in living animals. The technique relies on genetically modified mice that produce the firefly luciferase gene—the gene that makes fireflies “glow.” Tumor cells can also be marked with this gene, injected into animals, and followed with luminescence imaging during tumor development.

Jansen also described in vivo optical spectroscopy, the only type of optical spectroscopy currently being used at Vanderbilt for clinical applications in human beings. This technique uses fiber optics to direct light into a tissue and collects a spectrum of light coming back out, revealing information about the tissue.

It is being used during brain tumor surgery to distinguish the tumor and its border from the surrounding normal tissue. Using MRI and CT to determine the tumor border is difficult, Jansen said. Optical spectroscopy offers real-time detection of the tumor border, avoiding the wait for biopsy analysis during surgery.

“All three of these techniques — OCT, bioluminescent imaging, optical spectroscopy — are available and working, and application-specific modifications can be made,” Jansen said.

Dr. Frank E. Carroll Jr., professor of Radiology and Radiological Sciences, directs VIVID’s Monochromatic X-ray Core.

Standard X-rays are radiation with a range of different wavelengths/energies, whereas monochromatic X-rays are radiation of a single wavelength. Carroll and colleagues initially used the FEL to prove that monochromatic X-rays work for imaging, and they are now working with a company called MXISystems to build a portable monochromatic X-ray machine.

“We are the only place in the world exploring the use of monochromatic X-rays,” Carroll said. “With monochromatic X-rays, the radiation dose to the patient goes way down and the information goes way up.”

Carroll and colleagues expect to start a study in the spring comparing monochromatic X-ray images to mammograms. Women who have an abnormal mammogram and require a biopsy will be invited to participate.

Carroll will also serve as VIVID’s link to the “gold standards” of in vivo imaging — MRI/Ultrasound/CT — to evaluate by comparison the new in vivo imaging methods developed by VIVID investigators.

Mouse cancer models will be useful to VIVID studies, and the imaging center expects to draw on Vanderbilt’s participation in the NCI Mouse Models of Human Cancers Consortium to gain access to established mouse cancer models. Dr. Robert J. Coffey Jr., Ingram Professor of Cancer Research and principal investigator for the mouse consortium effort at Vanderbilt, emphasized the range of mouse models available through institutions participating in the consortium.

Of the NCI-designated cancer centers, only Vanderbilt-Ingram, Memorial Sloan-Kettering, and UCLA received grants for both the Mouse Models of Human Cancers Consortium and the In Vivo Imaging Center.

VIVID is accepting project proposals until October 1, 2000. The center expects to fund three or four development projects that focus on imaging cancer-related molecules with plans to apply the concepts to clinical cancer diagnosis and therapy.

“Hopefully we will be able to parlay VIVID into a full center grant after the first three years,” Piston said.

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