MI pioneers seek inspiration in new academic settings

Two of molecular imaging's movers and shakers have relocated, a move that promises to catapult the field into a new era. Now at institutions with a host of resources and collaboration opportunities, Dr. Sam Gambhir and Thomas Meade, Ph.D, are confident that their research will benefit radiologists, oncologists, surgeons, and gene therapists.

Gambhir, the former director of the Crump Molecular Imaging Institute at the University of California, Los Angeles, now directs the molecular imaging program at Stanford University. A team of 30 made the trek north with him to take advantage of Stanford's offer of space and seed funding to develop a program that will translate their landmark work in small animals to the clinic.

Meade recently left the Beckman Institute at the California Institute of Technology for Northwestern University, where he plans to lay the foundations of a new program focused on the Chemistry of Life Processes Institute. The program will bring biologists, chemists, clinicians, engineers, and other scientists into the same building to facilitate collaboration and allow them to draw upon each others' strengths.

"This is going to be a great place," Gambhir said. "Stanford has excellent basic science talent and a strong pharmacology department, in addition to quality cell and molecular biology, biochemistry, engineering, radiology, and nuclear medicine departments."

Gambhir will continue the work begun at UCLA on developing tracers for imaging with PET. It was his development of microPET using small animals that enabled him to optimize tracers and define their pharmacokinetics, setting the stage for human application.

One focus is gene therapy, a field that has long struggled with delivering genes to target cells and tissues. The inability to determine the whereabouts of the therapeutic genes has been a challenge. Gambhir has developed a set of reporter genes that, when expressed, lead to enzymes that activate tracers that can then be detected by PET. Herpes simplex virus 1 thymidine kinase (HSV1-tk), for example, activates by phosphorylating tracers such as ganciclovir and penciclovir.

Human trials on pancreatic cancer have recently begun in Spain, Gambhir said. The treatment involves introducing HSV1-tk, which inhibits cell replication, to the area from which tumor has been removed. Injecting fluorinated penciclovir through the bloodstream gives information about the presence of HSV1-tk and its tumor-killing activity. A human trial to treat prostate cancer is slated to begin early next year.

Planned for March is the treatment of glioblastoma using cell-based therapy with T cells designed to recognize tumors and equipped with the HSV1-tk reporter gene. Imaging-activated penciclovir gives clinicians information about the number of transcribed and translated reporter genes in tumor cells. Knowledge about the presence or absence of HSV1-tk in tumor cells helps clinicians determine how to proceed with treatment.

Gambhir is also developing multimodality reporter genes that can be used with both PET and optical imaging systems that cost less than PET and are easier to use with small animals. He has been working with a reporter gene that is a fusion of three genes, allowing for optical fluorescence in cells, optical bioluminescence in small animals, and PET imaging in humans.

HARNESSING ENZYMES

Meade is a chemist with a background in biology and biochemistry and NIH postdoctoral training at Massachusetts General Hospital's radiology department. He has developed electronic biosensors of DNA and proteins and designed novel MR contrast agents that are biochemically activated in vivo to monitor gene expression. EgadMe is an example of an MR contrast agent that occupies eight of the nine coordination sites on gadolinium, with the ninth occupied by galactopyranose. Beta-galactosidase, which is expressed along with the target gene, cleaves galactopyranose, activating EgadMe and allowing it to be viewed using MR.

With beta-galactosidase finding use in the arena of basic science, Meade has been trying to harness other enzymes to help clinicians visualize gene expression and physiological processes in patients. These enzymes include kinases, glucoronidases, metalloproteinases, caspases, and cathepsins, each of which can act on a different metabolite tethered to the contrast agent to indicate the expression of disease-specific genes or the delivery of drugs. His company, Metaprobe, is focusing on bringing this technology to the clinic.

Contrast agents that are activated with the expression of disease-specific genes allow clinicians to make more accurate diagnoses and better treatment decisions, Meade said. He envisions a future in which mammography, for example, will give radiologists information about gene expression characteristic of cancer cells, instead of relying on anatomy.

"Instead of employing more invasive techniques such as needle biopsies to diagnosis a suspicious lesion, the new agents will be developed to noninvasively distinguish lesions through physiology," he said.

Meade is also working on the challenge of reliably transporting MR contrast agents across cell membranes and the blood-brain barrier. So far, his research team has successfully identified small molecular chaperones, such as a chain of 12 arginine residues, that can lead intravenously delivered agents into the cell.