Know Your Enemy

Doctors at the University of Louisville dedicated a $12 million cancer treatment and research facility this summer that will substantially improve the ability of physicians and scientists to combat Kentucky's No. 2 killer.

The Molecular Imaging Research Center, housed in a 13,500-square-foot addition to the James Graham Brown Cancer Center, boasts state-of-the art equipment that allows physicians to precisely locate developing cancer tissue, study the effectiveness of prescribed treatments and, ultimately, develop new drugs to stop cancer in its tracks.

The MIRC's June 14 opening, which comes on the heels of an announcement by UofL and Norton Healthcare to open a joint cancer hospital, will further boost the cancer center's campaign to win premier accreditation as a Comprehensive Cancer Center from the National Cancer Institute.

"This puts the cancer center at the forefront of cancer research and treatment and moves us closer to a National Cancer Institute designation as a comprehensive cancer center," says Donald Miller, M.D., the center's director. "The ability of our researchers to investigate cancer and develop new therapies will be second to none."

The MIRC features three complementary components: a PET/CT scanner to view living tissue, a cyclotron to create isotopes needed for PET/CT imaging, and two nuclear magnetic resonance spectrometers to study the three-dimensional structures of molecules.

"This is an unusual facility in that it houses many of the components associated with molecular imaging all under one roof," says Greg Postel, M.D., chairman of the radiology department at UofL.

"Nationwide, there are a few larger institutions that have some of the individual components that we do, but they're not housed together like they are here. By bringing all these resources together, we have a unique opportunity to substantially improve patient care while also significantly expanding our research into new cancer treatments."

Kentucky's only fully integrated PET/CT -- short for Positron Emission Tomography/Computed Tomography -- scanner will have an immediate impact on cancer treatment at UofL because it offers doctors the most advanced tools for identifying cancerous tissue, assessing the development of tumors and fine-tuning treatments for efficacy.

A PET/CT actually is two scanners in one. The CT portion produces an anatomical map of a patient, complete with bone structure and the precise locations of organs and other soft tissue. Simultaneously, the PET portion takes a snapshot of the metabolic processes occurring inside those tissues, giving doctors insight into which tissues are malignant and which are benign.

"PET evaluates a number of different metabolic parameters," Postel explains. "The one we look at most frequently is glucose utilization. In many disease states -- including cancer -- malignant tissues utilize glucose at a faster rate than normal tissue, and so there is greater degree of glucose uptake in those areas.

"By injecting patients with radioactive agents that contain glucose, PET is able to detect the rate of utilization of glucose by different tissues within the body, and we can see that as an area of altered metabolism. This helps us detect a lesion when it's small and may not otherwise have been noted."

Before the advent of integrated PET/CT scanners, doctors had to combine imagery from two different sessions -- one conducted using a PET scanner, and another with a CT scanner -- to glean the same information.

But it often was difficult to analyze these images because they were impossible to align with total accuracy. By combining a patient's "metabolic report card" with precise anatomical data recorded during the same scan, PET/CT scanners give physicians the most accurate information possible for diagnosis, staging and treatment.

The PET/CT would not, however, be able to function without the radioactive isotopes that are injected into patients before scanning. These isotopes are produced by the MIRC's second major component, its cyclotron.

The cyclotron, or particle accelerator, is operated by physicists who work for a Tennessee-based company called P.E.T. Net Pharmaceuticals. As part of its agreement with UofL, P.E.T. Net supplies the Brown Cancer Center with radiopharmaceuticals at reduced cost, but it also sells the isotopes to other treatment facilities in the region.

Geographic proximity is an important factor with radiopharmaceuticals because they decay rapidly and can become less useful in a matter of minutes, Postel explains.

"You really need the cyclotron on site to produce the isotopes," he says. "Otherwise, they have to be produced at a remote site and flown in, which is a logistical dilemma.

"That also prevents you from doing research because some of the isotopes that we're planning to use for research purposes have half-lives in the neighborhood of just a few minutes."

Postel notes that radiopharmaceuticals can be tailored to help researchers study any number of metabolic processes besides glucose uptake, which means UofL's PET/CT scanner also will play a key role in assessing cardiac and neurological disorders, including Parkinson's and Alzheimer's diseases.

"PET can benefit treatment of a whole variety of diseases," Postel says. "For example, if you wanted to evaluate patients with acute stroke, you could do a study that looks at oxygen utilization."

UofL researchers also plan on using the technology to guide the development of experimental radiopharmaceuticals and cancer-fighting compounds, thanks to a smaller "micro-PET" slated for installation in 2003.

"We're working to attract a pharmaceutical company that will come to Louisville, set up a base of operations here in the MIRC and work with us to develop new isotopes and drugs for different disease states," Postel says.

"The micro-PET will make us a very attractive partner to these companies because it will allow us to study new isotopes and drugs in animal models.

"The sky's the limit in terms of what is possible here," Postel adds.

"Louisville is now in a position to offer cancer treatment and research programs that are commensurate with the best in the world. I think we are assembling an arsenal of tools that will enable us to really be a major player in cancer treatment and prevention."

One of those tools is the MIRC's final component, the Nuclear Magnetic Resonance spectrometer. Strictly a research tool, the NMR uses powerful superconducting magnets and radio waves to produce three-dimensional images of molecular structures.

"With a PET scanner, you look at anatomical detail," explains Andrew Lane, Ph.D., UofL's James Graham Brown Professor of Structural Biology. "With an NMR spectrometer, you look at individual molecules in their natural environment. Or if you choose to, you can take them out and examine them in great detail inside a test tube."

Armed with this information, researchers hope to design compounds that interfere with the processes that cause cancer cells to develop -- targeting rogue proteins or turning "off" errant genes, for example -- while reducing the debilitating side effects so often associated with more conventional types of chemotherapy.

NMR works by turning individual atoms into tiny radio receivers, Lane explains.

"The nuclei of atoms are themselves magnetic. Hydrogen, carbon, nitrogen, phosphorous all have different magnetic properties.

"When we put these little magnets into a big magnetic field -- our NMR -- they all point north, just like a compass needle. We then irradiate them with low-energy radio waves, about 600 to 800 MHz, and each of these individual atoms begins to absorb that radiation at a specific frequency."

By measuring the various absorption frequencies, researchers can locate all the atoms in a given protein.

From there, they can create detailed pictures of the protein's structure and design ways to target its operation by creating drugs that bind to it, blocking its ability to carry out whatever function it plays in cancer development.

"Everything inside cells is highly regulated, usually by one protein interacting with another or by a protein interacting with a piece of DNA," Lane explains.

"With cancer the regulation has gone wrong, so things are produced when they are not supposed to be, or they are produced in too great or too little a quantity.

"We want to get at these actual fundamental mechanisms of cancer development and progression because we want to find out who our enemy is.

"To do that, we need to know what they look like so we can design novel drugs to go against these newly identified targets.

"If you don't know what the enemy looks like and how it works," Lane continues, "all you can ever do is randomly make trillions and trillions of molecules and then try them out to see if you find the one that does work."

In actuality, it's even more complicated than that.

"You've also got to make your drug bind to your target molecule but not stick to another molecule that looks rather similar, because all proteins have quite a lot of things in common.

"The issue of specificity -- trying to target a specific protein in a soup of 10,000 proteins -- is rather non-trivial. And when you don't have specificity, you do a lot of other things to your cells that cause unintended side effects. Not much is worse than cancer, but side effects can be pretty nasty."

While the task is a challenging one, Lane is excited about the potential rewards made possible with technology like NMR spectroscopy and X-ray crystallography, a structural-analysis technique that researchers plan to bring to Louisville in 2003.

"Here in the cancer center, people are working to identify new targets instead of just tracing down the same old targets that researchers have been looking at for the last 30 years with limited success," Lane says.

"It's time to look for alternatives, and UofL is a good place to do it."