Pendergrass lecture: Molecular imaging opportunities abound

Michael E. Phelps, Ph.D, discusses molecular imaging in his presentation Monday of the 2004 Pendergrass New Horizons lecture.

A topic can be so dynamic it defies easy explanation. This was the case Monday as Michael E. Phelps, Ph.D, circumnavigated the subject of molecular imaging in his presentation of the 2004 Pendergrass New Horizons lecture.Phelps made it clear that molecular imaging has become a grand scientific smorgasbord, with lines of research crisscrossing in every direction. It has important implications for the evolution of radiological practice over the next 10 years, he said. "The determining factors will likely be the degree of change in molecular medical system biology, therapeutics, diagnostics, and economics," he said.A key question is whether radiology can adjust to diagnostic practices driven by biologic and molecular innovations, he said. Phelps, chair of molecular and medical pharmacology at the University of California, Los Angeles, finds common ground between molecular biologic strategies used to find new drug therapies and the techniques that are inspiring molecular approaches to imaging cellular and subcellular processes associated with disease. He argued that molecular medicine will help pharmaceutical companies find replacement revenue for $75 million in sales that will evaporate as key patents expire in the next few years. Molecular imaging is being adopted as a tool in drug research and will be applied clinically to measure responses to therapies as new agents enter the field."Molecular diagnostics and therapeutics will be drawn together," he said.Many technologies, including engineering and physical, biologic, and medical sciences, are coming together to make molecular imaging possible, according to Phelps. Links are forming between imaging and pharmaceutical companies, for example, GE's $9 million acquisition of Amersham Pharmaceuticals in 2003. Siemens and Philips are also collaborating with pharmaceutical firms. Hundreds of millions of dollars are being invested to develop this science. Human PET and microPET technologies were developed to harmonize imaging capabilities in patients and animals, so innovative approaches based on new kinds of biochemical assays could be tested on small animals before being applied to humans. PET/CT bridges the imaging of biology and structure, he said.Molecular imaging implies that radiologists will be able to examine the molecules that underlie biology to make diagnoses, Phelps said. It requires a new understanding about the nature of disease. Systems biology is taking a cue from information science. Code is written as RNA instructions that are converted into the language of proteins that form integrated cell circuits organized into networks."They form the cultures of our organ systems, be they liver, heart, or brain," he said.Cancer cells reprogram themselves to defeat the body's immune system and outside therapeutic interventions. They cut off communications with normal cells and develop an independent supply of nutrients through angiogenesis. Biochemical circuitry that would normally trigger apoptosis following genetic mutations is modified, and the cancer's propensity to migrate and proliferate increases, he said. Gleevec, a molecularly based therapy for gastrointestinal stromal tumor, illustrates how these principles work, according to Phelps. It inhibits C-KIT, a particular tyrosine kinase, protein involved in intercellular communication. In some cases, Gleevec causes tumors to shrink dramatically. In other instances, the tumors continue to grow. UCLA researchers Charles Sawyer, Ph.D., and Owen Witte, Ph.D., used system biology to discover why responses are so variable, according to Phelps. The presence of overamplified C-KIT shows that tyrosine kinase is critical to cell survival. By inhibiting tyrosine kinase, Gleevec triggers cell death. The lack of C-KIT overamplification means the cells do not depend on the protein, making Gleevec less robust. PET is a molecular camera, potentially capable of imaging any one of about 500 potential radiopharmaceutical probes to examine various biologic processes. FDG illustrates how PET reports subcellular molecular activity. The value of FDG for detecting cancer stems from the 25-fold amplification of glycolysis that arises as cancer cells shut down the Krebs cycle and the production of ATP, according to Phelps. This forces the cell to rely on glucose metabolism as an energy source.An understanding of other aspects of molecular biology led to the development of F-18 FLT, a radiopharmaceutical agent tied to DNA replication and cell division. The two agents may ultimately play complementary roles for measuring the response of cancers to therapy.Phelps also discussed the molecular underpinning of Alzheimer's disease and how PET can diagnose that condition. "The point here is not so much about PET. It is to encourage all of us to characterize disease by its biology, not its structure," he said.