Shortfalls in use of anatomic biomarkers create opportunities

Medical imaging is poised to play a key role in drug research, including evaluating therapy and characterizing disease.

Drug researchers still rely on traditional diagnostic protocols for assessing therapeutic response. But they are also devising CT, MRI, and PET/CT techniques to measure changes along the same biochemical pathways that experimental drugs use to fight disease, said Dr. Lawrence H. Schwartz, director of MRI at Memorial Sloan-Kettering Cancer Center in New York City.

Both approaches aim to visualize a physiologic process and to document how that process changes with the administration of a drug or therapy, said Schwartz during his Pendergrass New Horizons lecture at the 2005 RSNA meeting.

Anatomic changes have traditionally served as biomarkers of disease. In oncology, guidelines by the World Health Organization and Response Evaluation Criteria in Solid Tumors (RECIST) define how reductions in the diameter of tumors, measured with CT, correspond with complete, partial, stable, and progressive responses to cancer therapies.

But anatomic measurements alone have proven inadequate for response measurement for molecularly targeted therapies, Schwartz said. As a result, imaging has much to offer. Drug development schemes, designed to inhibit disease-producing biochemical or proteomic activity, have produced a new generation of cytostatic agents that kill cancers without affecting volume. Drugs targeted to specific protein kinases require surrogate imaging markers tuned to cell metabolism or proliferation to measure response and calculate optimal dosages.

Some imaging strategies attuned to such pathways report response within 24 hours after the initiation of therapy, Schwartz said. For example, changes in glucose metabolism are the key for measuring the early response of stromal tumors to tyrosine kinase-inhibiting Gleevec, a drug used to treat chronic myeloid leukemia.

Dynamic contrast-enhanced MRI quantifies the disruptive effects of experimental SU-11248 on endothelial growth factor-induced neovasculature. Perfusion CT is used to measure necrosis from the dual inhibition of cell proliferation and angiogenesis induced by SU-11248, an experimental drug in phase II trials for hepatocellular carcinoma.

Problems relating to the accuracy, reproducibility, and biological relevance of imaging as a biomarker must be addressed if these techniques are to realize their potential, Schwartz said. New biomarkers are needed, especially to complement targeted therapies. Existing biomarkers can be improved by more robust imaging techniques and refining image analysis. Standardized imaging techniques are needed to create image repositories and tools for analysis.

No individual, department, or company can completely validate an agent on its own, he said. Collaboration among academia, clinical practices, government, and industry is needed.

"We can make rapid progress in biomarkers that utilize imaging," he said.