patients' response to drugs
Researchers at the School of Medicine developed novel digital imaging technology that is capable of pinpointing protein expression patterns in cells that cause diseases such as breast and colon cancer.
"This is a breakthrough for new bio-specific drug discovery since it allows measurement of proteins that will determine if the patient is likely to respond to the therapy," says lead researcher Dr. David L. Rimm, associate professor of pathology at the medical school. "A good example is the testing of the HER-2 receptor prior to receiving HerceptinTM for breast cancer treatment. Our new technology can detect changes much more subtle than HER-2 that will facilitate development of new drugs."
The study, published in a recent issue of Nature Medicine, used tissue microarrays -- slides that each contain tiny tissue samples from hundreds of patients -- for breast and colon cancer developed from Yale's Tissue Archive. The archive contains many tissue samples with over 20 years of clinical outcome data. Estrogen receptor expression in breast cancer tissue microarrays were used to verify the accuracy of the automated results versus using the conventional pathologist-based technique that is the current standard of care.
The researchers also applied the technology to beta-catenin, a new molecular marker associated with colon cancer, and identified two novel tumor subsets not detectable by traditional pathology-based scoring.
"The existing technology used by pathologists is called feature extraction and is limited to determining semi-quantitative information based on the morphology of cell structures within the tissue," says Rimm. "The new technology uses molecular definition of cell compartments and allows comprehensive quantification of expression without losing spatial formation."
Rimm says that pathologists are extremely skilled at pattern recognition and this forms the basis of their ability to diagnose diseases. "As the molecular revolution envelopes pathology, it is becoming more important to determine how much of a given protein is expressed at a given site," he says. "Unfortunately, pathologists are not well equipped to make that determination. This new technology allows highly accurate measurement of protein expression and is not even limited to traditional cell compartments like cytoplasm and nucleus but can measure protein levels in other organelles such as the golgi apparatus, mitochondria or even a virtual compartment such as specific kinase."
Without this new technology, says Rimm, it would have been impossible to identify these new relationships between beta catenin protein expression patterns in colon cancer patients and clinical outcome.
"This new technology is yet another step for pathology to enter into the digital age," he notes. "Traditional pathology remains critical for a primary diagnosis, but in the future, quantitative assessment of expression levels of proteins in various locations will be extremely important for determining optimal therapy."
Rimm also says technology that improves assessment of the status of a disease, such as protein expression quantification and localization, will be a key tool for helping pathologists to assist in the discovery of new pharmaceuticals and for improving patient care by identifying biochemical markers that predict the likelihood of a positive response to specialized drug therapy.
Yale is working to establish a company called Histometrix, Inc. to further develop and commercialize this technology.
Other researchers on the study included Dr. Robert L. Camp, associate research scientist in the department of pathology, and Gina G. Chung, assistant professor in internal medicine and oncology.
-- By Karen Peart
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