A new technique may allow physicians to monitor patients’ responses to molecularly targeted drugs, according to researchers from the National Cancer Institute (NCI) and the Food and Drug Administration (FDA) *. The finding was one of three advances in proteomics – the study of proteins within cells – scheduled to be announced by researchers from the NCI-FDA Clinical Proteomics Program in a press briefing at the 94th Annual American Association for Cancer Research (AACR) Annual Meeting, which was canceled.
Monitoring Cancer Treatment
In the first study, the researchers successfully identified specific proteins that may be useful in monitoring patients treated for breast or ovarian cancer. Their approach, based on changing levels of active proteins inside tumor cells, could help physicians determine early during treatment whether a particular drug is working effectively for an individual cancer patient.
“The results of our study suggest this approach may help us tailor treatment to individual patients,” noted Virginia Espina, M.S., M.T. (ASCP), NCI, the lead investigator on the study.
Because molecularly targeted drugs are designed to target specific molecules that have gone awry in cancer cells, researchers can predict which of the cell’s many complex signaling pathways these drugs are likely to affect. In ongoing studies at NCI, researchers are using proteomic technology to monitor the key pathways likely to be influenced by the molecularly targeted drugs Gleevec®, Herceptin®, and Iressa®.
To monitor changes in tumor cell proteins, the researchers isolated cancer cells from tumor biopsies and measured the level of various proteins involved in the signaling pathways targeted by the drugs. The scientists measured not only the total amount of each protein, but also how much of the protein was in its active form. These proteins were measured prior to treatment and at selected times after treatment.
The researchers found that prior to treatment, patients with breast cancer who had a poor clinical outcome tended to have more of the active form of a protein known as AKT, which promotes cell survival. Treatment with Herceptin®, however, resulted in a change in the relative amount of the active form of AKT, enabling tumor cell death.
“Treatment with Herceptin® appears to alter the level of active AKT in tumors. We may be able to measure the degree of this change in patients who are receiving treatment to determine whether a drug that inhibits this signaling pathway is best for their individual cancer,” said Lance Liotta, M.D., Ph.D., co-director of the Clinical Proteomics Program and the senior NCI investigator on the study.
The researchers expect to be able to apply the proteomic approach to monitor the treatment of other cancers with molecularly targeted drugs, but further research is required to identify the best proteins to measure in those tumors.
Diagnosing Ovarian Cancer
In another study, in collaboration with Correlogic Systems Inc., NCI and FDA scientists have improved the NCI/FDA/Correlogic method of ovarian cancer diagnosis currently under evaluation**. The approach uses Correlogic’s artificial intelligence computer programs to analyze the patterns of proteins in the blood and can detect the presence of disease even at early stages. In a previously published study, researchers used the technique to successfully differentiate between blood samples taken from patients with ovarian cancer and those from unaffected individuals.
The researchers discovered patterns of proteins that correctly identify 100 percent of blood samples as being from either unaffected individuals or patients with ovarian cancer. This is an improvement on the previous analysis, which correctly identified 100 percent of the samples from patients with cancer, but only 95 percent of the non-cancer samples.
The researchers analyzed the proteins using mass spectroscopy, a technique that sorts proteins and other molecules based on their weight and electrical charge; they attribute the improvement in specificity primarily to the use of a higher resolution mass spectrometer in the most recent study. “The increased resolution allows us to distinguish more features within the patterns generated from the serum samples,” said Timothy Veenstra, Ph.D., of the Mass Spectrometry Center at NCI-Frederick.
Visualizing Protein Patterns
The NCI-FDA team has also developed new tools for visualizing and analyzing protein patterns***. Beyond identifying the presence of ovarian cancer and other diseases, these tools may allow researchers to determine how far the disease has progressed by matching specific proteomic patterns to a particular stage.
“The new tools improve upon previous methods of identifying discriminatory protein patterns by allowing researchers to visualize the entire set of proteins in a single view, as well as zoom in and out to focus on regions of interest within the data,” said Emanuel Petricoin III, Ph.D., co-director of the Clinical Proteomics Program and the senior FDA researcher on the project.
“Using these visualization tools, the identification of proteomic patterns that aid in disease diagnosis can be done with greater sensitivity and accuracy,” said Donald Johann Jr., M.D., of the NCI-FDA Clinical Proteomics Program, lead investigator of the study. “This new method reduces the risk of error, increases our productivity, and provides an efficient method to analyze large sets of protein data.