New therapy for pancreatic cancer
Washington: A team of Indian and American scientists have found a new way of treating pancreatic cancer that kills 9 in 10 of the newly diagnosed 40,000 patients in the US each year. (TOI Health Section, 30 Dec, 2008)
The new personalised therapy involves targeting a receptor whose activation may be responsible for some pancreatic
cancers, suggests a study by scientists at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland and Institute of Bioinformatics in Bangalore.
The receptor identified by the team is called phosphorylated epidermal growth factor receptor (pEGFR). It is the activated form of a
protein that binds to epidermal growth factor (EGF), which promotes cell growth and differentiation.
When EGF attaches to EGFR, it activates it as a tyrosine kinase enzyme, triggering reactions that cause cells to grow and multiply, according to a press release by the Johns Hopkins Kimmel Cancer Center.
EGFR is found at abnormally high levels on the surface of many
types of cancer cells, which may divide excessively in the presence of EGF.
In a new study, published online in the Journal of Proteome Research, the researchers suggest that physicians potentially could test patients for signs of pEGFR, then direct therapies such as EGFR inhibitors directly at the signal pathway it is part of to shrink or prevent pancreatic tumours.
EGFR inhibitors and other targeted
cancer therapies that interfere with specific molecules involved in cancer development so far have had limited success clinically.
But that may be because scientists are not hitting the correct molecular target, or applying them to all patients without selecting which ones are most likely to benefit, says senior study author Akilesh Pandey.
"You can't do targeted therapy without knowing that you have the right target," says Pandey, an associate professor at the Johns Hopkins Kimmel Cancer Center.
"We propose that the use of activated EGFR as a predictive tool for clinical response to EGFR inhibitors could lead to an improved outcome of clinical trials while sparing the large majority of the patients who might not benefit from these drugs," he adds.
For the study, Pandey and colleagues first analysed a series of pancreatic cell lines, looking for tyrosine kinase activity, finding that cells derived from one particular patient showed dramatic response.
Next, they studied these cells in greater detail using quantitative mass spectrometry, finding within the activated tyrosine kinase pathways an unusual activation of the EGFR pathway.
To test whether EGFR signalling was responsible for cell proliferation in the P196 cell line, researchers injected mice with cells from P196 and other pancreatic cell lines to grow tumours, then treated the mice with erlotinib, a drug that inhibits EGFR.
The drug made a dramatic difference in tumours from the cell lines that showed activation of EGFR, shrinking them almost entirely, but had no effect on tumours grown from cell lines that did not show activation of EGFR.
In additional experiments, the scientists used a technique called immunohistochemical labelling to study sections of tumour tissue, looking for presence of pEGFR.
While the sections of untreated tumours showed intense staining for pEGFR, the erlotinib-treated tumours showed no labelling - an indication that the drug had turned off the EGFR signal.
"By combining proteomic analysis with immunohistochemistry, we have shown EGFR as a novel target in a subset of pancreatic cancers," Pandey said.
"Three of three tumours that responded to erlotinib stained positive for pEGFR, as compared with zero of 11 that did not. This indicates pEGFR positivity is significantly associated with erlotinib sensitivity, and could be used as an efficient screening tool to select patients who are more likely to respond to EGFR inhibitors."
The study was supported by The Sol Goldman Trust for Pancreatic Cancer Research. Co-authors were H.C. Harsha, Antonio Jimeno, Henrik Molina, Anca B. Mihalas, Michael G. Goggins, Ralph H. Hruban, Richard D. Schulick, Ullas Kamath, Anirban Maitra and Manuel Hidalgo.
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