Hitting the epidermal growth factor receptor (EGFR) both high and low with a combination of drugs for targeted cancer therapy curbs cancer cell growth more effectively than using the drugs each by themselves, researchers from the University of Wisconsin-Madison reported in the August 1 issue of the journal Cancer Research.
EGFR drives unregulated growth in many types of cancer, and the new molecular cancer drugs, cetuximab (Erbitux™, ImClone), and gefitinib (Iressa™, AstraZeneca) have recently gained FDA approval as therapeutics targeted at the EGFR to inhibit cancer cell proliferation. A third EGFR inhibiting drug, and erlotinib (Tarceva™, Genentech), may have FDA approval within a year.
The Wisconsin study examined the combined effect of Erbitux™ with either Iressa™ or Tarceva™ to control growth of head and neck, prostate, and lung cancer cell lines grown in culture, and lung cancer tumors developing in animals.
Tandem application of either Erbitux™ and Iressa™, or Erbitux™ and Tarceva™, proved synergistically more effective than single drug trea™ent at several levels.
"The combination of Erbitux™ with either Iressa™ or Tarceva™ inhibited cancer cell growth both in cell culture and in live animals more effectively than any of the drugs alone," said the study's senior author, Paul Harari, M.D., associate professor of human oncology, University of Wisconsin Medical School and Comprehensive Cancer Center.
"The impact of these drugs in combination exceeded the effect each had on controlling the growth, cellular signaling, and tumor development when administered alone," added Shyhmin Huang, Ph.D., a senior scientist in Harari's laboratory and lead author on the publication.
The anti-EGFR drugs are of two types:
- The monoclonal antibody Erbitux™ hits the EGFR high, binding to a specific site on the receptor outside the cell membrane. Erbitux™ blocks the receptor from responding to extracellular signals that turn on the receptor's intracellular mechanisms. The EGFR is a kinase, a cellular protein designed to add high-energy phosphate groups to proteins inside the cell, switching those substrate proteins on to conduct cellular signaling.
- Iressa™ and Erlotinib, on the other hand, hit the EGFR low, at sites inside the cell membrane where the kinase activity is located. They are small molecules that interfere with the action of EGFR to phosphorylate proteins inside the cell. Iressa™ or Erlotinib block the EGFR kinases from adding phosphate groups to other proteins within the cell.
Used together, the monoclonal antibody and either of the small molecule kinase inhibitors amplified control of cancer cell growth and signaling. With the reduced EGFR-driven cell signaling, more of the cancer cells turn from proliferation to programmed cell death, a process known as apoptosis.
And in animal models, the drug combinations limit lung cancer cell growth and tumor development more effectively than any of the drugs used alone.
When used singularly in the clinic, the EGFR inhibitors are effective in a relatively small percentage of patients--perhaps 10 to 15 percent. Combinations of the EGFR drugs may further enhance tumor response and potentially benefit more patients who currently don't respond to a single EGFR inhibitor, Harari noted. Recent clinical trial results with the EGFR inhibitor erbitux combined with radiation in head and neck cancer show clear improvement in patient survival compared with radiation alone. The new study findings suggest that more effective EGFR signaling blockade with combination inhibitors might further augment these promising clinical results.
"Predictive 'molecular fingerprints' from human tumors that are regulated by the EGFR signaling pathway need to be evaluated so that we can target these drugs in combination for more effective clinical application," he added.
Other University of Wisconsin researchers contributing to this study were Eric Armstrong, Sergio Benavente and Prakash Chinnaiyan.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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