December 5, 2013, New York, NY– A Ludwig Cancer Research study has uncovered an entirely novel mechanism by which glioblastoma (GBM), the most common kind of brain cancer, evades targeted therapies. Published in the current issue of the journal Science, the paper describes how GBM tumor cells essentially hide the signaling molecule targeted by such therapies, adding a layer of complexity to current models of drug resistance in cancer. The findings could have far-reaching implications for the therapeutic regimens currently employed to treat GBM and suggest alternative approaches that could improve outcomes for cancer patients.
GBM tumors typically carry mutant forms of the EGF receptor. The gene for the most common of these mutant receptors, EGFRvIII, lies on small fragments of DNA known as double minute chromosomes and promotes uncontrolled cell proliferation. "You would expect that drugs that block EGF receptor signaling would devastate GBM tumors," says Paul Mischel, MD, Ludwig scientist based at the University of California, San Diego School of Medicine. Mischel led the multi-institutional study in close collaboration with Ludwig colleagues Web Cavenee, PhD, and Frank Furnari, PhD. "Yet such targeted drugs have not worked in GBM, and that has raised some serious questions among cancer researchers."
Only about 60 percent of cells express the aberrant receptor. To probe how this heterogeneity contributes to drug resistance, Mischel and his colleagues treated tumors taken from patients with targeted therapies. They found, to their surprise, that this prompted GBM cells to almost completely shut down their expression of EGFRvIII. But were the two cell types this yielded—those that expressed the EGFRvIII mutant, and those that did not—equally cancerous?
The answer: An unequivocal yes. The findings showed that GBM tumors don't survive targeted therapy by replacing susceptible cells with mutants unaffected by the drugs in question—a classical mechanism of resistance—but by hiding the target of those drugs. And they did this, surprisingly, by depleting the double minute chromosomes themselves. "Those DNA double minutes seem to hide out in a reservoir," says Mischel, "and when the drug is removed, the tumors come screaming back. When they return, the cells become susceptible once again to targeted therapy."
"Our research might have significant implications for how we dose patients," says Mischel. "A high-dose regimen of EGF receptor-targeting drugs, given in pulses, might be more effective than the continuous, lower-dose regimen employed today. That is a study that needs to be done."
The findings also amend a second prevailing model of drug resistance in cancer. Double minute chromosomes are thought to contribute to drug resistance mainly by encoding multiple copies of proteins that detoxify chemotherapy or drive cancer in other ways. But in GBM, tumors actually shut down a cancer-promoting gene to evade drug targeting. "Many kinds of tumors have extra-chromosomal DNA fragments that carry cancer-promoting genes," says Mischel. "So this new mechanism could be a far more common phenomenon in cancer than we've realized."
Mischel and his colleagues are now exploring that possibility.
Funding support for this research was provided by the Ludwig Institute for Cancer Research; the Ben and Catherine Ivy Foundation Fund; the National Institutes of Health (NIH); the Ziering Family Foundation in memory of Sigi Ziering (T.F.C. and P.S.M.); Art of the Brain Fund (T.F.C.); the James S. McDonnell Foundation (to F.B.F); the European Commission; Ruth L. Kirschstein Institutional National Research Service Award; and the UCLA Scholars in Oncologic Molecular Imaging (SOMI) Program (D.A.N).
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists with a 40-year legacy of pioneering cancer discoveries. Ludwig combines basic research with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested more than $1.6 billion in life-changing cancer research through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. http://www.ludwigcancerresearch.org
Paul Mischel is a member of the Ludwig Institute for Cancer Research and a professor in the department of pathology at the UC San Diego School of Medicine.
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