Human brain specimen with glioblastoma multiforme.
Brain Cancer Cells Hide While Drugs Seek
Tumor cells temporarily lose mutation to evade drugs targeting mutation
A team of scientists, led by principal investigator Paul S. Mischel, MD, a member of the Ludwig Institute for Cancer Research and professor in the Department of Pathology at the University of California, San Diego School of Medicine, has found that brain cancer cells resist therapy by dialing down the gene mutation targeted by drugs, then re-amplify that growth-promoting mutation after therapy has stopped.
The findings are published in the December 5, 2013 online issue of Science.
“This discovery has considerable clinical implications because if cancer cells can evade therapy by a ‘hide-and-seek’ mechanism, then the current focus (of drug therapies) is unlikely to translate into better outcomes for patients,” said Mischel.
In recent years, new cancer therapies have emerged that target tell-tale gene mutations to identify specific cancer cells for destruction. Unfortunately, a variety of “resistance mechanisms” have also emerged, among them incomplete target suppression, second-site mutations and activation of alternative kinases or enzymes that maintain growth-promoting signals to the cancer itself.
“Most research is aimed at developing better drugs or better drug combinations to suppress these downstream signals,” Mischel said. “However, one thing that has not been carefully considered is whether cancer cells can modulate the levels of – and thus their dependence on – the target of the drug, evade therapy, and then re-acquire the oncogene to promote tumor growth when the drug is withdrawn.”
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A micrograph by Thomas Deerinck of the National Center for Microscopy and Imaging Research at UC San Diego reveals the organization of stained glial cells (cyan), neurofilaments (green) and DNA (yellow) in a section of rat hippocampus.
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Metastasized human breast cancer cells (magnified 400 times, stained brown) in lymph nodes. Image courtesy of National Cancer Institute.
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How cancer hijacks healthy cell circuits to stay alive
Fundamentally, cancer is a disease of cell growth and function run amok. Frequently, the culprit is mutations in the proteins that regulate growth, such as epidermal growth factor receptor or EGFR, which has been implicated in a variety of cancers.
Among these is glioblastoma multiforme (GBM), a highly malignant brain cancer that has thus far defied satisfactory remedy. More than 9,000 new cases of GBM are diagnosed each year in the United States and effective treatments are limited. GBM tumors are aggressive and resistant to current therapies, such as surgery, radiation and chemotherapy. The median survival rate for newly diagnosed GBM patients is just 14 months.
Drugs devised to block mutant growth signals in GBM have so far proven only temporarily effective. Eventually, cancer cells adapt and overcome. Most current research has focused on how mutations in other proteins in cancer cells allow them to become drug resistant.
In a new paper, published in Cancer Discovery, a team of scientists co-led by Paul Mischel, MD, a principal investigator at the Ludwig Institute for Cancer at the University of California, San Diego and a professor of pathology in the UC San Diego School of Medicine, identify a unique mechanism that allows GBM cells to develop resistance to drugs targeting EGFR signaling.
The feat, according to Mischel and co-leader Steven Bensinger, VMD, PhD, at UCLA, is accomplished not through mutation, but by hijacking the signaling of a normal cell surface protein called platelet-derived growth factor receptor-beta or PDGFR-beta.
“It’s almost like a game of whack-a-mole,” said Mischel. “You use a drug to suppress a choice target and something else pops up to take its place and keep the cells alive—in this case a growth factor receptor that is perfectly normal in physiological terms.”
When scientists targeted both EGFR and PDGFR-beta in GBM tumors in animal models, the tumors were suppressed and drug resistance prevented. The next step is to develop clinical trials of treatments that target both involved proteins. And while this study focused on glioblastomas, Mischel and Bensinger believe the findings are relevant to other forms of cancer.
You can read the full Ludwig news release here.