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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.