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New clue to treating a lethal breast cancer metastasis

May 24, 2017

Targeted cancer therapies have significantly improved the outlook for many patients. But they have not proved successful in controlling the brain metastases of several types of cancer. Up to half of all patients treated with targeted therapies for a type of breast cancer that is driven by overexpression of the HER2 gene eventually develop brain metastases, which are inevitably fatal. Now, a study published in Science Translational Medicine and led in part by Rakesh Jain, an investigator at the Ludwig Center at Harvard and Director of the Steele Laboratories of Tumor Biology at the Massachusetts General Hospital (MGH), has identified a novel mechanism by which this cancer’s brain metastases resist drugs that target signaling by the proteins HER2 and PI3K. He and his team have also identified a treatment strategy that could overcome this resistance.

“While the failure of these drugs against brain metastasis has often been attributed to the blood brain barrier, some agents are small enough to penetrate into the brain,” says Jain. “In addition, the disrupted, leaky vasculature that develops in and around tumors—what we call the blood tumor barrier—allows some accumulation of anti-HER2 and anti-PI3K drugs in brain metastases. This work shows that the tumor microenvironment itself can compromise the efficacy of targeted therapies and should be taken into account as new treatment approaches are developed.”

Along with collaborating researchers—including a team led by the co-senior author Jeffrey Engelman, formerly with the Ludwig Center at Harvard and now Global Head of Oncology at the Novartis Institutes for BioMedical Research—Jain’s team set out to identify factors in the brain microenvironment that could alter growth and survival signals within HER2-positive breast cancer cells. The team picked out HER3, part of the same signaling pathway within cells that includes HER2, as a possible contributor to anti-HER2/PI3K resistance in breast cancer brain metastases.

They then confirmed in mouse models that cells from HER2-positive breast cancers became resistant to HER2-targeting treatment when they were implanted in the brain, but not in other tissues. The investigators also found that HER3 is overexpressed in brain metastases of HER2- positive breast cancers from both mice and human patients. While neither a drug that targets HER3 nor one that interferes with the interaction between HER2 and HER3 could slow the growth of brain metastases, combined treatment with both an anti-HER2 and an anti-HER3 drug significantly slowed tumor growth. The findings will have to be confirmed in patients, but they offer a major clue to addressing a major challenge of breast cancer therapy.

The news release from which this summary is adapted can be found here.