Preventing brain metastasis in breast cancer

Translational researcher Dr. Cyrus Ghajar of Fred Hutchinson Cancer Research Center received nearly $2.4 million from the National Cancer Institute for a five-year study designed to develop strategies to prevent brain metastasis in breast cancer patients.

Ghajar, who joined the Hutch in 2014, studies breast cancer metastasis, particularly the tiny seeds of disease known as disseminated tumor cells, or DTCs, which can circulate in the body and embed in distant tissues well before a cancerous tumor is detected.

When breast cancer becomes metastatic, cancerous cells spread throughout the body, commonly forming tumors in the liver, the lungs, the bones and, ultimately, the brain. While metastatic breast cancer is treatable, it is not curable.

Currently, no drugs exist to target DTCs before they wake up and begin forming tumors. Ghajar’s lab is focused on developing such approaches.

Brain metastases are a growing problem in cancers, Ghajar said, because “they can take many years to manifest but are lethal once they do.”

Metastases in the brain arise later than metastatic tumors, or “mets,” in other organs like the lungs or liver, he said. And the time it takes for them to emerge suggests that dormancy, or a “sleeping” phase, is involved.

“This is supported by clinical and experimental data, including our own preliminary data,” he said. “They show breast cancer cells become dormant upon entering the brain.”

If these tiny tumor cells could be kept dormant — or quiescent — brain metastasis could be prevented, Ghajar said. But it’s first necessary to achieve a better understanding of the mechanisms of dormancy in the brain, which are currently unknown.

Keep ‘em sleeping

With this new award, Ghajar and his team, led by postdoctoral researcher and neuroscientist Dr. Jinxiang (David) Dai, hope to define and characterize the brain’s microenvironmental drivers — the signals from the surrounding normal cells — that put and keep cancer cells asleep after they’ve disseminated there from a primary tumor in the breast.  

Their plan is to follow breast tumor cells upon their arrival to the brain in order to define the cues that make them dormant, and to unravel the consequent signaling that wakes them up.

In previous research, Ghajar’s lab showed that DTCs nestled close to the microvasculature, the tiny blood vessels of the bone marrow, survive chemotherapy because they’re being “protected” by that microenvironment.

This work led to the discovery that certain proteins known as integrins, which among other things help with cell signaling, could be used to interrupt this protective signaling. Clinical trials of integrin inhibition are in the offing.

Now, they hope to figure out how to similarly interrupt the protective process in the brain.

Their previous investigations have shown that dormant DTCs are housed within the brain’s vascular niche, where tiny perivascular “astrocytes” — a type of brain cell — keep them from growing.

“They absolutely contribute to DTC suppression,” Ghajar said. “The question is how.” 

Once Ghajar's team has gained a better understanding of the framework for how the brain’s microenvironment drives DTCs into a dormant state, they plan on leveraging that into therapies that keep tiny seeds of brain metastasis asleep indefinitely.

“We’re starting with a blank slate, so we don’t know where this will go,” he said. “But it is logical that we have to understand how our body puts tumor cells to sleep — and the brain uniquely — before we can hope to double-up on this process.

“The goal here is understanding how the brain drives tumor cells into dormancy, and how tumor cells overcome this, to develop prophylactics for brain metastasis prevention.”