Each year nearly 150,000 Americans are diagnosed with metastatic cancer that has spread to the brain. The number is projected to rise. As a result of a larger aging population, combined with improvements in cancer screening and care, up to 30 percent of patients with solid tumor cancers can expect their cancer to return, traveling to other parts of the body, including the brain.
Brain metastasis is often associated with cognitive decline, seizures, cranial neuropathies and poor prognosis.
“Not only is it very devastating and hard to treat, but when you really look at the patients, brain metastasis is worse than any other metastasis because patients can lose memory, the ability to express themselves and motor function,” said Ann Marie Pendergast, PhD, a veteran cancer researcher who began her career at Duke 20-plus years ago researching chronic myelogenous leukemia (CML) then moved to solid tumor research over the past decade.
Breast cancer is the second most common cause of cancer death for women worldwide, and metastases, including brain metastases, account for the vast majority of deaths from breast cancer. The types of cancer most likely to cause brain metastases are lung, breast, colon, kidney and melanoma.
Pendergast explained that what makes brain brain metastases especially difficult to treat is the inability for many available anti-cancer drugs to cross the blood-brain (BB) barrier, and that for those that do cross, if just a single compound is used, most tumors will eventually become resistant.
“The idea is to make combination therapies that can be used to target specific molecules in metastatic cancer cells and that efficiently cross the BB barrier, but that also collaborate with other therapies — so that resistance cannot emerge,” said Pendergast, explaining that this could include combinations of chemotherapy and immunotherapy or immunotherapy with targeted therapies.
Her lab, with funding from Duke, is making progress on this front.
Researchers in Pendergast’s lab are working to identify molecules that can be targeted to disrupt the pathways required for metastatic disease.
Pendergast has worked for years to understand a group of enzymes called ABL kinases. In normal cells, their functions include signaling cells to move and invade. Normally these invasion promoters are turned on only when needed, but her work has shown that they are plentiful and highly active during several steps in metastasis.
In February 2016, Pendergast, with Duke colleagues, Jun Wang, PhD, Clay Rouse, DVM, and Jeff S. Jasper,PhD, revealed, in Science Signaling, their discovery that ABL1 and ABL2 enhanced the ability of breast cancer cells to invade and break down bone in mice and that an ABL-specific inhibitor decreased breast bone metastasis in mice.
In December 2016, Pendergast, with Duke colleagues Jing Jin Gu, PhD, Clay Rouse, DVM, Xia Xu, PhD, Jun Wang, PhD, and Mark Onaitis, MD, found that the enzymes ABL1 and ABL2 are highly active during several steps in lung cancer metastasis to the brain, bone, and other organs. They discovered that if they inhibited ABL1 and ABL2 in mice with a drug, or removed the enzymes using gene editing, they could stop a crucial step in metastasis — extravasation — when cancer cells exit the bloodstream and push their way inside an organ. (JCI Insight)
“Our lab started with general metastasis, and research into the role of allosteric inhibitors, but it’s only in the last year that we have really focused on their role in brain metastasis,” said Pendergast.
The most common breast cancer subtypes to spread to the brain are human epidermal growth factor receptor 2 positive (HER2+) and triple-negative breast cancer(including basal-like). Approximately 50 percent of late-stage patients with either of these subtypes have breast brain metastases. Triple-negative breast cancer represents about 15-20 percent of all breast cancer cases, while HER2+ breast cancer represents about 20 percent of all breast cancer cases.
Pendergast, with lab colleagues Jing Jin Gu, PhD (Senior Research Scientist), Jacob Hoj (graduate student), and Courtney McKernan (Graduate Student) recently found that a particular allosteric inhibitor of the ABL protein kinases crosses the blood-brain barrier in preclinical mouse models and markedly impairs the growth of brain metastasis by breast cancer cells.
“An ABL kinase allosteric inhibitor is currently in clinical trials for therapy-resistant leukemias,” said Pendergast. “These new findings suggest it could also be repurposed for breast cancer metastasis to the brain.”
This winter, Pendergast and her team was the recipient of one of two grants awarded by the new Duke Center for Brain and Spine Metastasis— each one in the amount of $50,000, with the possibility of an extension to $100,000 in the second year. The award was for her continued research identifying these potentially actionable signaling networks that promote breast cancer metastasis to the brain. Pendergast anticipates that this particular project will take at least another five years, so her team has recently applied for a five-year NIH grant to extend the research.
As the preclinical work in mouse models continues, the team will be looking at combination therapies and seeking to identify the precise mechanisms that allow tumors to not only cross the blood-brain barrier but successfully colonize the brain and acquire resistance to current therapies. They’ve already identified, in mice, several molecular targets that are important for brain metastasis.
“The next step is to perform CRISPR knockout (gene editing) and other techniques that eliminate these molecules and then evaluate if the cancer cells can no longer migrate, invade and/or survive in the brain microenvironment,” Pendergast explained. “We can do this in vivo (in mouse models) and in vitro (in the dish) using three dimensional cultures that use a mixed culture of tumor cells and cells that are isolated from the brain microenvironment to try and answer that question.”
Pendergast said she decided that the area where the most research is needed is in the area of brain metastasis by solid tumors such as breast.
“Currently we have developed mouse models, three dimensional cell culture systems, and molecular screens that will allow for important breakthroughs toward understanding the mechanisms of brain metastasis and lead to the development of effective therapies,” she said.
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