Novel approach shows ‘promising’ potential to prevent brain metastases
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Key takeaways:
- Researchers identified a new approach that may help prevent cancer from metastasizing to the brain.
- The approach could serve as the basis for molecular-targeted therapies for brain metastases.
A novel therapeutic approach could intercept rogue cancer cells before they develop into brain metastases, according to study findings.
The enzyme inosine monophosphate dehydrogenase (IMPDH) is “critical to the survival of these brain metastasis cells” and could be used as a target for future drug development, Sheila K. Singh, MD, PhD, pediatric neurosurgeon at McMaster Children’s Hospital, and professor of surgery and director the Centre for Discovery in Cancer Research at McMaster University, in Ontario, Canada, told Healio.
“There are no molecular-targeted therapies [for brain metastases],” Singh said. “We’ve just discovered the basis for one.”
‘A special, unique signature’
Brain metastases occur 10 times more often than primary brain cancer, and 90% of individuals diagnosed with a brain metastasis die within 4 to 12 months, according to study background.
Standard-of-care surgical resection and radiation therapy are palliative in nature.
“This is a problem that doesn’t have a good solution right now,” Singh said.
Singh and colleagues have been investigating brain metastases in her lab since 2007.
They previously published research that showed certain cells — which they called brain metastasis-initiating cells — drive brain metastases.
Then they used human cells in animal models — patient-derived xenograft models — to evaluate the “metastatic cascade,” detailing how cells break free of primary cancers and develop into brain metastases.
They used a green fluorescent protein to track human metastases in mice and captured them as soon as they crossed the blood-brain barrier.
“We sequenced them and discovered this new signature — we called it the pre-metastatic signature,” Singh said. “The pre-metastatic signature is a special, unique signature that the cells only take on as they’re in that stage where they’re first invading the brain.
“We found that there is a universal, pre-metastatic signature across all cancers,” Singh added. “Our rationale became, what if we could treat the cells and kill them before they get into the brain.”
‘Promising’ results
The Broad Institute of MIT and Harvard developed the Connectivity Map, described on its website as a “comprehensive catalog of cellular signatures.” Researchers can use it to determine if any approved drugs could affect specific genes.
Singh and colleagues ran their signature through the Connectivity Map, which showed 380 drugs that could affect at least one of 3,951 deregulated genes in melanoma, lung and breast cancer. These cancers account for 85% of primary malignancies that metastasize to the brain.
They tested those drugs on mice and found mycophenolic acid, an immunosuppressant used to prevent organ rejection following kidney transplants, could block the brain metastasis pathway.
“Seven percent of human cells got into the brain at that pre-metastatic state,” Singh said. “When we pretreat with mycophenolic acid, it goes down to almost zero. We’re really blocking that spread.”
Further investigations found mycophenolic acid inhibits “de novo purine synthesis through IMDPH inhibition,” Singh said.
“It increases the survivorship [of mice] by 1.5 to 2 times,” she added. “It doesn’t increase their survivorship indefinitely, but the reduction in brain metastases is 60% to 80%.”
However, they could not use a high enough dose to cure due to toxicities. Also, mycophenolic acid has poor blood-brain barrier penetration.
“That’s why these results are really promising because, given all those limitations, it still showed a huge reduction in brain metastases, and it’s still reducing the pre-metastatic cells from getting in,” Singh said.
Therapeutic window
Mycophenolic acid could be used to prevent the development of brain metastases now, but researchers acknowledge the drug leads to toxicities and adverse effects.
“The question we’re asking is: Can we develop a better version of mycophenolic acid that somehow could selectively target IMPDH in the cancer cells and not so much in the normal cells?” Singh said. “That’s our new challenge.”
The therapeutic window could exist because metastatic cells require significantly more energy than normal cells.
“Normal cells are just kind of doing their daily functions,” Singh said. “They’re not actively proliferating. They’re in a steady state.”
Singh and colleagues already have evaluated more than 500 molecules that could be used to target IMPDH, according to a press release.
“We’ve made lots of advances,” Singh said. “We are making compounds that are blood-brain barrier penetrant now. We still have quite a few lead compounds to work our way through before we find the perfect one, and then that’s the one we'll advance into clinical trials.”
The group already has designed clinical trials for lung cancer.
“We’ve already spoken to all of the world’s leading lung cancer experts to say, ‘What would cause you to allow us to treat your [patients with lung cancer] with this drug?’” Singh said. “We’re interviewing the key opinion leaders in the field. The most important thing is we’ve started a biomarker campaign. We have to figure out how to define the patient population that are at high risk for getting brain metastases after they’ve finished their treatment for their lung cancer.”
Singh and colleagues previously published data on two potential biomarkers they could use for lung cancer — SPOCK1 and TWIST2.
“Those are two genes that are involved in a developmental process that’s hijacked by cancer cells called epithelial mesenchymal transition,” Singh said. “That makes sense because that’s the process that cells undergo to become migratory.”
Singh said she hopes they will have begun clinical trials within 5 years.
“I’m hoping that we will develop therapies that are more helpful than anything that’s being used to treat these patients right now, because they face a very grim prognosis,” she said. “This is an area of high unmet need and we’re very happy to be working in it.”
References:
- Broad Institute. Connectivity Map (CMAP). Available at https://www.broadinstitute.org/connectivity-map-cmap. Accessed Oct. 29, 2024.
- Kieliszek AM, et al. Cell Rep Med. 2024;doi:10.1016/j.xcrm.2024.101755.
- McMaster chemists and neurobiologists team up to tackle cancer that spreads to the brain (press release). Available at https://brighterworld.mcmaster.ca/articles/mcmaster-chemists-and-neurobiologists-team-up-to-tackle-cancer-that-spreads-to-the-brain/. Published Oct. 4, 2024. Accessed Oct. 29, 2024.
For more information:
Sheila K. Singh, MD, PhD, can be reached at ssingh@mcmaster.ca.
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