BETHESDA, Md.—Building off some earlier, promising research,a team of researchers at the National Cancer Institute (NCI) of the NationalInstitutes of Health have found that the drug vorinostat, a histone deactylaseinhibitor, may be able to cross the blood-brain barrier and stave off brainmetastases—something that may be particularly welcome news to breast cancer patients.
In the study, "Vorinostat Inhibits Brain MetastaticColonization in a Model of Triple-Negative Breast Cancer and Induces DNADouble-Strand Breaks," and published in late September in the journal ClinicalCancer Research, the researchers reportedthat in a mouse model, vorinostat is able to cross the blood-brain barrier andreduce the development of large metastatic tumors in mice brains by 62 percentwhen compared to mice that did not receive the drug.
Vorinostat is approved in the United States for use inhumans for the treatment of a cancer called cutaneous T-cell lymphoma, but ofcourse it can also be used experimentally to study its effectiveness againstother cancers. Where the NCI team wanted to focus its work was on breastcancer, because of its relation to brain cancer.
Therapies have improved significantly for breast cancer, theNCI researchers note, and thus survival rates of breast cancer patients have aswell. But at the same time, the incidence of breast cancer spreading to thebrain is on the rise.
This is troubling because brain metastases of breast cancerhave proven to be largely untreatable due to the inability of so many drugs topass the blood-brain barrier. As a result, the one-year survival estimate forbreast cancer patients after a diagnosis of brain metastasis is around 20percent.
Earlier research published by some of the very sameresearchers in June in Molecular Cancer Therapeutics showed that vorinostat could enhance the effect ofradiation therapy in mice with brain cancer metastasis. In that study, micethat received implants of human breast tumors in their brains lived the longestafter treatment with both vorinostat and radiation. This demonstrated,according to the researchers, that the drug enhances the sensitivity of cancercells to radiation therapy.
And thus the genesis of the latest study came about. Sinceit was known that vorinostat could slow the growth of primary tumors of varioustypes in mice—with strong suggestions from earlier research that the drug can betaken up by the brain—the researchers decided to find out more about itseffects on metastatic tumors.
Using a mouse model of human breast cancer, the NCI-led teamcultured human breast cells and injected them into mice with compromised immunesystems. The breast cancer cells then migrated to the brain, formingmetastases.
The researchers found that vorinostat was absorbed readilyinto normal mouse brains, and accumulation of the drug was up to three-foldhigher in some metastases treated with this drug when compared to surroundingbrain tissue.
"Brain metastases of breast cancer represent an increasingproblem, primarily concentrated in the triple-negative and HER-2–positivesubsets of patients," the NCI researchers wrote. "Vorinostat stands as a noveltype of drug, not included in the standard of care for breast cancer butexhibiting brain permeability and the ability to prevent the formation of brainmetastases in a preclinical model."
They admit that vorinostat has not shown significantsingle-agent activity against widely metastatic breast cancer, but note that itexhibited a favorable toxicity profile. In addition to staving off largemetastases, vorinostat also reduced the development of micrometastases in miceby 28 percent when compared with mice that did not receive this therapy.
"Drugs that can cross the blood-brain barrier and reduce thesize and incidence of metastatic tumors are urgently needed," says Dr. PatriciaS. Steeg of NCI's Center for Cancer Research, and one of the study authors.Looking at the earlier research, she adds: "Taken together with our currentfinding, researchers have now established a preclinical basis for testing thisdrug in clinical trials in humans."
The researchers believe they have linked the ability ofvorinostat to reduce metastatic lesions in the brain to a novel"double-barreled mechanism." That is, the drug can cause breaks in both strandsof a DNA helix and also can lower the activity of a DNA repair gene calledRad52. The researchers hypothesize that the inability of the cancer cells torepair DNA damage would then slow the rate of tumor cell metastasis.
