Johns Hopkins researchers report that an experimental drug that blocks a signaling pathway important in cancer development significantly slowed the growth of aggressive brain tumors in mice. The effect, moreover, persisted even after treatment was stopped, they say.
When scientists gave the drug, a gamma-secretase inhibitor called MRK003, to a group of mice with brain tumors, they observed “a modest but significant slowing of tumor growth week to week as well as prolonged survival,” says study director Charles Eberhart, M.D., Ph.D., professor of pathology, ophthalmology and oncology at the Johns Hopkins University School of Medicine. Cell samples taken from MRK003-treated tumors were less able to generate neurosphere clones and formed less aggressive secondary tumors in a new group of mice. Neurospheres are clusters of neural stem cells commonly associated with brain cancer.
MRK003 blocks a chemical pathway within stem cells called Notch, which scientists have shown is important for the growth of cancer-promoting stem cells.
The research, described in an article published online June 14 in the journal Clinical Cancer Research, suggests MRK003 and other gamma-secretase inhibitors hold promise in the treatment of humans with glioblastomas, which are among the most aggressive solid tumors in adults, Eberhart says. Most patients die within two years of diagnosis, and there are no widely effective treatments.
For the study, Eberhart and colleagues injected neurospheres coaxed from two glioblastoma cell lines into mice. The neurospheres developed into stem cells that formed tumors. Once tumors were detected with weekly brain scans, the investigators randomly assigned mice to receive MRK003 once a week by mouth for five to six weeks, or no treatment (the control group). Mouse brains were imaged each week to check the progress of tumor growth.
Tumors derived from a glioblastoma cell line not responsive to the standard chemotherapy drug temozolomide showed a 49 percent slower growth rate in mice treated with MRK003 than in the control animals. These mice survived an average six days longer from the start of treatment. In tumors derived from a second glioblastoma cell line responsive to temozolomide, tumor growth in mice treated with MRK003 was 62 percent slower than in controls, and the mice survived an average 12 days longer from the start of treatment.
In additional studies of the treated mice, researchers found that the drug was able to penetrate the brain and block Notch signaling. They measured this by looking for cellular levels of messenger RNA — a substance that mediates the transfer of genetic information when cells build proteins — in the family of genes in the Notch pathway. Tumors in all of the treated mice had 47 to 75 percent reductions the Notch-related gene called Hes5. Significant reductions also were seen in the Notch target genes Hes1 and Hey1 in some of the animals.
Unexpectedly, the investigators found that cells re-grown from MRK003-treated tumors had difficulty forming new neurosphere clones. When some of these lab-grown cells were later injected into a different group of mice, the resulting tumors grew slowly, suggesting that “Notch blockade can have prolonged effects on tumor biology,” Eberhart says. “The treatment had some sort of durable result that persisted for weeks or months after initial therapy stopped.”
Given the aggressive nature of glioblastoma, Eberhart cautions, “It is likely that this therapy will need to be combined with other treatments like chemotherapy or radiation to achieve long-term survival for patients.”
This drug and other Notch inhibitors currently are being tested in patients with advanced or metastatic solid tumors. They have also been evaluated as potential therapies for childhood leukemia.
The research was supported by the National Institutes of Health and the James S. McDonnell Foundation. Coauthors were Brent A. Orr, Samantha Semenkow and Eli E. Bar of Hopkins and Qian Chu of Huazhong University of Science and Technology in Wuhan, China, who received partial fellowship support from Merck.
Eberhart disclosed a patent licensed to Stemline Therapeutics and a commercial research grant from Merck. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.
Links:
Clinical Cancer Research: http://clincancerres.aacrjournals.org/cgi/content/abstract/1078-0432.CCR-12-2119