Researchers from the Kimmel Cancer Center at Johns Hopkins found that the combination of the experimental anticancer drug TAK228 (also called samanizertibom) with an existing anticancer drug (trametinibom) can be effective in reducing the growth of pediatric gliomas, low-grade, as compared with any other drug.
Low-grade gliomas are the most common childhood brain cancer. These tumors arise from the glial cells of the brain, which support and nourish neurons. Modern methods of chemotherapy used to treat the disease, although prolong life, often carry side effects or are not tolerated in children. Approximately 50% of children receiving standard treatment, the tumors grow again, pointing to the need to develop better targeted treatment.
A new study showed that the combination therapy to be tested on the glioma cell lines collected from sick children, stops the growth of tumor cells. Scientists have reported that the combination of drugs reduced tumor volume in mice and prolong the life of rodents. In experimental animals receiving experimental treatment significantly decreased blood flow to tumors. The researchers suggested that the therapy may result in a "starvation" of tumors and, as a result, limit their growth.
The study was published in «Neuro-Oncology».
Previous studies have shown that low-grade gliomas in children include gene mutations that increase the activity of two cell signaling pathways: mTORC1 / 2 and MAPK. Both ways help proteins that promote cell growth. TAK228, being tested in clinical trials of adult patients with cancer, inhibits the mTOR. Trametinib approved for the treatment of melanoma, it inhibits the MAPK. According to the researchers, using drugs, targeting only one way, cancer cells found opportunities to use the second way.
In the new study, researchers tested the TAK228 and trametinib cells in low-grade gliomas obtained from children with cancer and grown in the laboratory. Combining the two drugs resulted in a reduction of growth by 50% The novel therapy inhibited the activity of more than 50% in the mTOR signaling pathway and MAPK and reduced cell proliferation by more than 90%. The combination of drugs killed three times more cancer cells than to destroy each medication separately.
Then researchers began treatment of mice implanted with glioma tumors of low malignancy grade using TAK228, trametiniba, a combination of two drugs or placebo combination. The term of life of the animals treated with a combination of drugs was three times greater than that of animals treated with one drug (36 days vs. 12 days). When using the new therapy tumors were 50% less after a two-week treatment period as compared to monotherapy. Combination therapy in animal models has led to the suppression of mTOR and MAPK pathways by more than 80%. The number of growing cells in these tumors decreased by more than 60%. The blood supply of tumors was reduced by 50-95%.
Scientists said that it is necessary to spend more pre-clinical studies to determine the best and safest drug dosage regimen, partly because trametinib remains in the body for four to five days, but the way of the MAPK, which it aims, needs healthy cells for normal growth in children.