A promising new drug combination for a common brain tumor in children

A new combination therapy targeting resistant and recurrent low-grade gliomas slowed tumor growth and killed tumor cells in laboratory and mouse models.

Researchers at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins University School of Medicine have combined carboplatin, a standard chemotherapy drug that works effectively against these brain tumors, and everolimus, which blocks an enzyme called mTOR, which in previous research had the effect of stimulating the growth of these tumors. The combination increases the damage to DNA and cell death in laboratory models. Their conclusions were published in the February 14, 2019 issue Neuro-Oncology.

Low grade glioma in children is the most common brain tumor in children and can often be treated by surgery alone. However, some patients have tumors in places that make surgery too risky, such as near the optic nerves or in the mid-cerebral region, or have their tumors that grow back after surgery.

Eric Raabe, MD, Ph.D., badociate professor of oncology and brain tumor specialist at Johns Hopkins' Kimmel Cancer Center, explains that tumors recur in approximately 50% of patients treated for a glioma of low grade and require additional treatment by chemotherapy. Recurrent tumors are often resistant to chemotherapy. The researchers wondered if the combination of carboplatin and everolimus would be more effective.

When treated with carboplatin alone, four different human cell lines from low grade glioma cancer cells either failed to respond to the drug or continued to grow. Similarly, some cell lines were resistant to everolimus alone.

When they treated the same cell lines with a combination of carboplatin and everolimus, the cells either died or developed slower, and the researchers found similar results in murine models without additional toxicity. .

"We found a dramatic inhibition of growth after the badociation of a low concentration of everolimus with carboplatin," says Raabe. "We found that everolimus disrupted a key mechanism used by cancer cells to detoxify carboplatin.The ability of everolimus to increase the potency of carboplatin suggests that this combination could be used effectively in patients. "

In a previous clinical study conducted in 2014, Raabe and other researchers were able to confirm the safety of the mTOR blocking everololus in patients with low grade glioma. in the child and discovered that some patients were responding to the drug. However, they have never tested the tumor tissue of these patients to understand the molecular role of mTOR.

"The current national clinical study on everolimus in low-grade gliomas in children requires that the tumor tissue of each patient be evaluated for the expression of mTOR markers likely to predict the outcome." response to everolimus, "said Raabe. "In this way, we hope to find out who is most likely to react to the drug in order to get closer to our goal of giving the right medicine to the right patient at the right time.In the future, we may be able to give # 39; everolimus with carboplatin to patients with high expression of mTOR. According to our research, we predict that these tumors will probably be resistant to carboplatin unless we simultaneously block mTOR. "

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Provided by
Faculty of Medicine, Johns Hopkins University