Targeting the mTOR pathway could treat pediatric gliomas
A known genetic pathway is active in many difficult-to-treat pediatric brain tumors known as low-grade gliomas. This finding offers a potential new target for the treatment of these cancers.
In laboratory studies, researchers found that the pathway, called mammalian target of rapamycin (mTOR), was highly active in pediatric low-grade gliomas, and that mTOR activity could be blocked using an experimental drug, leading to decreased growth of these tumors. Their findings were published in Neuro-Oncology (2013; doi:10.1093/neuonc/not132).
“We think mTOR could function as an Achilles heel,” said study coauthor Eric Raabe, MD, PhD, an assistant professor of pediatrics, oncology, and pathology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. “It drives cancer growth, but when mTOR is inhibited, the tumor falls apart.”
Overall, brain tumors affect more than 4,000 children each year in the United States, and they are the leading cause of cancer deaths in children, according to Raabe. Low-grade gliomas are the most common group of tumors of the central nervous system in children. Current treatments for these tumors include surgery and chemotherapy, which often cause significant side effects.
Many of these tumors are located in areas like the optic pathway, where they cannot be easily removed by surgery without causing damage, including blindness. In addition to vision loss, some of Raabe's patients have endured paralysis or learning problems as a result of the tumor or treatment. “Even though these tumors are considered ‘low-grade' and not particularly aggressive, many patients suffer severe, life-altering symptoms, so we desperately need better therapies,” he said.
The Johns Hopkins investigators studied tissue samples from 177 pediatric low-grade gliomas, including the most common type—tumors called pilocytic astrocytomas—from patients treated at Johns Hopkins and other centers. They also tested the effect of blocking mTOR with an investigational agent known as MK8669 (ridaforolimus) in two pediatric low-grade glioma cell lines.
The mTOR pathway has been shown to be active in a variety of cancers, and drugs that block proteins in the pathway, such as rapamycin, are widely available. The pathway signals through two protein complexes, mTORC1 and mTORC2, which lead to increased cell growth and survival.
The researchers found activity of the mTORC1 pathway in 90% of low-grade gliomas studied, and 81% of tumors showed activity of both mTORC1 and mTORC2. Components of the mTOR pathway were more commonly found in tumors from optic pathways compared with those from other areas of the brain, according to senior study author Fausto Rodriguez, MD, assistant professor of pathology and oncology at Johns Hopkins.