November 7, 2013
Genetic Pathway Could Be New Target For Pediatric Tumor Treatment
redOrbit Staff & Wire Reports - Your Universe Online
Low-grade gliomas – a type of pediatric brain tumor that is difficult to care for medically – could potentially be treated using a known genetic pathway, according to new research published in Thursday’s edition of the journal Neuro-Oncology.In laboratory studies, Dr. Fausto Rodriguez, assistant professor of pathology and oncology at Johns Hopkins, and colleagues reported that the mammalian target of the rapamycin (mTOR) pathway was highly active in pediatric low-grade gliomas, and that blocking that pathway using an experimental drug could decrease the growth of those tumors.
“We think mTOR could function as an Achilles heel. It drives cancer growth, but when mTOR is inhibited, the tumor falls apart,” explained study co-author Dr. Eric Raabe, an assistant professor of pediatrics, oncology and pathology at the Johns Hopkins Kimmel Cancer Center. “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 added that brain tumors affect over 4,000 American children each year, and are also the leading cause of cancer-related deaths among people under the age of 18. Low-grade gliomas are the most common type of tumors found in the central nervous systems of youngsters and current treatments for the condition include surgery and chemotherapy – a toxic process that often comes with severe side effects, explained the team.
Furthermore, many low-grade gliomas are located in areas where they cannot be easily removed, such as the optic pathway. Removing tumors located there can lead to loss of vision and preface even blindness, and Raabe also reports that some patients have suffered learning disabilities or paralysis following treatment or tumor removal.
As part of their study, Rodriguez and his colleagues analyzed tissue samples from 177 pediatric low-grade gliomas from patients treated at Johns Hopkins and other medical facilities. They also used an experimental medication known as MK8669 (ridaforolimus) to block mTOR in a pair of pediatric low-grade glioma cell lines.
The mTOR pathway has been found to be active in several different types of cancers, and drugs that block proteins in that pathway (like MK8669) are readily available, the researchers said. mTOR signals through mTORC1 and mTORC2, two protein complexes that lead to increased cell growth and survival.
According to Rodriguez, his team found activity in the mTORC1 pathway in 90 percent of all low-grade gliomas studied, and 81 percent of those tumors demonstrated activity of both mTORC1 and mTORC2.
Components of the mTOR pathway were more commonly found in tumors in the optic pathways compared to those found in other parts of the brain, the researchers added. Furthermore, they found that the mTOR-blocking drug caused a more than 70 percent reduction in cell growth over six days in one cell line, and up to a 21 percent decrease in cell growth over a four-day period in a second cell line.
“Since the pathways are more active in some areas of the brain, compared with others, it suggests that the outcomes of drug treatments targeting those pathways may differ as well,” Rodriguez said. He and Raabe now plan to build upon the research in animal models and test additional inhibitors.