Gene regulatory path revealed as target for therapy of aggressive pediatric brain cancer
Working with cells taken from children with a very rare but ferocious form of brain cancer, scientists have identified a genetic pathway that acts as a master regulator of thousands of other genes and may spur cancer cell growth and resistance to anticancer treatment.
Their experiments with cells from patients with atypical teratoid/rhabdoid tumor (AT/RT) also found that selumetinib, an experimental anticancer drug currently in clinical trials for other childhood brain cancers, can disrupt part of the molecular pathway regulated by one of these factors, according to a research team at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. They were led by Eric Raabe, MD, PhD, an assistant professor of oncology at the Johns Hopkins.
AT/RT mostly strikes children 6 years and younger, and the survival rate is less than 50% even with aggressive surgery, radiation, and chemotherapy. These treatments can also disrupt thinking, learning, and growth. AT/RT accounts for 1% of more than 4,500 reported pediatric brain tumors in the United States, but it is more common in very young children, and it represents 10% of all brain tumors in infants.
"What's exciting about this study is that it identifies new ways we can treat AT/RT with experimental drugs already being tested in pediatric patients," Raabe said.
Because few outright genetic mutations and potential drug targets have been linked to AT/RT, Raabe and his colleagues turned their attention to genes that could regulate thousands of other genes in AT/RT cancer cells and specifically LIN28.
"These factors provide stem cells with characteristics that cancer cells also have, such as resistance to environmental insults. These help tumor cells survive chemotherapy and radiation," said Raabe. "These proteins also help stem cells move around the body, an advantage cancer cells need to metastasize."
One report, published in Oncotarget (2014;6(5):3165-3177), described cell lines derived from pediatric AT/RT patients and the tumors themselves. Two members of the LIN28 family of genes were highly expressed in 78% of the samples. By blocking LIN28 expression with specially targeted gene silencers called short hairpin RNAs, the researchers curbed the tumor cells' growth and proliferation and triggered cell death.
When Raabe and colleagues blocked LIN28A in AT/RT tumor cells transplanted into mice, the mice's life span more than doubled, from 48 to 115 days.
Using selumetinib in cell line experiments, the scientists cut AT/RT tumor cell proliferation in half and quadrupled the rate of cell death in some cell lines. Raabe said the drug appeared to be disrupting a key molecular pathway controlled by LIN28.
In a second study, described in the Journal of Neuropathology and Experimental Neurology (2015; doi:10.1097/NEN.0000000000000161), Raabe and his colleagues examined another factor in the LIN28 pathway, called HMGA2, which is also highly expressed in AT/RT tumors. They again used short pieces of RNA to silence HMGA2, which led to lower levels of cell growth and proliferation, increased cell death, and doubled the survival rate of mice with implanted tumors.
Raabe said his team's work with LIN28 and HMGA2 both help understand why cancers like AT/RT are so aggressive, and "also identify their Achilles' heels. We have shown that if we target these key proteins downstream of LIN28 in AT/RT, the tumors unravel."