Working with cells taken from children with a very rare but aggressive form of brain cancer, Johns Hopkins Kimmel Cancer Center scientists have identified a genetic pathway that acts as a master regulator of thousands of genes, and may spur cancer cell growth and resistance to anticancer treatment. Their work was published in Oncotarget and the Journal of Neuropathology and Experimental Neurology.
Their experiments with cells from patients with atypical teratoid/rhabdoid tumor 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 led by Eric Raabe, MD, PhD, Assistant Professor of Oncology at the Johns Hopkins University School of Medicine.
Genetic Variations in Atypical Teratoid/Rhabdoid Tumors
Atypical teratoid/rhabdoid tumor mostly strikes children aged 6 and younger, and the survival rate is less than 50%, even with aggressive surgery, radiation, and chemotherapy. Atypical teratoid/rhabdoid tumor 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, representing 10% of all brain tumors in infants.
“What’s exciting about this study is that it identifies new ways we can treat atypical teratoid/rhabdoid tumor with experimental drugs already being tested in pediatric patients,” said Dr. Raabe. Because few outright genetic mutations—and potential drug targets—have been linked to atypical teratoid/rhabdoid tumor, Dr. Raabe and colleagues turned their attention to genes that could regulate thousands of other genes in atypical teratoid/rhabdoid tumor cells. Experiments in fruit flies had already suggested a gene known as LIN28 could be important in regulating other genes involved in the development of brain tumors. Specifically, the LIN28 protein helps regulate thousands of RNA molecules in normal stem cells, giving them the ability to grow, proliferate, and resist damage.
“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 Dr. Raabe. “These proteins also help stem cells move around the body, an advantage cancer cells need to metastasize.”
Blocking LIN28A and HMGA2 Improves Survival in Mice
In a report on one of their studies, published by Weingart et al in Oncotarget, the researchers examined cell lines derived from pediatric atypical teratoid/rhabdoid tumor patients and the tumors themselves. They found that the two members of the LIN28 family of genes were highly expressed in 78% of the samples.
Researchers then blocked LIN28 expression with specially targeted gene silencers—called short hairpin RNAs—which curbed the tumor cells’ growth and proliferation, and triggered cell death. When Dr. Raabe and colleagues blocked LIN28A in atypical teratoid/rhabdoid tumor cells transplanted into mice, they were able to more than double the mice’s life span, from 48 to 115 days.
Using selumetinib in cell line experiments, the scientists cut atypical teratoid/rhabdoid tumor cell proliferation in half and quadrupled the rate of cell death in some cell lines. Dr. Raabe says the drug appeared to be disrupting a key molecular pathway controlled by LIN28.
In a second study, published by Kaur et al in the Journal of Neuropathology and Experimental Neurology, the investigators examined another factor in the LIN28 pathway, called HMGA2, which is also highly expressed in atypical teratoid/rhabdoid tumor tumors. They again used short pieces of RNA to “silence” HMGA2, which led to lower levels of cell growth and proliferation, and increased cell death. Blocking HMGA2 also doubled the survival rate of mice implanted with tumors derived from pediatric atypical teratoid/rhabdoid tumor cell lines, from 58 to 153 days.
Dr. Raabe said his team's work with LIN28 and HMGA2 should not only lead to understanding why cancers like atypical teratoid/rhabdoid tumor are so aggressive, but “also identify their Achilles' heels. We have shown that if we target these key proteins downstream of LIN28 in atypical teratoid/rhabdoid tumor, the tumors unravel.”
Dr. Raabe is the corresponding author for the Oncotarget and Journal of Neuropathology and Experimental Neurology articles.
These studies were supported by Alex's Lemonade Stand Foundation, the National Institutes of Health's National Cancer Institute, the National Institutes of Health, and the St. Baldrick's Foundation. Some cell lines used in the study were generated with financial support from Grayson's Gift and the Michael Hoefflin Foundation.
For full author disclosures, please visit www.impactjournals.com/oncotarget and journals.lww.com/jneuropath/pages/default.aspx.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.