Dr. Weeks’ Comment: Cancer STEM cells need to be addressed and remedied if we are to gruel help people with cancer. Kids ought not be allowed to hold cell phones up to their heads and ought not to be exposed to other electrically polluting devices. However, once they get brain cancer, focus on the cancer STEM cells.
Gene regulatory path revealed as target for therapy of aggressive pediatric brain cancer
AT/RT mostly strikes children 6 and younger, and the survival rate is less than 50 percent even with aggressive surgery, radiation and chemotherapy, treatments that can also disrupt thinking, learning and growth. AT/RT accounts for 1 percent of more than 4,500 reported pediatric brain tumors in the U.S., but it is more common in very young children, and it represents 10 percent 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 says. 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. 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,” says Raabe. “These proteins also help stem cells move around the body, an advantage cancer cells need to metastasize.”
In a report on one of their studies, published Dec. 26 in the journal Oncotarget, the researchers examined cell lines derived from pediatric AT/RT patients and the tumors themselves. They found that the two members of the LIN28 family of genes were highly expressed in 78 percent of the samples, and that blocking LIN28 expression with specially targeted gene silencers called short hairpin RNAs 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, 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 AT/RT tumor cell proliferation in half and quadrupled the rate of cell death in some cell lines. Raabe says 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, 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 and increased cell death. Blocking HMGA2 also doubled the survival rate of mice implanted with tumors derived from pediatric AT/RT cell lines from 58 to 153 days.
Raabe says his team’s work with LIN28 and HMGA2 should not only lead to understanding why cancers like AT/RT are so aggressive, but “also identify their Achilles’ heels. We have shown that if we target these key proteins downstream of LIN28 in AT/RT, the tumors unravel.”
Explore further: Cell signaling pathway goes awry in common pediatric brain tumor
selumetinib
An orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK or MAPK/ERK kinase) 1 and 2. MEK 1 and 2 are dual-specificity kinases that are essential mediators in the activation of the RAS/RAF/MEK/ERK pathway, are often upregulated in various cancer cells, and are drivers of diverse cellular responses, including proliferation. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)