Scientists Harness Super Toxic siRNAs from Huntington’s for Cancer Treat.
Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington’s disease (HD). This extreme repetition and expansion module is prominent in patients of Huntington’s and now, scientists at the Northwestern University have identified a new class of related molecules that are about 100 times more toxic to cancer cells than the previously described ones- siRNAs- which occur naturally in patients with certain neurological diseases including Huntington’s disease.
These siRNAs, the scientists find, are generated from the TNR regions including small siRNA‐sized repeat fragments.
Previous research by the team yielded results that suggested these siRNA molecules were amazing cancer-killing assassins that evolved in living organisms millions of years ago to fight cancer before the more complex adaptive immune system developed. This research inspired the team to investigate whether there were diseases involving similar RNA mechanisms that also correspond with lower rates of cancer.
“I thought maybe there is a situation where this kill switch is overactive in certain people, and where it could cause loss of tissues,” says first author on the study Andrea Murmann. “These patients would not only have a disease with an RNA component, but they also had to have less cancer.”
In the current study, in order to test out these “super assassins”, the researchers delivered the molecule in nanoparticles to mice with human ovarian cancer. The treatment significantly reduced the tumor growth with no toxicity to the mice. More importantly, the tumors did not develop resistance to this form of cancer treatment.
“This molecule is a super assassin against all tumor cells,” said senior author Marcus Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine. “We’ve never seen anything this powerful.”
Additionally, the research team used the siRNA molecule to treat human and mouse ovarian, breast, prostate, liver, brain, lung, skin, and colon cancer cell lines. They found that the molecule killed all cancer cells in both species. Previous work from members of this research team had identified an ancient kill switch present in all cells that destroy cancer—which they thought might underlie the current data.
“We believe a short-term treatment cancer therapy for a few weeks might be possible, where we could treat a patient to kill the cancer cells without causing the neurological issues that Huntington’s patients suffer from,” Peter said. Huntington’s patients have a lifetime exposure to these toxic RNA sequences, but generally don’t develop symptoms of the disease until age 40, he noted.
