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Huntington’s Disease Provides Potentially Powerful New Cancer Weapon; Small Interfering RNAs (siRNAs) Based on Huntingtin Trinucleotide Repeats (TNRs) Are Highly Toxic to Cancer Cells

Patients with Huntington’s disease, a fatal genetic illness that causes the breakdown of nerve cells in the brain, have up to 80 percent less cancer than the general population. Northwestern Medicine scientists have discovered why Huntington’s is so toxic to cancer cells and have harnessed some of the disease’s characteristics for a novel approach to treat cancer, according to a new study published online on February 12, 2018 in EMBO Reports. The article is titled “Small Interfering RNAs Based on Huntingtin Trinucleotide Repeats Are Highly Toxic to Cancer Cells.” Huntington’s is caused by a prominent trinucleotide repeat (TNR) expansion in the numbers of the CAG triplets in the huntingtin (HTT) gene responsible, when mutated, for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions, including small interfering RNA (siRNA)‐sized repeat fragments. The HTT gene is present in every cell and the defect that causes the disease is also highly toxic to tumor cells. These siRNAs from the mutated huntingtin gene attack genes in the cell that are critical for survival. Nerve cells in the brain are vulnerable to this form of cell death, however, cancer cells appear to be much more susceptible. “This molecule is a super assassin against all tumor cells,” said senior author Marcus Peter, PhD, the Tom D. Spies Professor of Cancer Metabolism and of Medicine in the Division of Hematology and Oncology. “We’ve never seen anything this powerful against cancer cells.” The researchers showed that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the six members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR‐based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice.

To test the super assassin molecules in a treatment situation, Dr. Peter collaborated with C. Shad Thaxton, MD, PhD, Associate Professor of Urology, to deliver the molecules in nanoparticles to mice with human ovarian cancer. The treatment significantly reduced the tumor growth with no toxicity to the mice, Dr. Peter said. Importantly, the tumors did not develop resistance to this form of cancer treatment.

Dr. Peter and Dr. Thaxton are now refining the delivery method to increase its efficacy in reaching the tumor. The other challenge for the scientists is figuring out how to stabilize the nanoparticles, so they can be stored.

First and co-corresponding author Andrea Murmann, PhD, Research Assistant Professor of Medicine in the Division of Hematology and Oncology, also used the molecules to treat human and mouse ovarian, breast, prostate, liver, brain, lung, skin, and colon cancer cell lines. The siRNAs killed all cancer cells in both species.

The Huntington’s cancer weapon was discovered by Dr. Murmann, who had worked with Dr. Peter on previous studies ( that identified an ancient kill-switch present in all cells that destroys 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,” Dr. Murmann said. “These patients would not only have a disease with an RNA component, but they also had to have less cancer.”

She started searching for diseases that have a lower rate of cancer and had a suspected contribution of RNA to disease pathology. Huntington’s was the most prominent.

When she looked at the repeating sequences in huntingtin, the gene that causes the disease, she saw a similar composition to the earlier kill switch that Dr. Peter had found. Both were rich in the C and G nucleotides (molecules that form the building blocks of DNA and RNA).

“Toxicity goes together with C and G richness,” Dr. Murmann said. “Those similarities triggered our curiosity.”

In the case of people who have Huntington’s, the gene huntingtin has too many repeating sequences of the triplet sequence CAG. The longer the repeating sequence, the earlier they will develop the disease.

“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,” Dr. 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.
Every child of a parent with Huntington’s has 50/50 chance of carrying the faulty gene. Today there are approximately 30,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease.

This article is based on a Northwestern release authored by Marla Paul, who is the health sciences editor for Northwestern University Media Relations. Ms. Paul is a veteran journalist, formerly a staff writer at the Chicago Sun-Times, and her writing has appeared in the Chicago Tribune and many national publications (


Famous American folk singer Woody Guthrie died of Huntington’s disease at the age of 55.

[Press release] [EMBO abstract]