Why is Cancer Uncommon in Huntington's Disease Patients?

Recent findings have revealed why patients with Huntington’s disease (HD) have up to 80% less cancer than the general population, and could lead to a novel approach for cancer treatment.

Results from a study recently published in the journal EMBO Reports found that the mutated huntingtin (HTT) gene in patients with HD generates a class of small molecules that are highly toxic to cancer cells, but not healthy cells.¹

The study, “Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells,” was led by Marcus Peter, PhD, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine.

“This molecule is a super assassin against all tumor cells,” he said in a press release. “We’ve never seen anything this powerful.”²

While the HTT gene is present in every cell of the human body, the gene carries a mutation in patients with HD, leading to an excess of a 3-nucleotide sequence known as CAG. Healthy people have between 10 and 35 CAG repeats in their HTT genes, but those with HD can have anywhere from 36 to more than 120. That defect, the underlying cause of the disease, is highly toxic to tumor cells, and the repeating sequences affect cells by inducing the formation of small interfering RNA (siRNA) molecules, and attack genes that are necessary for survival. While nerve cells in the brain are vulnerable to this form of cell death, cancer cells appear to be much more susceptible.

Peter collaborated with Colby Shad Thaxton, MD, PhD, also of the Feinberg School of Medicine, and, together, the two used nanoparticles to deliver an siRNA into mice models of human ovarian cancer to test the molecules’ potential against cancer cells. Nanoparticles were injected 5 times a week for 2 weeks, with half of the models receiving treatment for an additional week. It was observed that treatment significantly reduced overall tumor growth, even in large tumors — which are typically more impervious to treatment – attesting to their predisposition to siRNA molecules.

Additionally, it was seen that the nanoparticles slowed tumor growth without inducing toxic side effects in the mice, and that tumor cells did not become resistant to the treatment over time.

Peter and Dr Thaxton are currently working to refine the delivery method of the nanoparticles, with the hope of increasing the efficacy of reaching the tumor. A secondary challenge for the pair is finding a way to stabilize the nanoparticles so that they can be stored.

First and co-corresponding author Andrea Murmann, research assistant professor in medicine at Feinberg, also found that the molecule successfully killed cancer cell lines in human and mouse models of ovarian, breast, prostate, liver, brain, lung, skin, and colon 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," Murmann said. "These patients would not only have a disease with an RNA component, but they also had to have less cancer."

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References:

1. Peter M, Thaxton CS, Murmann A. Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells. Embo Reports. (2018) e45336. http://embor.embopress.org/content/early/2018/02/07/embr.201745336. Accessed March 30, 2018.
2. Huntington’s disease provides new cancer weapon [news release]. Chicago, IL. Northwestern University; February 12, 2018. https://www.eurekalert.org/pub_releases/2018-02/nu-hdp020818.php. Accessed March 30, 2018.