Harnessing Huntington’s Disease to fight cancer

A collaboration between Simpson Querrey Institute resident faculty member C. Shad Thaxton, MD, PhD, associate professor of urology, and Marcus Peter, PhD, the Tom D. Spies Professor of Cancer Metabolism at the Feinberg School of Medicine, has led to a potentially new approach to treat cancer. Together, Thaxton and Peter were intrigued by the question of why individuals with Huntington's disease have significantly lower rates of cancer than the general population, and whether or not the mechanism which protects them could be used to prevent and treat cancer in patients without Huntington's.

"Huntington's disease is one of many neurodegenerative diseases caused by trinucleotide-specifically CAG-repeats in the human genome," Thaxton explained. "In Huntington's disease, it has been shown that the longer the CAG repeat in the huntingtin gene, the lower the cancer risk in the individual. It turns out that these repeat sequences in the genome are leading to the production of short RNAs that may be therapeutic for cancer."

By identifying specific siRNA sequences based upon the CAG repeat sequences, the Peter lab was able to demonstrate that these short RNA duplexes can be used to potently induce cancer cell death.

Delivering RNAs in in vivo studies is challenging, and this is where expertise developed in the Thaxton lab was required. "Marcus needed a group with experience in formulating and stabilizing these nucleic acids so they could be delivered in an in vivo study. So, we teamed up. We had collaborated with Marcus before on a similar project, using the templated lipoprotein nanoparticle platform that my group developed to deliver siRNAs in an ovarian cancer disease model. In that case, the particles worked very nicely in both in vitro and in vivo studies, and so he came to us again to ask if we could formulate these new CAG repeat sequences in our targeted, nanoparticle form."

In vivo studies using the siRNA sequences identified by the Peter lab-again using an ovarian cancer model-proved successful in the treatment of cancer in mice. In addition to reducing tumor growth, there were no measured toxic side effects of the treatment. Findings from the study were published on February 12 in EMBO Reports.

Speculating about the future impact of the collaboration and the research, Thaxton noted there are several other collaborators with whom the lab is currently working on similar projects, and many others that have approached the group about testing other therapeutic RNAs as a result of the work with the Peter lab. Collaborative work of this kind allows the Thaxton Lab to continue to refine and perfect systemic siRNA delivery strategies based upon the templated lipoprotein nanoparticle platform. Thaxton said, "Long term, it might bring in new resources so that we can continue to improve upon our current strategies and to develop new platforms and technologies for delivering therapeutic nucleic acids."

Thaxton's laboratory is located at the Simpson Querrey Institute for BioNanotechnology.