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Insights into Huntington’s disease gene may lead to novel cancer therapies
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Northwestern University researchers may have discovered why patients with Huntington’s disease have up to 80% less cancer than the general population.
If confirmed, these insights may help lay the foundation for novel oncology treatment approaches.
Patients with Huntington’s disease have an overabundance of a certain type of repeating RNA sequences in the huntingtin gene.
These repeating sequences — in the form of small, interfering RNAs — attack genes in the cancer cell that are critical for cell survival, according to background information provided by the researchers.
“This molecule is a ‘super assassin’ against all tumor cells,” Marcus E. Peter, PhD, the Tom D. Spies professor of cancer metabolism at Northwestern University Feinberg School of Medicine and leader of the translational research in solid tumors program at Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said in a press release. “We have never seen anything this powerful.”
HemOnc Today spoke with Peter about this discovery, why the huntingtin gene is so toxic to cancer, how this information could be used to develop effective treatments, and the direction future research efforts should take.
Question: What led you to this discovery?
Answer: For the past decade, we have been pursuing a novel mechanism that we believe evolution has developed and installed in every one of our cells to fight cancer cells the moment they arise. We recently stumbled across something that fits this expectation. It is based upon a molecular engine in the cell that has been known for a while but has not been implicated in this activity that we have now assigned to it. Information is developed and stored in our body in the form of DNA, and DNA then gives rise to proteins that execute multiple functions of a cell. In between proteins and the DNA is another class dubbed RNA. There is a particular function of RNA in addition to its function of basically translating the information in the genome into proteins. RNAs that do not give rise to proteins and have a different purpose in the cell are known as noncoding RNAs. One of the activities of these noncoding RNAs is to suppress gene expression of the other RNAs that do give rise to proteins. These small RNA molecules are expressed in a cell, target the other RNAs and suppress the production of proteins, thereby providing the means of negative regulatory mechanisms to prevent certain proteins from being expressed. Having said all of this, now we get to the components in Huntington’s disease that we have identified.
Q: Why is the huntingtin gene so toxic to cancer?
A: It turns out that this negative activity of certain noncoding RNAs is very effective at killing cancer cells. We believe this is because these RNAs engage or target many RNAs in the cell that every cell needs for survival, including cancer cells. We believe that nature itself developed a mechanism to kill a cell based upon the expression of certain noncoding RNAs that then target hundreds of ‘survival genes’ simultaneously, thereby causing the death of the cell. A cancer cell has no way to become resistant to this effect. This is consistent with the mechanism that we postulated, and we believe we now have evidence that this is built into every cell. It allows a cell to induce these toxic, small, noncoding RNAs to commit suicide in a way that cancer cells can never become resistant to. The gene that is mutated in Huntington’s disease contains a special kind of repeat sequences that are known to cause the disease. There is evidence that these long repeat sequences are converted in the cells to small RNAs that, just like noncoding RNAs, suppress expression of certain genes. This may contribute to the disease pathology in these patients. However, it also engages the mechanism that kills cancer cells, explaining why patients with Huntington’s disease have reduced cancer incidence. We have synthesized small RNAs based on Huntington’s repeat sequences and found them to be significantly toxic to all cancer cells.
Q: How can this information be used to develop new, effective treatments?
A: When we delivered these repeat-based RNAs in a preclinical mouse model of ovarian cancer using nanoparticles, the tumors shrunk and there was no toxicity in the treated mice. We believe for a number of reasons that normal cells are protected from this mechanism that may have been created to fight cancer cells. Now that we know the structure and sequence of these small RNAs, there are multiple steps that need to be taken to optimize and test this. The important question now is whether this will cause toxicity in humans.
Q: What is next for research?
A: There are multiple steps and enormous costs involved in research of this magnitude. We are at the very beginning of our research efforts and we are attacking this in multiple ways in hopes of being able to at least bring this information to a stage at which we can get a ‘yay or nay’ out of this and know if this going to work. There are multiple ways of testing this. We will continue to improve on the nanoparticles we have used, but because the RNA can be delivered in multiple ways, the next steps will include designing a virus to deliver the small RNAs and seeing if the virus can seek out cancer cells. We will again test this in mouse models of human cancers.
Q: Is there anything else that you would like to mention?
A: Although we are still at an early concept stage in developing this into a new form of cancer therapy, we learned from this experience that it is important to stay open-minded to new concepts of attacking cancer. Most scientists appreciate the value of interdisciplinary research. However, that often means scientists and clinicians with different expertise collaborating, such as a physician working with a physicist. Studying the interface between completely different disease entities — for example, neurodegenerative diseases and cancer — can be highly informative and can yield important biological insights that are a rich source of new ideas to fight diseases. – by Jennifer R. Southall
For more information:
Marcus E. Peter, PhD, can be reached at Robert H. Lurie Medical Research Center, Room 6-123, 303 E. Superior St., Chicago IL 60611; email: m-peter@northwestern.edu.
Reference:
Murmann AE, et al. EMBO Rep. 2018;doi:10.15252/embr.201745336.
Disclosures: The study was funded in part by an NIH/NCI grant and The Northwestern University Feinberg School of Medicine Developmental Therapeutic Institute. Peter reports no relevant financial disclosures.