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Weaponizing the Biochemistry of Huntington's Disease as a General Cancer Therapy


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Posted 14 February 2018 - 01:44 AM


An interesting observation that has arisen over the years of epidemiological study of human age-related disease is that there are a number of distinct inverse relationships between incidence of cancer and incidence of some forms of neurodegeneration. This was in the news a few years ago in the case of Alzheimer's disease for example. Why would people with a higher risk of cancer suffer lower rates of Alzheimer's disease, however? We can only speculate at this point, but the more recent discovery I'll point out here adds fuel for that speculation. The Alzheimer's-cancer relationship is modest in size and somewhat complex in detail in comparison to the quite dramatic and straightforward Huntington's-cancer relationship. People with the dysfunctional forms of the huntingtin gene that cause this neurodegenerative condition have a greatly reduced cancer risk.

Why is this the case? Researchers have now discovered that the aberrant huntingtin proteins implicated in Huntington's disease are actually a lot more damaging to cancerous cells than to neurons in the brain. While that is no great comfort to those who suffer the slow deterioration of Huntington's disease, the prospect of turning this discovery into a general cancer therapy is quite real. Something that reliably and rapidly kills all of the cancers it is tested against, while harming neurons only very slowly, is a much better class of candidate treatment than most chemotherapeutics. (And meanwhile, a number of groups are working on gene therapies to address harmful huntingtin gene variants; Huntington's disease - and most other inherited diseases - will vanish from the wealthier parts of the world over the next few decades).

This approach to killing cancerous cells is noteworthy because it appears to be non-specific, reliably attacking many different types of cancer. The only way to make earnest progress in bringing cancer under control is for the research community to focus on treatments that can be applied to many different cancers - or, for preference, to all cancers - with minimal cost of adjustment by cancer type. There are hundreds of types of cancer, and attempting to produce therapies specialized to the molecular peculiarities of a specific type is too inefficient. Too much time and funding has been poured into such approaches, and both of those resources are limited. That is not the way forward. The future of the field of cancer therapeutics lies in treatments that can be applied as-is to defeat near any type of cancer. So we should watch for promising examples such as the research here.

Huntington's disease provides new cancer weapon

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. Huntington's is caused by an over abundance of a certain type of repeating RNA sequences in one gene, huntingtin, present in every cell. The defect that causes the disease also is highly toxic to tumor cells. These repeating sequences - in the form of so-called small interfering RNAs (siRNA) - 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. We've never seen anything this powerful." To test the super assassin molecule in a treatment situation, 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. Importantly, the tumors did not develop resistance to this form of cancer treatment. The molecule was also used to treat human and mouse ovarian, breast, prostate, liver, brain, lung, skin, and colon cancer cell lines. The molecule killed all cancer cells in both species.

Earlier research had 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. These patients would not only have a disease with an RNA component, but they also had to have less cancer." The researchers 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 they looked at the repeating sequences in huntingtin, the gene that causes the disease, she saw a similar composition to the earlier kill switch. 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. Those similarities triggered our curiosity. 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."

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

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). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients.

We now show 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. We propose to explore TNR-based siRNAs as a novel form of anticancer reagents.


View the full article at FightAging




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