Scientists develop new cancer therapy to stop tumor growth

Scientists develop new cancer therapy to stop tumor growth. 

A new therapy targets cancer cells, whose modified micro-RNA strands naturally block cell division. 

Researchers at Purdue University have developed a new type of cancer treatment that can trick cancer cells into absorbing RNA fragments that naturally block cell division.

A study published recently in Oncogene showed that in 21 days, tumors treated with this therapy remained the same size, while untreated tumors grew three times larger.

Cancer can start from almost anywhere in the human body. It is characterized by cells dividing uncontrollably, which may be able to ignore signals to die or stop dividing, or even evade the immune system. The therapy, tested in a mouse model, combines a delivery system that targets cancer cells with a specially modified version of microRNA-34a, a molecule that acts “like a car brake” to slow down or stop cell division, said lead author Andrea Kasinski, associate professor of biological sciences at Purdue University’s William and Patty Miller School of Biology.

In addition to slowing down or reversing tumor growth, targeting microRNA-34a also strongly inhibited the activity of at least three genes (known to drive cancer and resistance to other cancer therapies) for at least 120 hours. The results suggest that the patented therapy is the latest iteration of more than 15 years of work to use microRNA to destroy cancer, which can be effective alone and in combination with existing drugs when used against cancers that have already developed resistance.

“When we got the data, I was overjoyed. I believe this approach is better than the current standard of care and that patients will benefit from it,” said Kasinski, a member of the Purdue Cancer Research Institute.

MicroRNA-34a is a short double-stranded RNA – a string of ribonucleotides that connect like teeth on a zipper along the length of a sugar-phosphate chain. The two strands of microRNA are unevenly compressed together, with one strand guiding a protein complex to the working site in the cell and the other strand being destroyed.

In healthy cells, microRNA-34a is abundant, but its presence is significantly reduced in many cancer cells.

Although the idea of reintroducing microRNA-34a into cancer cells seems simple, the research team had to overcome many challenges to devise an effective treatment. Naturally occurring RNA degrades quickly, so to increase the durability of the treatment, the research team stabilized microRNA-34a by adding several small clusters of atoms along the length of the chain. The team modeled their chemistry on structures approved by the FDA, which researchers at biotechnology company Alnylam used for similar short interfering RNAs. Experiments on mouse models showed that the modified microRNA-34a lasted at least 120 hours after introduction.

As a bonus, fully modified microRNA-34a is invisible to the immune system, which usually attacks double-stranded RNA introduced into the body.

To ensure that the modified microRNA-34a enters cancer cells, the research team attached the double strand to a folic acid molecule. The surface of all cells in our body has receptors that bind to folic acid and take vitamins into cells, but many cancers (breast cancer, lung cancer, ovarian cancer and cervical cancer) have much more folic acid receptors on their cell surface than healthy cells. The tiny microRNA-34a and folic acid compound penetrates through the dense tissue of the tumor and binds to folic acid receptors on the cell surface. It is then absorbed into small cell membrane bags called vesicles. Once inside the cell, some microRNA-34a can escape from vesicles and slow down cell division.

The targeted specificity of the treatment reduces the amount of compound that must be administered to be effective, which in turn reduces potential toxicity, side effects and costs. The team can also prepare a separate version for prostate cancer cells that targets different cell surface receptors, as prostate cancer cells do not produce too many folic acid receptors. Kasinski and her team are confident in the value of their latest version and are preparing for clinical trials.

Reference: “First fully modified versions of miR-34a with outstanding stability, activity and anti-tumor efficacy”, authors: Ahmed M. Abdelaal, Ikjot S. Sohal, Shreyas Iyer, Kasireddy Sudarshan, Harish Kothandaraman, Nadia Laman, Philip Low and Andrea Kasinski, September 5, 2023, Oncogene.
DOI: 10.1038/s41388-023-02801-8

At Purdue University, Kasinski collaborated with Philip S. Low, Presidential Scholar of Drug Discovery and Ralph C. Corley Distinguished Professor of Chemistry, inventor of the FDA-approved drug Cytalux; research assistant professor Nadia Ahmed M. Abdelaal, first author and graduate student in Kasinski’s lab; and researchers Harish Kothandaraman, Kasireddy Sudarshan, Shreyas Iyer and Ikjot S. Sohal.

The study was funded by the National Institutes of Health and the Department of Defense.