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Plant-derived SVC112 hits cancer stem cells, and leaves healthy cells alone

The red, tube-shaped flowers of the firecracker bush (Bouvardia ternifolia), native to Mexico and the American Southwest, attract hummingbirds. The bush also produces the chemical bouvardin.

Tin Tin Su, PhD, and her colleagues have shown that bouvardin can slow a cancer’s ability to make proteins which tell cancer cells to grow and spread. A paper published in the journal Cancer Research shows that the molecule SVC112, based on bouvardin, acts specifically against head and neck cancer stem cells (CSCs), resulting in better tumour control and less toxicity to healthy cells than existing, FDA-approved protein synthesis inhibitors. The researchers hope that these promising results will continue to human clinical trials of SVC112 in head and neck cancer patients.

“Proteins are the keys to initiating genetic programs in the cells to tell them Now you grownow you stay put, now you metastasize. And those proteins are called transcription factors,” says paper co-senior author, Antonio Jimeno, MD, PhD, director of the Head and Neck Cancer Clinical Research Program and co-leader of the Developmental Therapeutics Program at CU Cancer Center, member of the Gates Center for Regenerative Medicine, and the Daniel and Janet Mordecai Endowed Chair for Cancer Stem Cell Research at the CU School of Medicine.

CSCs are a subpopulation of cancer cells that act as factories – they manufacture cells that make up the bulk of the cancer’s tissue. CSCs often resist treatments, and are able to survive and restart tumour growth after treatment has finished.

“Many groups have linked the production of transcription factors to the survival and growth of cancer stem cells, but inhibitors have just been too toxic – they come with too many side effects. Definitely our studies suggest that this drug could be an advantage over existing drugs. It inhibits protein synthesis in a way that no other drug does and that’s why we’re excited,” says Su.

The results have shown that SVC112 acts specifically against proteins like Myc and Sox2, which are needed by cancer stem cells, while leaving healthy cells relatively unharmed. The team did this by comparing the effects of the drug in “matched pairs” of cancer cells and healthy cells which were grown from samples donated by five head and neck cancer patients in Colorado. The group also repeated the experiments with the FDA-approved protein synthesis inhibitor, omacetaxine mepesuccinate (also called homoharringtonin, or HHT). 

“Having cancer cells along with matched non-cancer cells from the same patient is pretty unique. When we tested these matched pairs with SVC112 and with HHT, what we saw is the approved drug eliminated both cancer and normal cells, whereas SVC112 had selectivity – it affected cancer cells but not healthy cells – so theoretically the effects on the normal tissue will be less,” Su says. In fact, the results showed that healthy cells were between 3.8 and 5.6 times less sensitive to SVC112 than were cancer cells (healthy cells and cancer cells were equally sensitive to the FDA-approved drug HHT).

For the next step, SVC112 was used to treat head and neck tumours grown in mouse models from samples of human tumours. Previous work had shown that SVC112 sensitised previously radiation-resistant CSCs to radiation treatment, so the team tested SVC112 and radiation both alone and in combination.

“What we saw is that only when you decrease the population of cancer stem cells to under 1 percent of the total makeup of a tumour did the tumour shrink,” Jimeno says. “It’s like cancer stem cells are in the control tower, directing the growth of the tumour. If you impair enough of these directors, other cancer cells don’t know what to do and cancer growth slows down or stops.”

The ongoing work continues in two directions – Su’s team is continuing to propel the drug towards the clinic, and Jimeno’s team is working to understand what causes the drug’s action, and how best to combine it with other treatments, as well as its potential uses for other cancer types.  

“This is the first report of the drug, from the drug’s chemical structure, its basic effects on commercial cell lines, to its mechanism of action with patient-derived cell lines and more complex action on CSCs, all the way to animal models from patient samples,” Jimeno says.

Proposals are already underway to take the next important step: Testing SVC112 in an early human clinical trial.

SEE ORIGINAL STUDY

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