New Non-Toxic Drug: SVC112, Derived From Flowers Of Bouvardia Ternifolia Plant Targets Cancer Stem Cells And Prevents Metastasis
Source: Thailand Medical News Jan 09, 2020 4 years, 11 months, 2 weeks, 9 hours, 9 minutes ago
The flowers of the firecracker bush (
Bouvardia ternifolia), native to Mexico and the American Southwest, which are red and tube-shaped is now the attention of
cancer researchers all around the world. These flowers provides the chemical
bouvardin, which the lab of University of Colorado
Cancer Center and CU Boulder researcher, Dr Tin Tin Su, Ph.D., and others have shown to slow a
cancer's ability to make proteins that tell
cancer cells to grow and spread. Now a paper based on nearly half a decade of work, published in the journal
Cancer Research, shows that the molecule
SVC112, based on
bouvardin and synthesized by Dr Su's Colorado-based pharmaceutical startup, SuviCa, Inc. acts specifically against head and neck
cancer stem cells (
CSCs), resulting in better tumor control with less toxicity to healthy cells than existing, FDA-approved protein synthesis inhibitors. The group hopes these promising preclinical results will lay the groundwork for human clinical trials of
SVC112 in head and neck
cancer patients.
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"Typically, proteins are the keys to initiating genetic programs in the cells to tell them ‘Now you grow, now you stay put, now you
metastasize’. And those proteins are called transcription factors," says paper co-senior author, Dr Antonio Jimeno, MD, Ph.D., during an interview with
Thailand Medical News.
Dr Jimeno is 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 or
cancer stem cells are a subpopulation of
cancer cells that, like healthy stem cells, act as factories, manufacturing cells that make up the bulk of a
cancer's tissue. Unfortunately,
CSCs often resist treatments like radiation and chemotherapy, and can survive to restart tumor growth once treatment ends.
Dr Su, who is also co-leader of the CU Cancer Center Molecular and Cellular Oncology Program added, "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 as 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.”
Significantly, the group's work showed that
SVC112 acts specifically against proteins like Myc and Sox2 needed by
cancer stem cells, whil
e leaving healthy cells relatively unharmed. They did this by comparing the effects of the drug in "matched pairs" of
cancer cells and healthy cells grown from samples graciously donated by five head and neck cancer patients in Colorado. For further comparison, the group did the same experiments with the FDA-approved protein synthesis inhibitor known as omacetaxine mepesuccinate (also called homoharringtonin, or HHT).
Dr Su further added, "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 ie it affected
cancer cells but not healthy cells, so theoretically the effects on the normal tissue will be less.”
Dr Tin Tin Su, PhD, and colleagues show promise of new drug
SVC112 against cancer stem cells Credit: Paul Muhlrad
In fact, 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).
The researchers’next step was using
SVC112 to treat head and neck tumors grown in mouse models from samples of human tumors. Earlier work had shown that
SVC112 sensitized previously radiation-resistant CSCs to radiation treatment, and so the group tested
SVC112 and radiation alone and in combination.
Dr Jimeno added, "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 tumor did the tumor shrink. It's like
cancer stem cells are in the control tower, directing the growth of the tumor. If you impair enough of these directors, other
cancer cells don't know what to do and
cancer growth slows down or stops."
Further ongoing work continues in two major directions, with Dr Su's team continuing to propel the drug toward the clinic and Dr Jimeno's team working to understand of the basic biology driving the drug's action, how to best combine it with other treatments such as radiation or immunotherapy, and its potential uses in other
cancer types.
Dr Jimeno commented, "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."
Typically, early drug development undertaken outside the funding structure of established pharmaceutical sponsors often requires contributions from many sources, and the current project is no exception, receiving support from subcontracts to SuviCa's Small Business Innovation Research (SBIR) award, a National Institutes of Health grant to the Su lab, pilot funding from the CU
Cancer Center, and philanthropy support from the Gates Center and the CU School of Medicine.
Dr Jimeno further added, "We are so grateful for the belief from all these organizations and individuals, and especially to our patients, whose courage has been essential in making the models we need to test this new drug."
The medical researchers are already underway to take the next important step: Testing
SVC112 in an early human clinical trial. Trials are expected as early as mid 2020.
Reference : Stephen B Keysar et al, Inhibiting translation elongation with SVC112 suppresses cancer stem cells and inhibits growth in head and neck squamous carcinoma, Cancer Research (2020). DOI: 10.1158/0008-5472.CAN-19-3232
