Research demonstrates Hoth Therapeutics HT-KIT for mast cell cancers reduces size and spread

Targeting KIT by frameshifting mRNA transcripts as a therapeutic strategy for aggressive mast cell neoplasm

Hoth Therapeutics, highlights recent findings from North Carolina State University, that its new treatment for mast cell cancers, known as HT-KIT, reduces the number of mast cells by "mutating" the messenger RNA (mRNA) before it can deliver instructions for manufacturing the gene responsible for cell proliferation.

"Current treatments for mast cell cancers target signalling from the receptor encoded by the c-KIT gene, and the efficacy of current therapies can be negatively affected by c-KIT mutations associated with disease development," says Glenn Cruse, assistant professor of immunology at North Carolina State University and a Scientific Advisor to Hoth and corresponding author of the research. "We are targeting the gene itself, regardless of mutation. If we target the gene that drives progression, then we can target the disease."

"We are altering the message that makes the protein – flipping an 'on' switch to 'off,'" Cruse says. "If you get mRNA to produce a protein that is mutated and severely truncated, your cell will recognize that and degrade the message so that the protein isn't produced."

The researchers used their frameshifted c-KIT mRNA approach on mast cell leukaemia cells in vitro and found that KIT protein expression, signalling and function were reduced. The cancer cells stopped proliferating and began dying within hours. In a mouse model, tumour growth and infiltration of other organs were reduced, and tumour cell death increased when the frameshifted c-KIT mRNA was induced.

"The other advantage to our technique is that it solves the problem of degradation evasion," Cruse says. "Occasionally faulty messages will evade degradation and their mutated proteins get produced anyway. But proteins produced by the frameshifted c-KIT mRNA are inert, or non-functional. So even if they get produced, they cannot cause more harm."

The research appears in Molecular Therapy and is supported by the National Institutes of Health. NC State postdoctoral researcher Douglas Snider is the first author. The technology described in the paper has been exclusively licensed by Hoth Therapeutics and is being developed as HT-KIT.

Earlier this year, Hoth announced that its novel HT-KIT exhibited highly positive results in humanized mast cell neoplasm models, representative in vitro and in vivo models for aggressive, mast cell-derived cancers such as mast cell leukaemia and mast cell sarcoma. The anti-cancer therapeutic, which is currently in development, use mRNA frameshifting that induces apoptosis of neoplastic mast cells.