Treatment With HT-KIT Shows Early Preclinical Activity in GIST Models

HT-KIT, a novel targeted therapy for gastrointestinal stromal tumors (GIST), demonstrated the ability to significantly reduce tumor burden in humanized mouse models, disrupt KIT signaling pathways and induce tumor cell death, according to a news release from Hoth Therapeutics, Inc. which detailed these preclinical findings.

"These exciting findings mark a significant milestone in the development of HT-KIT as a potential new therapeutic for patients with GIST," Robb Knie, CEO of Hoth Therapeutics, said in the news release. "By targeting KIT mutations, which are a major driver of GIST progression, HT-KIT has shown remarkable efficacy in preclinical models, demonstrating its potential as a transformative treatment option for this difficult-to-treat cancer."

Preclinical evaluation of HT-KIT, according to the news release, demonstrated tumor cell death as early as 24 hours following treatment induction; although a lower dose of treatment led to delayed outcomes, it still resulted in substantial cell death by 72 hours. Moreover, HT-KIT suppressed cell growth and proliferation in GIST-T1 cells, as shown by both reduced cell counts and decreased fluorescence intensity in proliferation assays.

In a humanized xenograft model, statistically significant differences in tumor volume were seen by day 8 when HT-KIT was given at 12.5 milligrams per kilogram intravenously every three days, and became more pronounced over time. Finally, upon excision, tumors from HT-KIT–treated mice were smaller and lighter than those from animals given the control treatment, reinforcing tumor volume measurements, according to investigators.

"These results provide compelling preclinical proof-of-concept for HT-KIT in GIST treatment," said Knie. "By directly targeting the underlying genetic drivers of GIST, HT-KIT has the potential to overcome limitations of existing therapies and provide a new therapeutic strategy for patients with KIT-driven malignancies."

The release concludes by noting that the company, Hoth Therapeutics, is currently conducting additional preclinical studies to further validate HT-KIT's efficacy and safety profile. Notably, there are plans to initiate regulatory discussions for first-in-human trials with the agent.

What Are GISTs?

GIST, although a rare cancer, is an aggressive one, and is often driven by activating mutations in the KIT receptor. The disease begins in the digestive system, most commonly in the stomach and small intestine, according to the Mayo Clinic website. Although small GISTs may cause little to no problems for the patient, they typically will grow slowly, and as it grows, it can cause symptoms which present themselves in the form of belly pain and nausea. GISTs are most common in adult patients and are very rare in children.

The Mayo Clinic website goes on to say that it is unclear what triggers the development of GISTs, though it is believed that they arise from specific nerve cells embedded in the walls of digestive organs, which are crucial for the muscle contractions that propel food through the body. The makeup of GIST involves alterations in the DNA of these nerve cells, and in GIST cells, these genetic changes lead to rapid and uncontrolled cell growth. This surplus of cells can accumulate, forming a tumorous mass that can invade and damage surrounding healthy tissues. Over time, these cancerous cells can detach and spread to distant parts of the body, metastasizing.

Because patients treated with current therapeutic options, like tyrosine kinase inhibitors, often develop resistance over time, this can lead to disease progression. In turn, HT-KIT aims to address an unmet medical need within the treatment space by offering a novel approach to patients with this disease while still disrupting tumor cell growth.

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