Exec. Summary: Veltion Therapeutics LLC (VTP) is developing novel, potent and specific inhibitors of ATF4 as antifibrotic agents, specifically for intestine and lung fibrosis. The high rate of severe acute and long-term normal tissue toxicities post-radiotherapy limits the effectiveness of the treatment, results in poor tumor control and negatively impacts the patients’ quality of life. The proposed work may ultimately lead to better protection of normal tissue during radiotherapy but also chemotherapy treatment, rendering these treatments more effective against malignancies.

Responsible party at Veltion Therapeutics: SIELECKI, THAIS M, and KOUMENIS, CONSTANTINOS
Type of grant: Part 1 ('phase 1') STTR
Abstract published: September 21, 2021
Project Summary: Veltion Therapeutics LLC (VTP) is developing novel, potent and specific inhibitors of ATF4 as antifibrotic agents, utilizing radiation-induced intestinal and lung fibrosis as initial, proof-of-concept indications in the preventive setting. One of the major limitations of chemo/radiotherapy is the toxicity in normal tissues such as the intestine and lung, in the form of ulceration, bleeding, pneumonitis and fibrosis, which is mostly associated with the irreversible end-stage chronic inflammation. Activated fibroblasts have been characterized as the major cell type that contribute to the onset and manifestation of intestinal and lung fibrosis post-chemoradiation. Preliminary results using a conditional knockout ATF4 model showed a strong positive correlation between ATF4 expression and functional activation of fibroblasts, characterized by ATF4-dependent regulation of collagen levels and deposition. Critically, genetic inhibition of ATF4 in mouse models did not result in overt toxicities, indicating that a clinically exploitable therapeutic window may exist for such agents. Veltion Therapeutics LLC believes that disrupting ATF4 activity with small molecule inhibitors could lead to inhibition of the onset and progression of fibrosis. Our team has developed a robust cell-based screen and is completing screening of a curated library of 44,000 preselected small molecules. In scope is to also validate the specificity in in vitro assays for collagen production and deposition The team postulates that the proposed work will lead to better protection of normal tissues rendering chemo/radiotherapy treatments more effective against malignancies and improve the quality of life of millions of cancer patients.