# Targeting the Integrated Stress Response effector ATF4 for mitigation of treatment-induced fibrosis

> **NIH NIH R41** · VELTION THERAPEUTICS LLC · 2021 · $335,671

## Abstract

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. Veltion Therapeutics is collaborating with Dr. Constantinos Koumenis at the University of
Pennsylvania, a pioneer in oncology research and the pro-tumorigenic and pro-metastatic role of ATF4 as well
as for screening and developing radioprotectors and mitigators. He has published extensively on the
pathobiology of radiation-induced fibrosis, and has collaborated extensively with co-I, Dr. Melpo Christofidou-
Solomidou on chemical-induced fibrosis. 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. Moreover, fibrosis is also an important
characteristic of pancreatic (PanCa) and lung cancers that has been shown to correlate with worse disease
outcomes.
 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. 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. With the first 2,500 compounds screened, we have identified 8 compounds with IC50
in the low µM range against ATF4. In this application, we propose to: (a) Expand our assay for inhibitors of
ATF4 activity to a 44,000 compound library and validate the specificity and potency of 30-50 identified
inhibitors in in vitro assays for collagen production and deposition (b) Use the 3 most effective inhibitors
to determine their MTD and efficacy in mouse models of radiation-induced fibrosis. Positive results from
these studies will form the basis of PK/PD and toxicity studies as well as broader testing against chemotherapy-
induced fibrosis in additional models of fibrosis in a Phase II STTR. 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.

## Key facts

- **NIH application ID:** 10324364
- **Project number:** 1R41CA261378-01A1
- **Recipient organization:** VELTION THERAPEUTICS LLC
- **Principal Investigator:** Constantinos Koumenis
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,671
- **Award type:** 1
- **Project period:** 2021-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10324364

## Citation

> US National Institutes of Health, RePORTER application 10324364, Targeting the Integrated Stress Response effector ATF4 for mitigation of treatment-induced fibrosis (1R41CA261378-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10324364. Licensed CC0.

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