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

靶向综合应激反应效应器 ATF4 以减轻治疗引起的纤维化

基本信息

批准号：
10324364
负责人：
Constantinos Koumenis
金额：
$ 33.57万
依托单位：
VELTION THERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324364
关键词：
5&apos Untranslated Regions Abdomen Ablation Acute Amino Acids Applications Grants Autophagocytosis Biological Assay Cancer Etiology Cancer Patient Cells Cessation of life Characteristics Chemicals Chest Chronic Collagen Deposition Dermal Development Diagnosis Disease Disease Outcome Effectiveness Evaluation Exhibits Extracellular Matrix Fibroblasts Fibrosis Gastrointestinal Neoplasms Genes Genetic Glucose Hemorrhage Hydroxyproline Hypoxia In Vitro Inflammation Intestinal Fibrosis Intestines Knock-out Late Radiation Injury Lead Leucine Zippers Libraries Long-Term Survivors Luciferases Lung Lymphoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mass Spectrum Analysis Maximum Tolerated Dose Metastatic Neoplasm to the Lung Modeling Mus Normal tissue morphology Nutrient Oncology Oxidative Stress Oxygen PERK kinase Pathway interactions Patients Pennsylvania Phase Phenotype Phosphotransferases Play Preventive Process Production Property Publishing Pulmonary Fibrosis Pulmonary Inflammation Quality of life Radiation Radiation Fibrosis Radiation Oncology Radiation induced damage Radiation therapy Recovery Regulation Reporter Research Risk Role Severities Small Business Technology Transfer Research Specificity Stress Structure-Activity Relationship Testing Therapeutic Tissues Toxic effect Toxicology Treatment Effectiveness Trichrome stain Ulcer United States Universities Up-Regulation Validation Work attenuation base biological adaptation to stress cell type chemical property chemoradiation chemotherapy conditional knockout deprivation efficacy testing endoplasmic reticulum stress experimental study improved in vitro Assay inhibitor/antagonist irradiation lead optimization mouse model novel nutrient deprivation pharmacokinetics and pharmacodynamics prophylactic response sarcoma screening small molecule small molecule inhibitor small molecule libraries survival outcome transcription factor tumor tumor growth tumor microenvironment tumorigenic

项目摘要

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.

总结