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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.

概括 Veltion Therapeutics LLC (VTP) 正在开发新型、有效且特异性的 ATF4 抑制剂，用于抗纤维化剂，利用辐射诱导的肠和肺纤维化作为初始的概念验证适应症预防性设置。 Veltion Therapeutics 正在与哥伦比亚大学的 Constantinos Koumenis 博士合作宾夕法尼亚州，肿瘤学研究的先驱以及 ATF4 的促肿瘤和促转移作用至于筛选和开发辐射防护剂和缓解剂。他在《论语》上发表了大量文章辐射诱导纤维化的病理学，并与我的同事 Melpo Christofidou 博士进行了广泛的合作- 索洛米杜（Solomidou）论化学诱导的纤维化。化疗/放疗的主要局限性之一是毒性肠、肺等正常组织出现溃疡、出血、肺炎和纤维化，主要与不可逆的终末期慢性炎症有关。此外，纤维化也是一个重要因素胰腺癌 (PanCa) 和肺癌的特征已被证明与更严重的疾病相关结果。活化的成纤维细胞已被定性为有助于发病和发生的主要细胞类型。放化疗后肠道和肺纤维化的表现。使用条件淘汰赛的初步结果 ATF4模型显示ATF4表达与功能激活之间存在很强的正相关性成纤维细胞，其特征是依赖 ATF4 调节胶原蛋白水平和沉积。天鹅绒疗法 LLC 认为，用小分子抑制剂破坏 ATF4 活性可能会抑制 ATF4 的发生和发展。纤维化的进展。我们的团队开发了一种强大的基于细胞的筛选，并正在完成对 44,000 个精选库的筛选预选的小分子。通过筛选前 2,500 种化合物，我们已鉴定出 8 种具有 IC50 的化合物相对于 ATF4，在低 µM 范围内。在此应用中，我们建议：（a）扩大我们对抑制剂的测定对 44,000 个化合物库进行 ATF4 活性检测，并验证已识别的 30-50 个化合物的特异性和效力体外胶原蛋白生成和沉积测定中的抑制剂 (b) 使用 3 种最有效的抑制剂以确定它们在辐射诱导纤维化小鼠模型中的 MTD 和功效。积极的结果来自这些研究将构成 PK/PD 和毒性研究以及更广泛的化疗测试的基础 - 在 II 期 STTR 的其他纤维化模型中诱导纤维化。该团队假设拟议的工作将更好地保护正常组织，使化疗/放疗治疗更有效恶性肿瘤并改善数百万癌症患者的生活质量。