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

• 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
• 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' 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

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 Veltion Therapeutics LLC（VTP）正在开发新型，有效和特异性的ATF 4抑制剂作为抗纤维化药物。 药物，利用辐射诱导的肠和肺纤维化作为最初的概念验证适应症， 预防性设置。Veltion Therapeutics正在与University of the University的Constantinos Koumenis博士合作， 宾夕法尼亚州，肿瘤学研究的先驱，以及ATF 4的促肿瘤发生和促转移作用 筛选和开发辐射防护剂和缓解剂。他发表了大量关于 辐射诱导纤维化的病理生物学，并与我的同事Melpo Christofidou博士进行了广泛合作- Solomidou治疗化学性纤维化。化疗/放疗的主要局限性之一是化疗/放疗的毒性。 以溃疡、出血、肺炎和纤维化的形式损害正常组织如肠和肺， 大多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的 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表征为有助于发病的主要细胞类型， 放化疗后肠和肺纤维化的表现。使用条件性敲除的初步结果 ATF 4模型显示，ATF 4表达与细胞功能激活之间存在强正相关性。 成纤维细胞，其特征在于胶原蛋白水平和沉积的ATF 4依赖性调节。Veltion治疗 LLC认为，用小分子抑制剂破坏ATF 4活性可能导致抑制ATF 4的发作， 纤维化的进展。 我们的团队已经开发出一种强大的基于细胞的筛选方法，并正在完成对44，000个策展文库的筛选。 预选的小分子。在筛选的前2，500种化合物中，我们鉴定了8种具有IC 50的化合物 在低µM范围内，与ATF 4相比。在本申请中，我们提出：（a）扩展我们的用于以下抑制剂的测定： 对44，000个化合物文库进行ATF 4活性鉴定，并验证30-50个鉴定化合物的特异性和效力 胶原蛋白产生和沉积的体外测定中的抑制剂（B）使用3种最有效的抑制剂 以确定它们在辐射诱导的纤维化的小鼠模型中的MTD和功效。积极成果 这些研究将构成PK/PD和毒性研究以及更广泛的化疗试验的基础- 在II期STTR的其他纤维化模型中诱导纤维化。该小组，假设拟议的工作， 将导致更好地保护正常组织，使化疗/放疗治疗更有效地对抗 治疗恶性肿瘤，改善数百万癌症患者的生活质量。