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:
  • 金额:
    $ 33.57万
  • 依托单位:
  • 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

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

项目成果

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Constantinos Koumenis其他文献

Constantinos Koumenis的其他文献

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{{ truncateString('Constantinos Koumenis', 18)}}的其他基金

Translational Studies in FLASH Particle Radiotherapy
FLASH粒子放射治疗的转化研究
  • 批准号:
    10333797
  • 财政年份:
    2022
  • 资助金额:
    $ 33.57万
  • 项目类别:
Translational Studies in FLASH Particle Radiotherapy
FLASH粒子放射治疗的转化研究
  • 批准号:
    10573278
  • 财政年份:
    2022
  • 资助金额:
    $ 33.57万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10333802
  • 财政年份:
    2022
  • 资助金额:
    $ 33.57万
  • 项目类别:
Project 1: FLASH vs. Standard radiotherapy for treatment of PDAC and sparing normal intestine tissues
项目 1:FLASH 与标准放疗治疗 PDAC 并保护正常肠道组织
  • 批准号:
    10573280
  • 财政年份:
    2022
  • 资助金额:
    $ 33.57万
  • 项目类别:
Project 1: FLASH vs. Standard radiotherapy for treatment of PDAC and sparing normal intestine tissues
项目 1:FLASH 与标准放疗治疗 PDAC 并保护正常肠道组织
  • 批准号:
    10333798
  • 财政年份:
    2022
  • 资助金额:
    $ 33.57万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10573304
  • 财政年份:
    2022
  • 资助金额:
    $ 33.57万
  • 项目类别:
Core B: Small Animal Radiation Core
核心B:小动物辐射核心
  • 批准号:
    10360421
  • 财政年份:
    2017
  • 资助金额:
    $ 33.57万
  • 项目类别:
Core B: Small Animal Radiation Core
核心B:小动物辐射核心
  • 批准号:
    10005187
  • 财政年份:
    2017
  • 资助金额:
    $ 33.57万
  • 项目类别:
Improving radiation response by targeting O2 metabolism via the PI3K/mTOR pathway
通过 PI3K/mTOR 通路靶向 O2 代谢来改善放射反应
  • 批准号:
    8886591
  • 财政年份:
    2015
  • 资助金额:
    $ 33.57万
  • 项目类别:
Program as an Integrated Effort
计划作为一项综合工作
  • 批准号:
    8596402
  • 财政年份:
    2013
  • 资助金额:
    $ 33.57万
  • 项目类别:

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