Ferroptosis resistance as a key driver in acquired radiation resistance

铁死亡抗性是获得性辐射抗性的关键驱动因素

基本信息

批准号：
10707126
负责人：
Boyi Gan
金额：
$ 27.92万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707126
关键词：
Anabolism Automobile Driving CRISPR screen Cell Death Cell Line Complement Cystine Data Glutathione Goals Immunotherapy Iron Link Lipid Peroxidation Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of lung Malignant neoplasm of thorax Mediating Modeling Normal Cell Normal tissue morphology Outcome Pathway interactions Radiation Radiation therapy Radiation-Sensitizing Agents Radiosensitization Recurrent disease Resistance Role TP53 gene Testing Therapeutic Therapeutic Effect Therapeutic Studies Toxic effect Translating Tumor Suppression Xenograft procedure cancer cell cancer therapy comparative effectiveness evaluation innovation mutant novel novel therapeutic intervention radiation resistance radiation-induced injury radioresistant therapeutically effective therapy resistant tumor tumor microenvironment

项目摘要

Project 1 Summary Ferroptosis is a form of regulated cell death that is triggered by iron-dependent lipid peroxidation. Previous studies by us and others identified ferroptosis as a critical tumor suppression mechanism and suggested that inducing ferroptosis holds promise for cancer treatment. Recently, we and others showed that radiotherapy (RT) can potently induce ferroptosis and identified ferroptosis inducers (FINs) as radiosensitizers to tumors with intrinsic radioresistance (such as KEAP1 or p53 mutant tumors). However, the mechanistic and therapeutic relevance of ferroptosis to acquired radioresistance remains largely unexplored. Our long-term goals are to understand the mechanistic basis of ferroptosis in acquired therapy resistance and to rationally target ferroptosis in acquired resistance and disease recurrence in cancer treatment. The objectives of this application are to determine the mechanisms by which ferroptosis resistance contributes to acquired radioresistance in thoracic cancers (including lung and esophageal cancers), and to assess FINs as a therapeutic strategy to overcome acquired radioresistance in these cancers. Our preliminary data support the central hypotheses that (i) ferroptosis resistance represents a key mechanism underlying acquired radioresistance in lung and esophageal cancers and (ii) combining FINs with immunotherapy is an effective therapeutic strategy to overcome acquired radioresistance without causing significant damage to normal tissues. To test our hypotheses, we will pursue the following specific aims: Specific Aim 1. To define the mechanisms by which ferroptosis resistance drives acquired radioresistance. Specific Aim 2. To determine the effectiveness of combining FINs with RT in overcoming acquired tumor radioresistance. Specific Aim 3. To determine the potential effects of FINs on radiation-induced toxicity in normal cells and tissues. It is expected that our proposed studies will identify novel mechanisms of ferroptosis and acquired radioresistance and identify effective new therapeutic strategies to overcome acquired radioresistance in thoracic cancer treatment. Our proposal is highly innovative because it focuses on previously unexplored pathways linking ferroptosis to acquired radioresistance. Our proposed studies will have a significant impact on both our understanding of the fundamental mechanisms of ferroptosis and therapy resistance and our ability to target ferroptosis in acquired radioresistance in cancer treatment.

项目1概要铁死亡是一种受调节的细胞死亡形式，由铁依赖性脂质触发过氧化。我们和其他人之前的研究发现铁死亡是一种关键的肿瘤抑制作用机制并表明诱导铁死亡有望用于癌症治疗。最近，我们和其他人表明放射治疗（RT）可以有效诱导铁死亡并确定铁死亡诱导剂 (FIN) 作为具有内在放射抗性的肿瘤（例如 KEAP1 或 p53 突变肿瘤）的放射增敏剂。然而，铁死亡与获得性放射抗性的机制和治疗相关性仍然存在很大程度上尚未探索。我们的长期目标是了解获得性铁死亡的机制基础治疗耐药性并合理针对获得性耐药和疾病复发中的铁死亡癌症治疗。该应用程序的目标是确定以下机制：铁死亡抵抗有助于胸部癌症（包括肺癌和癌症）的获得性放射抵抗食管癌），并评估 FIN 作为克服获得性癌症的治疗策略这些癌症的放射抗性。我们的初步数据支持以下中心假设：(i) 铁死亡抵抗力代表了肺和肺部获得性放射抗性的关键机制食管癌和 (ii) 将 FIN 与免疫疗法相结合是一种有效的治疗策略克服获得性放射抗性，而不会对正常组织造成重大损害。来测试我们的假设，我们将追求以下具体目标：具体目标 1. 通过以下方式定义机制：铁死亡抵抗驱动获得性放射抵抗。具体目标 2. 确定 FIN 与 RT 相结合在克服获得性肿瘤放射抗性方面的有效性。具体目标 3. 至确定 FIN 对正常细胞和组织中辐射引起的毒性的潜在影响。这是预计我们提出的研究将确定铁死亡和获得性放射抗性的新机制并确定有效的新治疗策略来克服胸部获得性放射抗性癌症治疗。我们的提案具有高度创新性，因为它侧重于以前未探索过的领域将铁死亡与获得性放射抗性联系起来的途径。我们提出的研究将具有重大意义对我们对铁死亡和治疗抵抗的基本机制的理解的影响以及我们在癌症治疗中针对获得性放射抗性中的铁死亡的能力。