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摘要铁凋亡是由铁依赖性脂质触发的调节细胞死亡的一种形式过氧化。我们和其他人先前的研究将铁铁作用鉴定为抑制严重的肿瘤机制并提出诱导铁铁作用具有癌症治疗的希望。最近，我们和其他人则表明，放疗（RT）可以有效诱导铁铁疗法并鉴定出螺旋病诱导剂（FIN）作为具有内在辐射抗性的肿瘤（例如Keap1或p53突变肿瘤）的放射增敏剂。然而，铁凋亡与获得的放射性持续存在的机械和治疗相关性在很大程度上没有探索。我们的长期目标是了解被收购中的铁凋亡的机理基础治疗抗药性和合理靶向性铁氧化物的抗性抗性和疾病复发癌症治疗。该应用程序的目标是确定铁凋亡耐药性有助于胸腔癌的获得的放射线（包括肺和包括肺和食管癌），并评估鳍作为克服所获得的治疗策略这些癌症中的放射线。我们的初步数据支持（i）铁凋亡的中心假设抗性代表了肺中获得的辐射的基础的关键机制，食道癌和（ii）将鳍与免疫疗法结合在一起是一种有效的治疗策略克服获得的放射线，而不会对正常组织造成重大损害。测试我们的假设，我们将追求以下特定目的：特定目的1。定义机制耐铁的耐药性驱动了获得的放射线。特定目标2。确定在克服获得的肿瘤放射线抗性中将鳍与RT结合的有效性。特定目标3。确定鳍对辐射诱导的正常细胞和组织毒性的潜在影响。这是预计我们提出的研究将识别出新的铁铁作用机制，并获得了放射性的机制并确定有效的新治疗策略来克服胸腔中获得的放射线癌症治疗。我们的建议具有很高的创新性，因为它专注于以前未开发的将铁铁作用与获得的辐射抗性联系在一起的途径。我们提出的研究将具有重要的对我们对铁铁作用的基本机制和耐药性的影响以及我们在癌症治疗中获得性辐射抗性中靶向螺栓毒性的能力。