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

• 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
• 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

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 铁凋亡是一种由铁依赖性脂质介导的细胞死亡 过氧化作用我们和其他人以前的研究确定了铁凋亡作为一个关键的肿瘤抑制 这表明诱导铁凋亡有望用于癌症治疗。最近，我们和 其他研究表明，放射治疗（RT）可以有效地诱导铁凋亡，并确定了铁凋亡诱导剂 作为具有内在放射抗性的肿瘤（如KEAP 1或p53突变型肿瘤）的放射增敏剂。 然而，铁下垂与获得性放射抵抗的机制和治疗相关性仍然存在， 大部分未开发。我们的长期目标是了解后天性铁性下垂的机制基础， 治疗抵抗，并合理地针对获得性抵抗和疾病复发中的铁下垂， 癌症治疗本申请的目的是确定 铁凋亡抗性有助于胸部癌症（包括肺癌和肺癌）的获得性放射抗性。 食管癌），并评估FIN作为治疗策略，以克服获得性 在这些癌症中的辐射抗性。我们的初步数据支持的中心假设，（i） 抗性代表肺中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有效的治疗策略， 克服获得性辐射抗性而不对正常组织造成显著损害。来测试我们 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： 铁凋亡抗性驱动获得性辐射抗性。具体目标2。确定 FINs与RT组合在克服获得性肿瘤放射抗性中的有效性。具体目标3。到 确定FIN对正常细胞和组织中辐射诱导毒性的潜在影响。是 我希望我们的研究能够发现铁凋亡和获得性辐射抗性的新机制 并确定有效的新的治疗策略，以克服胸部获得性放射抵抗， 癌症治疗我们的建议是高度创新的，因为它侧重于以前未探索的 将铁凋亡与获得性辐射抗性联系起来的途径我们提出的研究将有重大意义 对我们理解铁缺乏症的基本机制和治疗抵抗的影响 以及我们针对癌症治疗中获得性辐射抗性中的铁凋亡的能力。