Project 3: Targeting KEAP1-Mediated Radioresistance in Lung Cancer

项目 3：靶向 KEAP1 介导的肺癌放射抗性

• 批准号: 10334201
• 负责人: Maximilian Diehn
• 金额: $ 38.06万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334201
• 关键词: Anabolism; Cancer Model; Cancer Patient; Cell Line; Cells; Chest; Clinical; Clinical Trials; Collaborations; Complement Inactivators; Complement Receptor; Conflict (Psychology); Databases; Development; Dose; Esophagus; Free Radicals; Future; Genetic Complementation Test; Genomics; Genotype; Glutaminase; Glutamine; Goals; Head and Neck Cancer; Human; In Vitro; KRAS2 gene; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Mus; Mutagenesis; Mutation; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Operative Surgical Procedures; Pathogenicity; Patients; Play; Publishing; Radiation; Radiation Oncology; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Recurrence; Resistance; Role; System; Techniques; Testing; Therapeutic Index; Toxic effect; Translating; Work; base; cancer imaging; cell killing; cohort; experimental study; high risk; improved; in vivo; inhibitor; irradiation; molecular marker; mutant; mutation screening; mutational status; novel; personalized strategies; personalized therapeutic; predictive marker; protein function; radiation delivery; radiation resistance; radioresistant; side effect; tumor

Abstract (Project 3) Radiation therapy (RT) plays a critical role in the treatment of non-small cell lung cancer (NSCLC). While advances in tumor imaging and radiation delivery techniques have significantly improved RT, advances in genomic and molecular understanding of tumors have largely failed to impact management of patients treated with RT. Therefore, development of “precision radiation oncology” approaches, defined as the use of molecular biomarkers to personalize RT, remains a major unmet need. Our long-term goal is to develop novel, molecularly-based precision radiation oncology approaches for NSCLC patients treated with RT. We previously demonstrated that NSCLCs with KEAP1 or NFE2L2 mutations are radioresistant and have high rates of local recurrence after RT. In this proposal we will develop a personalized radiosensitization strategy for KEAP1/NFE2L2 mutant tumors based on inhibition of glutaminase, which plays a critical role in biosynthesis of cellular free radical defenses. Prior studies have found conflicting results regarding the ability of glutaminase inhibition to radiosensitize NSCLC. Our central hypothesis is that glutaminase inhibition can radiosensitize KEAP1/NFE2L2 mutant but not wildtype NSCLCs and if correct would help explain the previous conflicting results. We will therefore test if our genotype-specific radiosensitization approach has efficacy in KEAP1/NFE2L2 mutant but not wildtype NSCLC in vivo. We will also test if our approach increases normal tissue toxicity. Additionally, we will identify specific KEAP1 mutations that cause radioresistance in order to enable identifying patients with radioresistant tumors. In collaboration with Project 1, we will also test if the complement inhibitor PMX205 can serve as an additional radiosensitizer for KEAP1/NFE2L2 mutant NSCLC. Finally, in collaboration with Project 2 we will test if glutaminase inhibition can radiosensitize NFE2L2-mutant head and neck cancers. If successful, our project will establish glutaminase inhibition as a precision radiation oncology strategy for personalized radiosensitization of KEAP1/NFE2L2 mutant NSCLC. This approach could widen the therapeutic index of RT since it would only expose patients at highest risk of local recurrence to the potential additional toxicities of adding a radiation sensitizer. Our results will serve as the basis for developing clinical trials to attempt to translate this strategy. These trials will involve genotyping of NSCLC patients undergoing RT in order to select patients with KEAP1/NFE2L2 mutations for concurrent treatment with RT and glutaminase inhibitors. Importantly, our findings will serve as proof-of-principle that can likely also translate to other tumor types with frequent KEAP1/NFE2L2 mutations.

摘要（项目3） 放射治疗（RT）在治疗非小细胞肺癌（NSCLC）中起着至关重要的作用。尽管 肿瘤成像和辐射输送技术的进步已显着改善了RT，进展 对肿瘤的基因组和分子理解在很大程度上未能影响治疗患者的治疗 与RT。因此，开发“精确辐射肿瘤学”方法，被定义为使用分子 个性化RT的生物标志物仍然是一个主要的未满足需求。我们的长期目标是开发小说， 基于RT治疗的NSCLC患者的基于分子的精确辐射肿瘤学方法。我们以前 证明具有KEAP1或NFE2L2突变的NSCLC是放射性的，局部率很高 RT后的复发。在此提案中，我们将制定个性化的放射敏化策略 基于谷氨酰胺酶的抑制作用Keap1/nFe2L2突变肿瘤，在生物合成中起着至关重要的作用 细胞自由基防御。先前的研究发现有关谷氨酰胺酶能力的矛盾结果 抑制放射敏感的NSCLC。我们的中心假设是谷氨酰胺酶抑制可以放射敏感 Keap1/nfe2l2突变体，但没有野生型NSCLC，如果正确的话，将有助于解释以前的冲突 结果。因此，我们将测试我们的基因型特异性放射敏方法在KEAP1/NFE2L2中是否易于 突变体，但不是体内野生型NSCLC。我们还将测试我们的方法是否增加了正常的组织毒性。 此外，我们将确定特定的KEAP1突变，这些突变引起辐射，以便识别 放射性肿瘤的患者。与项目1合作，我们还将测试补体抑制剂是否 PMX205可以用作KEAP1/NFE2L2突变体NSCLC的附加放射敏剂。最后，合作 使用项目2，我们将测试谷氨酰胺酶抑制是否可以放射敏感NFE2L2突变的头部和颈部癌。 如果成功，我们的项目将建立谷氨酰胺酶抑制作用，作为一种精确的辐射肿瘤学策略 KEAP1/NFE2L2突变体NSCLC的个性化放射敏化。这种方法可以扩大治疗性 RT的索引，因为它只会暴露于局部复发的最高风险的患者 添加辐射传感器的毒性。我们的结果将是开发临床试验以尝试的基础 翻译这种策略。这些试验将涉及接受RT的NSCLC患者的基因分型，以便选择 患有KEAP1/NFE2L2突变的患者与RT和谷氨酰胺酶抑制剂同时治疗。重要的是， 我们的发现将作为原理证明，也可能会转化为其他频率的肿瘤类型 KEAP1/NFE2L2突变。