Project 3: Targeting KEAP1-Mediated Radioresistance in Lung Cancer

摘要(项目3) 放射治疗(RT)在非小细胞肺癌(NSCLC)治疗中起着至关重要的作用。而当 肿瘤成像和放射传递技术的进步显著改善了RT，在 对肿瘤的基因组和分子的了解在很大程度上未能影响对接受治疗的患者的管理 使用RT。因此，发展“精确放射肿瘤学”的方法，定义为使用分子 用于个体化RT的生物标记物仍然是一个主要的未得到满足的需求。我们的长期目标是开发小说， 接受RT治疗的NSCLC患者的基于分子的精确放射肿瘤学方法。我们之前 研究表明，具有Keap1或NFE2L2突变的非小细胞肺癌具有辐射抗性，并具有高局部发生率 放疗后复发。在本提案中，我们将为以下对象开发个性化放射增敏策略 基于谷氨酰胺酶抑制的Keap1/NFE2L2突变型肿瘤，谷氨酰胺酶在生物合成中起关键作用 细胞自由基防御。先前的研究发现了关于谷氨酰胺酶能力的相互矛盾的结果 对非小细胞肺癌放射增敏的抑制。我们的中心假设是谷氨酰胺酶抑制可以增加辐射敏感性 Keap1/NFE2L2突变，但不是野生型NSCLC，如果正确，将有助于解释之前的冲突 结果。因此，我们将测试我们的基因型特异性放射增敏方法是否对Keap1/NFE2L2有效 体内存在突变型非小细胞肺癌，但不是野生型。我们还将测试我们的方法是否会增加正常的组织毒性。 此外，我们将鉴定引起辐射抗性的特定Keap1突变，以便能够鉴定 患有放射抵抗肿瘤的患者。与项目1合作，我们还将测试补体抑制剂是否 PMX205可作为Keap1/NFE2L2突变体NSCLC的额外放射增敏剂。最后，在协作方面 在项目2中，我们将测试谷氨酰胺酶抑制是否可以使NFE2L2突变的头颈癌变得对辐射敏感。 如果成功，我们的项目将建立谷氨酰胺酶抑制作为一种精确的放射肿瘤学策略 KEAP1/NFE2L2突变体NSCLC的个体化放射增敏作用这种方法可以扩大治疗的范围。 RT指数，因为它只会使局部复发风险最高的患者暴露于潜在的额外 添加辐射敏感剂的毒性。我们的结果将作为开发临床试验的基础 来翻译这一策略。这些试验将包括对接受RT的非小细胞肺癌患者进行基因分型，以便选择 同时接受RT和谷氨酰胺酶抑制剂治疗的Keap1/NFE2L2突变患者。重要的是 我们的发现将作为原则证据，很可能也可以转化为其他常见的肿瘤类型 Keap1/NFE2L2突变。

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.