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）的治疗中起着至关重要的作用。而 肿瘤成像和放射输送技术的进步显著改善了RT， 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管理 因此，“精确放射肿瘤学”方法的发展，定义为使用分子放射治疗。 用于个性化RT的生物标志物仍然是一个主要的未满足的需求。我们的长期目标是开发新颖， 基于分子的精确放射肿瘤学方法用于接受RT治疗的NSCLC患者。 研究表明，具有KEAP 1或NFE 2L 2突变的NSCLC具有放射抗性，并且具有高的局部肿瘤发生率。 在本提案中，我们将制定个性化的放射增敏策略， KEAP 1/NFE 2L 2突变型肿瘤基于对在生物合成中起关键作用的转氨酶的抑制。 细胞自由基防御系统先前的研究发现，关于转氨酶的能力， 抑制放射增敏NSCLC。我们的中心假设是，转氨酶抑制可以放射增敏 KEAP 1/NFE 2L 2突变体而不是野生型NSCLC，如果正确，将有助于解释先前的冲突。 结果因此，我们将测试我们的基因型特异性放射增敏方法在KEAP 1/NFE 2L 2中是否有效 突变型而非野生型NSCLC。我们还将测试我们的方法是否会增加正常组织毒性。 此外，我们将确定导致辐射抗性的特定KEAP 1突变，以便能够识别 放射性肿瘤患者。与项目1合作，我们还将测试补体抑制剂是否 PMX 205可作为KEAP 1/NFE 2L 2突变型NSCLC的额外放射增敏剂。最后，在合作中 在项目2中，我们将测试转氨酶抑制是否可以使NFE 2L 2突变型头颈癌放射增敏。 如果成功，我们的项目将建立转氨酶抑制作为一种精确的放射肿瘤学策略， KEAP 1/NFE 2L 2突变型NSCLC的个体化放射增敏。这种方法可以扩大治疗范围， 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风险， 添加辐射敏化剂的毒性。我们的结果将作为临床试验的基础， 翻译这个战略。这些试验将涉及接受RT的NSCLC患者的基因分型，以选择 KEAP 1/NFE 2L 2突变患者同时接受RT和转氨酶抑制剂治疗。重要的是， 我们的研究结果将作为原理证明，也可能转化为其他肿瘤类型， KEAP 1/NFE 2L 2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.