Molecular Strategies to Widen the Therapeutic Index of Radiotherapy

摘要（总体） 该项目资助的中心假设是，我们对肿瘤基因组学的了解和 微环境，结合我们对正常组织生物学的理解，可以用来保护正常组织。 组织免受辐射（RT）损伤，同时选择性地杀死肿瘤细胞，从而提高治疗指数。 该项目和核心，包括这笔赠款代表了一个高度综合的努力，一个单一的重点， 拓宽了放射治疗的治疗指数。项目1（Giaccia）将调节 肿瘤和正常组织的辐射防护通过补体途径，并将旨在了解 抑制C5 aR 1如何用于致敏胃肠道（GI）肿瘤和保护胃肠道（GI）肿瘤的机制基础。 来自RT的腹部组织。他们还将探索C5 aR 1抑制在其他正常组织中的作用， 与其他项目和核心的合作。项目2（Le）将专注于激活醛脱氢酶- 3A 1（ALDH 3A 1）减轻头颈癌（HNC）患者中RT诱导的严重口干， 柠檬烯，一种新的ALDH 3A 1激活剂，由他们的小组确定，在I期临床试验。在关注HNC的同时， 他们将评估d-柠檬烯在辐射保护其他正常组织中的作用， 项目和核心。项目3（Diehn）将为以下患者制定个性化的放射增敏策略： KEAP 1/NFE 2L 2突变型非小细胞肺癌（NSCLC），基于他们先前的工作， 作为NSCLC患者放射抗性的关键决定因素。他们将检验一个假设， 谷氨酰胺酶抑制剂优先使KEAP 1突变型NSCLC放射增敏，而不增强正常肺组织 毒性在关注NSCLC的同时，他们还将评估转氨酶抑制对其他NSCLC患者的影响。 KEAP 1/NFE 2L 2突变肿瘤及其对正常组织的影响，与其他项目和核心合作。 项目4（兰金）测试了抑制FTO（脂肪量和肥胖相关蛋白）（一种RNA）的假设， 脱甲基酶，将增强RT在多种实体瘤中的功效。这是基于他们的初步数据 显示FTO在许多癌症中过表达，包括宫颈癌、肺癌和HN癌，FTO抑制 通过抑制谷氨酰胺代谢减少癌细胞生长并增强RT敏感性。他们 将确定FTO抑制与RT联合治疗的治疗效果和作用机制。 多个癌症模型与其他项目和核心合作。他们还将研究FTO的影响 抑制正常组织对RT的反应。如果成功，D-柠檬烯，一种营养品，可以在 更大规模的II期和III期临床试验，以供未来临床使用。类似地，PMX 205（一种C5 aR 1抑制剂）和CB-839（一种C5 aR 1抑制剂）也可用于治疗癌症。 谷氨酰胺酶抑制剂）目前正在临床试验中评估其他临床适应症，而药物 针对FTO正在积极开发中。因此，拟议的项目可能会迅速导致临床研究， 可能会影响癌症患者的治疗。

Abstract (Overall) The central hypothesis of this program project grant is that our knowledge of tumor genomics and the microenvironment, combined with our understanding of normal tissue biology, can be exploited to protect normal tissues from radiation (RT) damage while selectively killing tumor cells, leading to an improved therapeutic index. The projects and cores that comprise this grant represent a highly integrated effort with a single focus of widening the therapeutic index of radiotherapy. Project 1 (Giaccia) will modulate the radiosensitivity of tumors and radioprotection of normal tissues via the complement pathway and will aim to understand the mechanistic basis of how inhibition of C5aR1 serves to sensitize gastrointestinal (GI) tumors and protect abdominal tissues from RT. They will also explore the role of C5aR1 inhibition in other normal tissues in collaboration with the other projects and cores. Project 2 (Le) will focus on activating Aldehyde Dehydrogenase- 3A1 (ALDH3A1) to mitigate RT-induced severe dry mouth in head and neck cancer (HNC) patients by testing d- limonene, a novel ALDH3A1 activator identified by their group, in a phase I clinical trial. While focusing on HNC, they will evaluate the effect of d-limonene in radioprotecting other normal tissues in collaboration with the other projects and cores. Project 3 (Diehn) will develop a personalized radiosensitization strategy for patients with KEAP1/NFE2L2 mutant non-small cell lung cancer (NSCLC) based on their prior work that identified mutations in this pathway as key determinants of radioresistance in NSCLC patients. They will test the hypothesis that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant NSCLC without enhancing normal lung tissue toxicity. While concentrating on NSCLC, they will also evaluate the effects of glutaminase inhibition in other KEAP1/NFE2L2 mutant tumors and its effect on normal tissues in collaboration with other projects and cores. Project 4 (Rankin) tests the hypothesis that inhibition of FTO (Fat mass and obesity-associated protein), an RNA demethylases, would enhance the efficacy of RT in multiple solid tumors. This is based on their preliminary data showing that FTO is overexpressed in many cancers including cervical, lung and HN cancers, that FTO inhibition reduces cancer cell growth and enhances RT sensitivity through the inhibition of glutamine metabolism. They will determine the therapeutic effects and mechanism of action of FTO inhibition in combination with RT in multiple cancer models in collaboration with the other projects and cores. They will also study the effect of FTO inhibition on normal tissue response to RT. If successful, D-limonene, a nutraceutical, can be rapidly tested in larger phase II and III clinical trials for future clinical use. Similarly, PMX 205 (a C5aR1 inhibitor) and CB-839 (a glutaminase inhibitor) are currently being evaluated in clinical trials for other clinical indications while drugs targeting FTO are in active development. Thus the proposed projects could rapidly lead to clinical studies that could impact the management of cancer patients.