Molecular Strategies to Widen the Therapeutic Index of Radiotherapy

摘要(总体) 该计划项目拨款的中心假设是，我们对肿瘤基因组学的知识和 微环境，结合我们对正常组织生物学的理解，可以被用来保护正常的 放射(RT)损伤组织，同时选择性地杀死肿瘤细胞，从而提高了治疗指数。 组成这笔赠款的项目和核心代表着高度整合的努力，其重点是 拓宽放射治疗指标。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C5aR1对胃肠道肿瘤增敏和保护作用的机制基础 取自RT的腹部组织。他们还将探索C5aR1抑制在其他正常组织中的作用 与其他项目和核心合作。项目2(Le)将专注于激活乙醛脱氢酶- 3A1(ALDH3A1)通过检测d-D来减轻头颈癌(HNC)患者放疗诱导的严重口干 柠檬烯，一种由他们的小组确定的新型ALDH3A1激活剂，在I期临床试验中。在专注于HNC的同时， 他们将与其他正常组织合作，评估d-柠檬烯对其他正常组织的辐射防护效果。 项目和核心。项目3(Diehn)将为患有以下疾病的患者开发个性化的放射增敏策略 Keap1/NFE2L2突变的非小细胞肺癌(NSCLC)基于他们之前的工作，发现了突变 这一通路是非小细胞肺癌患者放射抵抗的关键决定因素。他们将检验这一假设 谷氨酰胺酶抑制优先辐射增敏Keap1突变型非小细胞肺癌而不增强正常肺组织 毒性。在专注于非小细胞肺癌的同时，他们还将评估谷氨酰胺酶抑制对其他 Keap1/NFE2L2突变肿瘤及其与其他项目和核心合作对正常组织的影响。 项目4(Rankin)测试了这样的假设：抑制FTO(脂肪质量和肥胖相关蛋白)是一种RNA 去甲基酶可提高RT治疗多发性实体瘤的疗效。这是基于他们的初步数据 研究表明，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，提高放射治疗的敏感性。他们 将确定抑制FTO与RT联合治疗的疗效及作用机制 与其他项目和核心合作的多种癌症模型。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，一种营养食品，可以在 更大的II期和III期临床试验，供未来临床使用。同样，PMX 205(一种C5aR1抑制剂)和CB-839(a 谷氨酰胺酶抑制剂)目前正在进行其他临床适应症的临床试验，而药物 瞄准FTO正在积极发展。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管理。

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.