Improving glioma radiotherapy by theragnostic targeting of tumor-supporting macrophages

放射治疗是胶质母细胞瘤(GBM)患者标准护理中不可或缺的一部分；然而， 尽管对放射治疗有初步反应，但基底膜瘤总是复发。一种改进GBM的建议策略 放射治疗包括结合放射治疗和针对肿瘤相关巨噬细胞的治疗 (TAMS)。然而，缺乏靶向治疗改善基底膜的既定机制 放射治疗对临床转化构成了障碍。因此，迫切需要建立机制。 通过靶向治疗改变了放射治疗。该项目的主要目标是确定 临床相关靶向整合的细胞毒作用机制及抗肿瘤作用 放射治疗方案。在这些研究中，TAMs的治疗靶点将通过改变用途来实现 FDA批准的药剂阿魏酸甘油。主要的假设是阿魏酸甘油酯会减少 免疫抑制，促进肿瘤的TAMS。这种TAMs的减少预计会增加胶质瘤细胞 -脑胶质瘤细胞异型生存信号转导与放射增敏 辐射诱导的抗肿瘤免疫反应。这一假设将通过放射治疗进行评估。 与临床护理标准相似的方案适用于两类患者：新诊断的患者 基底膜(目标1)；和复发性基底膜(目标2)。这将包括完成以下目标：目标1) 阿魏酸甘油酯与常规分离的阿魏酸甘油酯联合应用的细胞毒性机制及疗效研究 目的2)评价阿魏酸甘油增强低分割放射治疗的能力。目标1将 在体外共培养模型和同基因移植模型中评价阿魏酸甘油与放射治疗的联合应用 啮齿动物模型。目的2评价阿魏酸甘油酯与低分割放射治疗的联合治疗 与翻译相关的犬类伴侣研究。对于这两个目标，阿魏酸甘油酯在体内的释放和保留 肿瘤区域将使用磁共振成像(MRI)进行非侵入性验证。调查人员 我相信这项拟议的研究是创新的，因为它改变了现有的胶质瘤显像剂的用途 (阿魏酸甘油酯)，用于不可知论者的靶向。如果阿魏酸甘油酯不像预期的那样有效 加强放射治疗，这些研究将把重点转移到其他有前途的靶向治疗上 由调查小组开发。在完成建议的研究后，这项计划将会有 建立了靶向治疗与联合应用的细胞毒作用机制 放射治疗。预计这一贡献将是重大的，原因有两个：它将提供知识 关于TAMS在调节胶质瘤细胞对放射治疗的抵抗中的作用；它将导致发展 更有效的放射治疗策略。考虑到治疗癌症的放射治疗的盛行， 这种治疗方法的发展有可能改善许多患者的预后。

Radiotherapy is an indispensable part of the standard care for glioblastoma (GBM) patients; however, despite initial responses to radiotherapy, GBMs invariably recur. A proposed strategy for improving GBM radiotherapy involves combining both radiotherapy and therapy targeting tumor-associated macrophages (TAMs). However, lack of an established mechanism by which TAM-targeted therapy improves GBM radiotherapy has posed a barrier to clinical translation. Thus, there is an urgent need to establish mechanisms by which TAM-targeted therapy alters radiotherapy. The main objective of this project is to determine the cytotoxic mechanisms and anti-tumor efficacy of integrating TAM targeting within clinically relevant radiotherapy regimens. For these studies, therapeutic targeting of TAMs will be accomplished by repurposing the FDA-approved agent ferumoxytol. The main hypothesis is that ferumoxytol will reduce immunosuppressive, tumor-promoting TAMs. This reduction in TAMs is expected to increase glioma cell sensitivity to radiotherapy by both disrupting TAM-glioma cell heterotypic survival signaling and increasing radiation-induced anti-tumor immune responses. This hypothesis will be evaluated using radiotherapy regimens that are similar to clinical standards of care for two types of patients: those with newly diagnosed GBM (Aim 1); and those with recurrent GBM (Aim 2). This will include completion of the following aims: Aim 1) determine cytotoxic mechanisms and efficacy of combining ferumoxytol with conventionally fractionated radiotherapy; and Aim 2) evaluate ferumoxytol’s ability to augment hypofractionated radiotherapy. Aim 1 will evaluate the combination of ferumoxytol with radiotherapy in both in vitro coculture models and syngeneic rodent models. Aim 2 will evaluate the combination of ferumoxytol and hypofractionated radiotherapy in a translationally-relevant canine companion study. For both aims, the delivery and retention of ferumoxytol within tumor regions will be verified non-invasively using magnetic resonance imaging (MRI). The investigators believe the proposed research is innovative because it repurposes an established glioma imaging agent (ferumoxytol), for theragnostic TAM targeting. If ferumoxytol does not prove as effective as expected for enhancing radiotherapy, these studies will shift focus to other promising TAM-targeted therapeutics being developed by the investigative team. Upon completion of the proposed studies, this project will have established the therapeutic efficacy and cytotoxic mechanisms of combining TAM-targeted therapy with radiotherapy. This contribution is expected to be significant for two reasons: it will provide knowledge regarding the role of TAMs in modulating glioma cell resistance to radiotherapy; and it will lead to development of more effective radiotherapeutic strategies. Given the prevalence of radiotherapy for treating cancer, development of this therapeutic approach has the potential to improve outcomes for many patients.