Improving glioma radiotherapy by theragnostic targeting of tumor-supporting macrophages

放射治疗是胶质母细胞瘤（GBM）患者标准治疗中不可或缺的一部分;然而， 尽管最初对放射治疗有反应，但GBM总是复发。改进GBM的拟议战略 放射治疗包括放射治疗和靶向肿瘤相关巨噬细胞的治疗相结合 （TAM）。然而，缺乏TAM靶向治疗改善GBM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， TAM靶向治疗改变了放疗。该项目的主要目标是确定 将TAM靶向整合到临床相关的细胞毒性机制和抗肿瘤功效 放疗方案。对于这些研究，TAM的治疗靶向将通过重新利用 FDA批准的药物ferumoxytol主要假设是，ferumoxytol将减少 免疫抑制性肿瘤促进性TAM。TAM的这种减少预计会增加神经胶质瘤细胞的数量。 通过破坏TAM-胶质瘤细胞异型存活信号传导和增加对放射治疗的敏感性， 辐射诱导的抗肿瘤免疫应答。这一假设将使用放射治疗进行评估 方案类似于两类患者的临床护理标准：新诊断的 GBM（目标1）和复发性GBM（目标2）。这将包括完成以下目标： 确定细胞毒性机制和将ferumoxytol与常规分级的 目的2）评价ferumoxytol增强大分割放疗的能力。目标1将 在体外共培养模型和同基因组模型中评估ferumoxytol与放射治疗的组合。 啮齿动物模型。目的2将评价联合使用ferumoxytol和大分割放射治疗的疗效。 临床相关犬伴侣研究。对于这两个目的，在体内递送和保留ferumoxytol 将使用磁共振成像（MRI）非侵入性地验证肿瘤区域。调查人员 我相信这项研究是创新的，因为它重新利用了一种已经建立的神经胶质瘤成像剂 （ferumoxytol），用于治疗不确定性TAM靶向。如果ferumoxytol没有证明如预期的那样有效， 加强放射治疗，这些研究将把重点转移到其他有前途的TAM靶向治疗， 由调查小组开发。在拟议研究完成后，这项计划将 建立了TAM靶向治疗与 放疗预计这一贡献将是重要的，原因有二：它将提供知识 关于TAM在调节神经胶质瘤细胞对放疗的抗性中的作用;这将导致发展 更有效的辐射策略。鉴于放射疗法治疗癌症的普遍性， 这种治疗方法的发展有可能改善许多患者的结果。

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.