Improving glioma radiotherapy by theragnostic targeting of tumor-supporting macrophages

通过肿瘤支持巨噬细胞的治疗诊断靶向改善神经胶质瘤放射治疗

• 批准号: 10629547
• 负责人: Matthew Scarpelli
• 金额: $ 38.15万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629547
• 关键词: Brain Neoplasms; Canis familiaris; Caring; Cells; Clinical; Coculture Techniques; Comb animal structure; Companions; Development; Effectiveness; Ensure; FDA approved; Fractionated radiotherapy; Glioblastoma; Glioma; Goals; Human; Immunologic Stimulation; In Vitro; Knowledge; Macrophage; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Microglia; Mission; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Newly Diagnosed; Outcome; Patients; Predisposition; Prevalence; Progression-Free Survivals; Public Health; Radiation; Radiation therapy; Recurrence; Regimen; Research; Research Personnel; Resistance; Rodent; Rodent Model; Role; Safety; Signal Transduction; Supporting Cell; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Tumor Promotion; Tumor-associated macrophages; anti-tumor immune response; burden of illness; clinical translation; clinically relevant; cytotoxic; design; ferumoxytol; imaging agent; immunosuppressive macrophages; improved; improved outcome; in vivo; innovation; insight; iron deficiency; iron oxide nanoparticle; neoplastic cell; nervous system disorder; response; standard care; targeted agent; targeted treatment; therapeutic development; therapeutic target; therapy resistant; tool; tumor; tumor microenvironment

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.

放射疗法是胶质母细胞瘤（GBM）患者标准护理必不可少的一部分。然而， 尽管对放疗的初步反应，但GBM始终反复出现。提出的改善GBM的策略 放射疗法涉及将靶向肿瘤相关巨噬细胞的放射疗法和治疗结合 （tams）。但是，缺乏既定的靶向疗法可以改善GBM的既定机制 放射疗法已受到临床翻译的障碍。那迫切需要建立机制 通过这种靶向治疗改变了放射疗法。该项目的主要目的是确定 将TAM靶向临床相关的TAM靶向的细胞毒性机制和抗肿瘤效率 放射治疗方案。对于这些研究，将通过重新利用来实现TAM的治疗靶向 FDA批准的剂ferumoxytol。主要的假设是，铁氧基二醇将减少 免疫抑制，促进肿瘤的TAM。 TAM的这种减少有望增加神经胶质瘤细胞 通过破坏TAM-GLIoma细胞异型生存信号传导和增加的敏感性对放射治疗的敏感性 辐射引起的抗肿瘤免疫复杂。该假设将使用放射治疗评估 与两种类型的患者相似的治疗方案 GBM（AIM 1）；以及具有复发性GBM的人（AIM 2）。这将包括以下目标的完成：目标1） 确定将铁氧基与常规分数组合的细胞毒性机制和有效性 放射疗法；目标2）评估铁氧基增强次级放射疗法的能力。目标1意志 评估在体外结合模型和同性素性中，黄铁二醇与放射疗法的组合 啮齿动物模型。 AIM 2将在A 与翻译相关的犬合作伙伴研究。对于这两个目的，在内部的铁氧二醇的递送和保留 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 认为拟议的研究具有创新性，因为它可以重新利用已建立的神经胶质瘤成像剂 （铁氧基），用于热染色的TAM靶向。如果ferumoxytol不如预期的那样有效 增强放射疗法，这些研究将把重点转移到其他有前途的TAM靶向疗法中 由调查团队开发。拟议的研究完成后，该项目将有 建立了将TAM靶向治疗与 放疗。预计该贡献将是重要的，原因有两个：它将提供知识 关于TAM在调节神经胶质瘤细胞对放射疗法的抗性中的作用；这将导致发展 更有效的放射治疗策略。考虑到放疗治疗癌症的患病率， 这种理论方法的发展有可能改善许多患者的预后。