Multimodal MRI for guiding bacterial cancer therapy

多模态 MRI 指导细菌癌症治疗

• 批准号: 10633262
• 负责人: Renyuan Bai
• 金额: $ 36.39万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-02 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633262
• 关键词: Acceleration; Address; Algorithms; Anaerobic Bacteria; Animal Model; Antibiotic Therapy; Area; Bacteria; Bacterial Infections; Chemicals; Clinical; Clinical Trials; Data; Development; Doxycycline; Equilibrium; Germination; Goals; Histology; Human; Hypoxia; Image; Imaging Device; Imaging technology; Infection; Location; Magnetic Resonance Imaging; Measures; Medicine; Methods; Mission; Modeling; Monitor; Mus; Neurofibrosarcoma; Oncologist; Oxygen; Patient Recruitments; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Predictive Value; Proliferating; Protocols documentation; Public Health; Radiology Specialty; Research Personnel; Safety; Sepsis; Signs and Symptoms; Solid Neoplasm; Speed; Stratification; Surrogate Markers; Systemic infection; TP53 gene; Technology; Therapeutic; Therapeutic Effect; Time; Transgenic Organisms; Translating; Translations; Treatment Efficacy; United States National Institutes of Health; Vascularization; cancer therapy; clinical investigation; detection sensitivity; feasibility testing; image guided; improved; innovation; microbial; microbial based therapy; mortality; multidisciplinary; multimodality; non-invasive imaging; research clinical testing; response; sarcoma; success; technology platform; treatment planning; tumor; tumor hypoxia

In response to the specific FOA that explicitly focuses on microbial-based cancer therapy (Bugs as Drugs), we propose to develop reliable multimodal MRI guidance to improve the efficacy and safety of bacterial cancer therapies for treating poorly vascularized, hypoxic tumors, where conventional cancer therapies are inadequate. Even though some have managed to reach clinical trial status, the development of microbial-based therapeutics for solid tumors has been long hindered by inconsistent results. Researchers in the field of microbial-based therapeutics have a major problem of inadequate and inconsistent means of guiding, monitoring, and assessing results of administered microbial therapy. Currently, the patient recruitment criteria for bacterial therapy are not specific and suitability is mainly judged by tumor size. The surrogate markers for bacterial germination/infection are radiological signs of tumor destruction and/or clinical signs and symptoms of systemic infection. There is an urgent need for developing noninvasive imaging tools that can identify patients who likely respond (stratification) by tumor hypoxia and real-time, quantitively measure the germination and proliferation of therapeutic bacteria in target tumors. To address these unmet needs, we will develop and optimize two emerging imaging technologies in this study: a) bacteria-detecting Chemical Exchange Saturation Transfer (CEST) MRI method (namely bacCEST) to assess bacterial infection in the tumor, serving as a non-invasive means to monitor therapeutic effects and adjust the treatment plan, and b) Oxygen-Enhanced (OE) MRI to characterize tumor hypoxia and hence predict the tumors’ vulnerability to anaerobic bacteria. We hypothesize that that the efficacy and safety of bacterial treatment can be significantly improved using non-invasive, multimodal MRI methods that can characterize tumor hypoxia prior to treatment and monitor bacterial infection at early time points. We have strong preliminary data demonstrating the efficacy of C. novyi-NT and capabilities of advanced MRI technologies, and gathered a multidisciplinary team of oncologists and imaging experts to complete the following aims: 1) Establish bacteria-detecting bacCEST MRI as a surrogate marker for C. novyi-NT treatment, 2) Establish hypoxia- detecting OE MRI to stratify tumors and guide bacterial treatment, and 3) Establish multimodal MRI guidance to improve the efficacy and safety of bacterial cancer therapy. Successful completion of the proposed study will provide approaches for multimodal MRI guidance that can ultimately improve the success rate of cancer therapies using anaerobic bacteria, including but not limited to C. novyi-NT. This MRI platform technology, once translated to human scanners, will address an unmet need in bacterial treatment and can accelerate the development and clinical testing of bacterial therapies. It will also benefit other areas in medicine (e.g., infection medicine/sepsis), thereby pushing clinical capabilities forward.

为了响应明确关注基于微生物的癌症治疗（作为药物）的特定FOA，我们 提出可靠的多模式MRI指南以提高细菌癌的效率和安全性的提议 治疗常规癌症疗法不足的血管化，低氧肿瘤治疗不足的疗法。 即使有些人设法达到了临床试验状态，但基于微生物的治疗的发展 对于实体瘤而言，长期以来一直受到不一致的结果的阻碍。基于微生物领域的研究人员 治疗存在指导，监测和评估不足和不一致手段的主要问题 管理微生物治疗的结果。目前，细菌疗法的患者招募标准不是 特定和适合性主要由肿瘤大小来判断。细菌发芽/感染的替代标记 是肿瘤破坏和/或全身感染症状的放射学体征。有一个 迫切需要开发可以识别可能反应的患者（分层）的非侵入性成像工具 通过肿瘤缺氧和实时，定量测量治疗细菌的发芽和增殖 靶肿瘤。为了满足这些未满足的需求，我们将开发和优化两种新兴成像技术 在这项研究中：a）细菌检测化学交换饱和转移（CEST）MRI方法（即 Baccest）评估肿瘤中的细菌感染，作为监测治疗的一种非侵入性手段 效应并调整治疗计划，b）氧增强（OE）MRI以表征肿瘤缺氧和 因此，预测肿瘤对厌氧细菌的脆弱性。我们假设 使用非侵入性的多模式MRI方法可以显着改善细菌治疗 在治疗前表征肿瘤缺氧，并在早期监测细菌感染。我们有强大 初步数据证明了C. novyi-NT的效率以及高级MRI技术的能力，以及 聚集了一个由肿瘤学家和成像专家组成的多学科团队，以完成以下目的：1）建立 细菌将Baccest MRI视为C. novyi-NT治疗的替代标记，2）建立缺氧 - 检测OE MRI以分层肿瘤并引导细菌治疗，3）建立多模式MRI指导 提高细菌癌症治疗的效率和安全性。拟议的研究成功完成将 提供多模式MRI指导的方法，这些指导最终可以提高癌症的成功率 使用厌氧菌的疗法，包括但不限于C. novyi-NT。这种MRI平台技术曾经 翻译成人类扫描仪，将满足细菌治疗中未满足的需求，并可以加速 细菌疗法的开发和临床测试。它也将使医学其他领域受益（例如，感染 药物/败血症），从而向前推动临床能力。