Multimodal MRI for guiding bacterial cancer therapy

多模态 MRI 指导细菌癌症治疗

• 批准号: 10443928
• 负责人: Renyuan Bai
• 金额: $ 38.17万
• 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/10443928
• 关键词: Address; Algorithms; Anaerobic Bacteria; Animals; Antibiotic Therapy; Area; Bacteria; Bacterial Infections; Blood Vessels; 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; 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; base; cancer therapy; detection sensitivity; feasibility testing; image guided; improved; innovation; microbial; mortality; multidisciplinary; multimodality; non-invasive imaging; research clinical testing; response; sarcoma; success; 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疗法（细菌作为药物）的特定 FOA，我们 建议开发可靠的多模态 MRI 指导，以提高细菌癌的疗效和安全性 用于治疗血管化不良、缺氧的肿瘤，而传统的癌症疗法在这些方面是不够的。 尽管有些已经成功达到临床试验状态，但基于微生物的疗法的发展 长期以来，基于微生物领域的研究人员的结果不一致一直阻碍着实体瘤的研究。 治疗的一个主要问题是指导、监测和评估手段不充分且不一致 目前，细菌治疗的患者招募标准尚未确定。 特异性和适用性主要根据细菌萌发/感染的替代标志物来判断。 是肿瘤破坏的放射学体征和/或全身感染的临床体征和症状。 对非侵入性成像工具的迫切需求可以识别可能有反应的患者（分层） 通过肿瘤缺氧实时定量测量肿瘤内治疗性细菌的萌发和增殖情况 为了解决这些未满足的需求，我们将开发和优化两种新兴的成像技术。 本研究中：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，作为监测治疗的非侵入性手段 b) 氧增强 (OE) MRI 来表征肿瘤缺氧和 因此，我们预测了肿瘤对厌氧细菌的脆弱性。 使用非侵入性多模态 MRI 方法可以显着改善细菌治疗，这些方法可以 在治疗前表征肿瘤缺氧并在早期时间点监测细菌感染。 初步数据证明了 C. novyi-NT 的功效和先进 MRI 技术的能力，以及 聚集了一个由肿瘤学家和影像专家组成的多学科团队来完成以下目标：1）建立 细菌检测 bacCEST MRI 作为 C. novyi-NT 治疗的替代标记，2) 建立缺氧- 检测 OE MRI 以对肿瘤进行分层并指导细菌治疗，以及 3) 建立多模态 MRI 指导 成功完成拟议的研究将提高细菌癌症治疗的功效和安全性。 提供多模式 MRI 指导方法，最终提高癌症的成功率 使用厌氧菌的疗法，包括但不限于 C. novyi-NT 这种 MRI 平台技术。 转化为人体扫描仪，将解决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也将有益于医学的其他领域（例如感染）。 医学/脓毒症），从而推动临床能力向前发展。