Optimizing and Monitoring C.novyi Therapy of Metastic Colorectal Cancer

转移性结直肠癌的优化和监测 C.novyi 疗法

• 批准号: 7686208
• 负责人: SHIBIN ZHOU
• 金额: $ 22.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7686208
• 关键词: Anaerobic Bacteria; Animal Model; Animals; Antineoplastic Agents; Area; Attenuated; Bacteria; Bacterial Infections; Biological Assay; Biological Markers; Class; Clinical Research; Clinical Trials; Clostridium; Colorectal Cancer; Development; Environment; Experimental Neoplasms; Funding; Genes; Germination; Goals; Hypoxia; Image; Immune response; Invaded; Investigational New Drug Application; Label; Mammalian Cell; Methods; Modality; Monitor; Mus; Oryctolagus cuniculus; Outcome; Oxygen measurement, partial pressure, arterial; Patients; Personal Satisfaction; Phase; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Process; Proliferating; Public Health; Purpose; Radiation; Radiation therapy; Radiolabeled; Reproduction spores; Research; Research Support; Resistance; Safety; Surrogate Markers; System; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Treatment outcome; Tumor Tissue; United States Food and Drug Administration; Validation; anthrax lethal factor; base; cancer cell; cancer therapy; fialuridine; insight; interest; killings; neoplastic cell; novel; preclinical study; programs; radiotracer; response; tumor

Our long-term objective is to develop novel cancer therapies employing an attenuated strain of anaerobic bacteria called C. novyi-NT. When injected intravenously, C. novyi-NT spores are not toxic to healthy animals but can selectively germinate and spread within tumors, leading to substantial cures when combined with conventional therapies. Our IND (ref #BB-IND 12698) for C. novyi-NT single-agent therapy has recently been approved by the FDA and we are expecting to initiate a Phase I clinical trial within a month. As this clinical trial and the subsequent Phase II trial will involve C. novyi-NT, a "first-in-class" anticancer agent, sensitive surrogate makers are urgently needed to meet efficacy and safety concerns. Therefore, in the next funding cycle, our research effort will be focused on the development and validation of biomarkers that can predict therapeutic outcomes. The following specific aims reflect our short-term objectives. Aim 1. To develop circulating biomarkers for efficacy and toxicity associated with C. novyi-NT therapy in experimental systems: we will investigate three classes of biomarkers in preclinical studies in mice: (1) markers associated with host responses, (2) markers reflecting C. novyi-NT germination and invasion, and (3) markers indicating tumor response. Aim 2. To assess and develop circulating biomarkers in clinical trials: we will assess the biomarkers and assays developed in the animal models in Phase I and Phase II clinical trials, and validate them in subsequent larger clinical studies. Aim 3. To develop imaging modalities suitable for monitoring therapeutic responses: we have recently invented a method for imaging bacterial infection with radioactively labeled FIAU in animal models. In this aim, we will develop and implement this method to assess the correlation between C. novyi-NT colonization and treatment responses in both animal models and clinical trials. Aim 4. To investigate radiolabeled FIAU as a therapeutic agent: we will assess the possibility that [131IJFIAU can generate local radiation sufficiently potent to obliterate the well-oxygenated tumor rims resistant to C. novyi-NT. From the public health perspective, this new therapy we are developing utilizes a special strain of bacteria that only grows within tumors and kills cancer cells resistant to chemo and radiation therapies.

我们的长期目标是使用厌氧菌株开发新的癌症疗法 细菌称为C. novyi-nt。当静脉注射时，novyi-nt孢子对健康没有毒性 动物，但可以选择性地发芽并扩散在肿瘤中，合并后会导致大量治疗 进行常规疗法。我们的IND（Ref＃BB-IND 12698）用于C. Novyi-NT单药治疗 已获得FDA的批准，我们预计将在一个月内启动I期临床试验。这样 临床试验和随后的II期试验将涉及C. novyi-NT，这是一种“一流”的抗癌剂， 迫切需要敏感的替代制造商来满足疗效和安全问题。因此，在下一个 资助周期，我们的研究工作将集中在生物标志物的开发和验证上 预测治疗结果。以下特定目标反映了我们的短期目标。目标1 开发循环生物标志物，以实验中与Novyi-NT治疗相关的功效和毒性 系统：我们将研究小鼠临床前研究中的三类生物标志物：（1）标记 与宿主反应相关，（2）反映C. novyi-nt发芽和入侵的标记，以及（3） 标记表明肿瘤反应。目标2。在临床试验中评估和开发循环生物标志物：我们 将评估在动物模型中在I期和II期临床试验中开发的生物标志物和测定， 并在随后的较大临床研究中验证它们。目标3。开发适合的成像方式 监测治疗反应：我们最近发明了一种对细菌感染进行成像的方法 动物模型中的放射性标记为FIAU。在此目标中，我们将开发并实施此方法 评估两种动物模型中Novyi-NT定殖与治疗反应之间的相关性 和临床试验。目的4。将放射标签的FIAU作为治疗剂进行研究：我们将评估 [131ijfiau可以产生足够有效的局部辐射以抑制氧化良好的可能性 肿瘤边缘对C. novyi-nt具有抗性。 从公共卫生的角度来看，我们正在开发的这种新疗法利用了特殊的细菌 这仅在肿瘤内生长并杀死抗化疗和辐射疗法的癌细胞。