Development of PET imaging biomarkers to predict enhanced glioblastoma radiotherapy by a novel H-NOX oxygen carrier

开发 PET 成像生物标志物来预测新型 H-NOX 氧载体增强的胶质母细胞瘤放疗

• 批准号: 9240463
• 负责人: Simon R Cherry
• 金额: $ 60.27万
• 依托单位: OMNIOX, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240463
• 关键词: Adjuvant; Affinity; Animals; Award; Binding; Biochemical; Biological Markers; Biological Sciences; Blood Vessels; Brain; Brain Neoplasms; Brain imaging; California; Cancer Patient; Canis familiaris; Carrier Proteins; Cherry - dietary; Clinical; Clinical Research; Clinical Trials; Collaborations; Common Neoplasm; Data; Development; Diagnosis; Diffuse; Disease Progression; Down-Regulation; Drug Kinetics; Effectiveness; Engineering; Enzyme-Linked Immunosorbent Assay; Future; Glioblastoma; Glioma; Goals; Grant; Human; Hypoxia; Image; Immunohistochemistry; Intracranial Neoplasms; Label; Lead; Malignant neoplasm of brain; Measurement; Measures; Mediating; Medical; Modeling; Morphology; Mus; Newly Diagnosed; Normal tissue morphology; Outcome; Oxygen; Partial Pressure; Patient-Focused Outcomes; Patients; Pharmacodynamics; Phase; Positron-Emission Tomography; Preclinical Testing; Protein Family; Proteins; Protocols documentation; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Randomized; Rattus; Resected; Resistance; Resolution; Rodent; Safety; San Francisco; Scanning; Schedule; Series; Signal Transduction; Small Business Innovation Research Grant; Solid; Solid Neoplasm; Surrogate Endpoint; Technology; Testing; Tissues; Toxicology; Tracer; Treatment Efficacy; Trust; Tumor Burden; Tumor Oxygenation; Tumor Tissue; Universities; Variant; Veterinary Medicine; Veterinary Schools; cancer imaging; candidate marker; chemotherapy; clinically relevant; clinically translatable; cohort; companion diagnostics; design; drug candidate; imaging biomarker; imaging modality; imaging study; improved; in vivo; innovation; killings; mortality; neoplastic cell; novel; patient population; pre-clinical; preclinical study; predictive marker; prevent; radiation response; standard of care; subcutaneous; thermostability; transcription factor; translational approach; tumor; tumor growth; tumor heterogeneity

1. Project Summary/Abstract Hypoxia (low oxygen) is a known key driver of tumor aggressiveness and tumor resistance to radiation treatment (RT) in a variety of solid cancers1-8. Given that about 50% of cancer patients receive RT (~800,000 cases per year in the US), Omniox has developed a novel oxygen carrier protein, OMX, which is engineered to specifically deliver oxygen to low oxygen regions of tumors and enhance RT efficacy. Omniox is supported by NCI SBIR (Phase I, II, IIb) and Wellcome Trust translational awards to test its lead drug candidate as an adjuvant to standard-of-care RT for the treatment of newly diagnosed glioblastoma (GB) patients. Omniox has received FDA pre-IND support for, and is currently conducting, IND-enabling manufacturing and GLP toxicology studies for the first-in-human clinical trial scheduled at the University of California, San Francisco (UCSF) for 2017. Importantly, non-invasive PET imaging with hypoxia-selective agents has shown that hypoxic volume in GB tumors is strongly associated with rapid disease progression and poor survival1 due to its blunting effects on standard-of-care RT. Previous efforts to oxygenate tumors in human clinical trials have shown ambiguous results due in part to heterogeneity in tumor hypoxic burden and the lack of targeted approach for patient selection13. Therefore, the goal of this proposal is to develop predictive non-invasive PET imaging biomarkers that will identify the GB patient population that can substantially benefit from OMX therapy. Omniox and the UC Davis School of Veterinary Medicine completed a Phase 0 canine clinical trial to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of OMX in canine patients presenting with brain tumors. As part of the trial, Omniox partnered with Brain Biosciences to use their PET scanner designed specifically for brain imaging (CerePET™). Omniox and the key collaborators on this AIP grant, Drs. Simon Cherry (Aim 1) and Allison Zwingenberger (Aim 2) at UC Davis, and David Beylin of Brain Biosciences (Aims 1 and 2) are developing protocols for PET imaging of canine brain patients, with successful initial scans already generated. In this proposal, we will build on our positive preliminary results in rodents and canines to evaluate imaging of tumor hypoxia and OMX tumor accumulation as predictive biomarkers of OMX activity in an intracranial rat GB model and in canine glioma patients. These data will then be used to inform an IND application and a human biomarker clinical trial. Developed from the thermostable H-NOX protein family discovered at UC Berkeley, OMX is a trimerized, PEGylated H-NOX oxygen (O2)-binding variant engineered to diffuse deep into hypoxic tumor tissue commonly associated with leaky blood vessels. The H-NOX moiety has been engineered to have a high affinity for O2 whereby it retains O2 in normoxic tissue and specifically releases it in regions of severe hypoxia. Omniox has completed a series of preclinical studies that support this proposal: 1) OMX is biochemically well-characterized and is currently being manufactured at high yields and purity for GLP toxicology and human GB clinical trials 2) OMX has been safely administered to over a thousand mice and rats, several healthy Beagle dogs, globally hypoxic lambs, and fifteen canine brain cancer patients from our canine clinical trial (Table 1) 3) OMX extravasates across the leaky vasculature and accumulates in hypoxic tumor tissue as seen in: a) mouse and rat intracranial tumors using immunohistochemistry (IHC) (Fig. 1) and ELISA (data not shown); b) tumor bearing mice and rats using PET imaging of 89Zr-labeled OMX (Fig. 5); and c) in tumors of canine brain cancer patients as seen by IHC and ELISA (Fig. 6) 4) OMX administration oxygenates tumors as demonstrated by: a) the direct measurement of increased oxygen partial pressure (pO2 ) using an OxyliteTM probe inserted into hypoxic mouse tumor tissue (Fig. 2); downregulation of hypoxia-regulated transcription factors and downstream signaling as measured by IHC, FACS,(data not shown), and ELISA (Fig. 3); and c) hypoxia reduction in rat intracranial tumors as measured by 18F-FMISO signal, a PET hypoxia tracer, in a pilot imaging study (Fig. 5). 5) Mice bearing subcutaneous tumors treated with OMX prior to RT showed significant delays in tumor growth and a 50% cure rate compared to mice treated with RT alone (Fig. 4) 6) CerePET can be used to image rat and canine brains with high resolution (Fig. 7) In this proposal, we present an innovative translational strategy to develop and preclinically test a PET imaging companion diagnostic that can potentially be used as a predictive marker of drug candidate efficacy in future human clinical trials. We will build on our existing results in intracranial rat and mouse tumor models and canine glioma patients to optimize and validate a non-invasive clinically relevant imaging method that, if confirmed in human clinical studies, will enable selection of a targeted patient population whose RT treatment is likely to be substantially enhanced by OMX-mediated tumor oxygenation. ©2016 Omniox, Inc. CONFIDENTIAL – Not for Distribution

1.项目总结/摘要 缺氧（低氧）是已知的肿瘤侵袭性和肿瘤对辐射抵抗的关键驱动因素 治疗（RT）在各种实体癌1 -8。鉴于约50%的癌症患者接受RT（约80万）， Omniox开发了一种新的氧载体蛋白OMX， 特异性地将氧输送到肿瘤低氧区域并增强RT功效。Omniox由以下公司提供支持： NCI SBIR（I，II，IIb期）和Wellcome Trust翻译奖，以测试其先导候选药物作为 辅助标准护理RT治疗新诊断的胶质母细胞瘤（GB）患者。Omniox拥有 获得FDA的IND前支持，目前正在进行IND支持生产和GLP 计划在加州大学旧金山弗朗西斯科进行的首次人体临床试验的毒理学研究 （UCSF）2017年。重要的是，使用低氧选择性药物的非侵入性PET成像显示， GB肿瘤的体积与疾病的快速进展和较差的生存率密切相关， 以前在人体临床试验中对肿瘤的抑制作用， 显示出模棱两可的结果，部分原因是肿瘤缺氧负荷的异质性和缺乏靶向治疗。 选择患者的方法13.因此，本提案的目标是开发预测性非侵入性 PET成像生物标志物，将识别可从以下方面获益的GB患者人群： OMX疗法。 Omniox和加州大学戴维斯分校兽医学院完成了一项0期犬临床试验， OMX在犬患者中的安全性、药代动力学（PK）和药效学（PD）， 脑瘤作为试验的一部分，Omniox与Brain Biosciences合作，使用他们设计的PET扫描仪， 专门用于脑成像（CerePET™）。Omniox和AIP资助的主要合作者，Simon博士 加州大学戴维斯分校的Cherry（目标1）和Allison Zwingenberger（目标2）以及脑生物科学的大卫贝林（目标1 2）正在开发犬脑患者的PET成像方案，初步扫描已经成功 生成的.在本提案中，我们将基于啮齿动物和犬科动物的积极初步结果， 肿瘤缺氧和OMX肿瘤积聚成像作为OMX活性的预测生物标志物， 颅内大鼠GB模型和犬胶质瘤患者。这些数据将用于通知IND 应用和人类生物标志物临床试验。 OMX是从加州大学伯克利分校发现的热稳定H-NOX蛋白家族发展而来的， PEG化的H-NOX氧（O2）结合变体通常被工程化以扩散到缺氧肿瘤组织深处 与血管渗漏有关。H-NOX部分已被设计为对O2具有高亲和力 由此它将O2保留在含氧量正常的组织中，并在严重缺氧的区域中特异性地释放O2。 Omniox已经完成了一系列临床前研究，支持这一提议： 1)OMX具有良好的生物化学特性，目前正在以高产率生产， 用于GLP毒理学和人体GB临床试验的纯度 2)OMX已经安全地应用于超过1000只小鼠和大鼠，几只健康的比格犬， 全球缺氧的羔羊和15名来自我们的犬临床试验的犬脑癌患者（表1） 3)OMX通过渗漏的脉管系统外渗，并在缺氧肿瘤组织中蓄积，如图所示： a）使用免疫组织化学（IHC）（图1）和ELISA（数据未显示）的小鼠和大鼠颅内肿瘤 B）使用89 Zr标记的OMX的PET成像的荷瘤小鼠和大鼠（图5）;和c）在 通过IHC和ELISA观察到的犬脑癌患者的肿瘤（图6） 4)OMX给药使肿瘤氧合，如通过以下证明的： 氧分压（pO 2）使用OxyliteTM探针插入到缺氧小鼠肿瘤组织（图2）。 2）;缺氧调节的转录因子和下游信号传导的下调，如通过 IHC、FACS（数据未显示）和ELISA（图3）;和c）大鼠颅内肿瘤中的缺氧减少， 在初步成像研究中，通过PET缺氧示踪剂18F-FMISO信号测量（图5）。 5)在RT之前用OMX处理的携带皮下肿瘤的小鼠显示出肿瘤生长的显著延迟。 生长和50%的治愈率（图4） 6)CerePET可用于以高分辨率成像大鼠和犬的大脑（图7） 在这个建议中，我们提出了一个创新的翻译策略，开发和临床前测试PET 可以潜在地用作候选药物的预测标志物的成像伴随诊断 在未来的人体临床试验中的疗效。我们将建立在我们现有的结果颅内大鼠和小鼠 肿瘤模型和犬神经胶质瘤患者，以优化和验证非侵入性临床相关成像 如果在人类临床研究中得到证实，将能够选择目标患者人群， RT治疗很可能通过OMX介导的肿瘤氧合而显著增强。 ©2016 Omniox，Inc.机密-不得分发