TUMOR RADIOSENSITIZATION USING A NITRIC-OXIDE-NEUTRAL, TUNABLE OXYGEN-BINDING PRO

使用一氧化氮中性、可调氧结合 PRO 进行肿瘤放射增敏

• 批准号: 7612838
• 负责人: AJIT S SHAH
• 金额: $ 48.01万
• 依托单位: OMNIOX, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612838
• 关键词: Affinity; Ambulatory Care Facilities; Animals; Attenuated; Binding; Binding Proteins; California; Cancer Patient; Cells; Chemicals; Clinical; Clinical Management; Clinical Trials; Condition; Culture Media; Cultured Cells; Depth; Development; Diagnostic; Diffusion; Dose; Drug Kinetics; End Point; Endotoxins; Engineering; Enrollment; Escherichia coli; Exhibits; Experimental Neoplasms; Fluorescence Microscopy; Funding; Future; Goals; Heme; Hemoglobin; Human; Hypoxia; Image; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Investigational New Drug Application; Kinetics; Label; Laboratories; Large Intestine Carcinoma; Lead; Malignant Epithelial Cell; Misonidazole; Modeling; Molecular; Monitor; Mus; Nitric Oxide; Oncologist; Oxygen; Patients; Penetration; Phase; Phase II Clinical Trials; Pimonidazole; Pimonidazole Hydrochloride; Positron; Property; Protein Family; Public Health; Quantitative Microscopy; Radiation Oncologist; Radiation Therapy Oncology Group; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Radiotherapy Research; Range; Research; Research Infrastructure; Resistance; SCID Mice; Scheme; Screening procedure; Services; Solid Neoplasm; Staining method; Stains; Surface; Surrogate Endpoint; Tail; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Tracer; Treatment Efficacy; Tumor Oxygenation; Tumor Tissue; Universities; Validation; Veins; Week; Xenograft procedure; attenuation; base; cancer radiation therapy; cellular engineering; chemotherapy; clinically relevant; design; killings; novel; outcome forecast; preclinical study; research study; size; success; tool; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Low oxygen conditions (hypoxia) commonly found in solid tumors are considered a major obstacle for the clinical management of cancer by radiation therapy (radiotherapy, RT). Moreover, cancer patients with significantly hypoxic tumors tend to have a poor prognosis for survival. Given the clinical relevance of hypoxia, a long-time objective of experimental RT research has been to effectively radiosensitize solid tumors by attenuating or exploiting this pathophysiological state. Molecular oxygen (oxygen) is a natural and potent radiosensitizer; thus, one strategy for effectively treating hypoxic tumors by RT is to artificially increase their oxygenation. This project aims to use a novel oxygen-delivery technology developed at the University of California, Berkeley (UC Berkeley)-heme-nitric oxide/oxygen-binding (H-NOX) proteins-to revolutionize RT for cancer patients. The H-NOX technology embodies 4 major improvements over prior efforts in the field of oxygen delivery therapeutics: (1) oxygen-binding H-NOXs are neutral towards nitric oxide (NO), comparing favorably with the high NO reactivity and hypertensive properties of cell-free hemoglobin; (2) over 50 H-NOX candidates have been engineered, each with a specific oxygen affinity; the entire panel of vehicles demonstrate oxygen affinities across a 10-million fold range; (3) H-NOX vehicles are structurally stable above 75 oC, and chemically stable for weeks at room temperature; (4) H-NOX vehicles are modular, and can be surface-modified to alter size, oncotic properties, or tissue targeting. In short, the H-NOX technology provides a toolbox of oxygen delivery vehicles to test in hypoxic tissues and tumors for their capacity to raise oxygen levels and enhance RT and chemotherapy. To identify leading candidates for therapeutic development, select H-NOX candidates will be purified and applied to multilayered cell cultures (MCCs) exhibiting layers of hypoxia. Using sensitive quantitative microscopy, penetration of H-NOX into the tissue mass will be evaluated over time. Once the kinetics of tissue penetration are established, experiments will determine the alteration in tissue hypoxia as H-NOX vehicles penetrate and facilitate oxygen diffusion from the culture media to the hypoxic cell layers. Leading H-NOX candidates that demonstrate effective tissue penetration and reduction of hypoxia will be taken forward into animal studies. Mice carrying human tumor xenografts that exhibit significant hypoxia and resistance to RT will be treated with H-NOX vehicles and tumors will be evaluated for reduction in hypoxia compared to controls. Pharmacokinetic and toxicology studies will be performed in parallel to monitor the systemic effects of H-NOX administration. Should these experiments demonstrate reduction in tumor hypoxia, future experiments will evaluate enhanced RT tumor killing, and lead candidates will be promoted into development for testing in cancer patients carrying hypoxic tumors. PUBLIC HEALTH RELEVANCE: Low oxygen conditions (hypoxia) commonly found in solid tumors are considered a major obstacle for the clinical management of cancer by radiation therapy (radiotherapy, RT). For the 500,000 cancer patients treated with RT each year, more than 50% present with hypoxic tumors and respond poorly. This project aims to use a breakthrough, oxygen-delivery technology that is tunable, stable, and modular, to revolutionize RT for cancer patients.

描述（由申请人提供）：实体瘤中常见的低氧条件（缺氧）被认为是通过放射治疗（放疗，RT）进行癌症临床管理的主要障碍。此外，具有显著低氧肿瘤的癌症患者倾向于具有较差的存活预后。考虑到缺氧的临床相关性，实验RT研究的长期目标是通过减弱或利用这种病理生理状态来有效地对实体瘤进行放射增敏。分子氧（氧）是一种天然和有效的放射增敏剂;因此，通过RT有效治疗缺氧肿瘤的一种策略是人工增加其氧合。该项目旨在使用加州大学伯克利分校（UC Berkeley）开发的一种新型氧气输送技术-血红素-一氧化氮/氧结合（H-NOX）蛋白-来彻底改变癌症患者的RT。H-NOX技术体现了在氧递送治疗领域中的现有努力的4个主要改进：（1）氧结合H-NOX对一氧化氮（NO）是中性的，与无细胞血红蛋白的高NO反应性和高血压性质相比是有利的;（2）已经工程化了超过50种H-NOX候选物，每种都具有特定的氧亲和力;（3）H-NOX载体在75 ℃以上结构稳定，在室温下化学稳定数周;（4）H-NOX载体是模块化的，并且可以被表面改性以改变尺寸、粘附特性或组织靶向。简而言之，H-NOX技术提供了一个氧气输送工具箱，可以在缺氧组织和肿瘤中测试它们提高氧气水平和增强RT和化疗的能力。为了鉴定用于治疗开发的主要候选物，将纯化选择的H-NOX候选物并将其应用于表现出缺氧层的多层细胞培养物（MCC）。使用灵敏的定量显微镜，将随着时间的推移评估H-NOX渗透到组织块中。一旦建立了组织渗透的动力学，实验将确定当H-NOX载体渗透并促进氧从培养基扩散到缺氧细胞层时组织缺氧的改变。证明有效的组织渗透和减少缺氧的领先H-NOX候选物将被用于动物研究。将用H-NOX媒介物处理表现出显著缺氧和对RT的抗性的携带人肿瘤异种移植物的小鼠，并且将评价肿瘤与对照相比缺氧的减少。药代动力学和毒理学研究将平行进行，以监测H-NOX给药的全身效应。如果这些实验证明肿瘤缺氧的减少，未来的实验将评估增强的RT肿瘤杀伤，并将促进候选药物的开发，用于携带缺氧肿瘤的癌症患者的测试。 公共卫生关系：在实体瘤中常见的低氧条件（缺氧）被认为是通过放射疗法（放射疗法，RT）临床管理癌症的主要障碍。在每年接受RT治疗的50万名癌症患者中，超过50%的患者存在缺氧肿瘤，并且反应不佳。该项目旨在使用一种突破性的氧气输送技术，该技术是可调的，稳定的和模块化的，以彻底改变癌症患者的RT。