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

描述（由申请人提供）：在实体肿瘤中常见的低氧条件（缺氧）被认为是通过放射治疗（放疗，RT）临床治疗癌症的主要障碍。此外，肿瘤明显缺氧的癌症患者生存预后往往较差。鉴于缺氧的临床相关性，实验性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使实体肿瘤放射增敏。分子氧（oxygen）是一种天然而有效的放射增敏剂；因此，通过RT有效治疗缺氧肿瘤的一种策略是人为地增加其氧合。该项目旨在使用加州大学伯克利分校（UC Berkeley）开发的一种新的氧气输送技术——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技术在氧传递治疗领域有4个主要的改进：(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反应性和高血压特性相比是有利的；(2)已经设计了50多种H-NOX候选物，每种候选物都具有特定的氧亲和力；整个车辆面板在1000万倍的范围内显示出氧气亲和力；(3) H-NOX车辆在80℃以上结构稳定，在室温下化学稳定数周；(4) H-NOX车辆是模块化的，并且可以通过表面修饰来改变尺寸、肿瘤特性或组织靶向性。简而言之，H-NOX技术提供了一个供氧候选工具箱，用于在缺氧组织和肿瘤中测试其提高氧水平和增强放疗和化疗的能力。I期研究成功地确定了一种主要的候选药物，可以穿透肿瘤深处，提高缺氧区的氧气水平。II期研究将侧重于确定H-NOX铅候选物的RT增强程度，并对其进行优化，以获得最佳的生物分布、肿瘤氧合、RT增强和安全性。符合这一特征的H-NOX先导候选物将有资格进行ind研究，为临床试验做准备。根据NCI放射调节剂工作组发布的开发放射增强疗法的指南，本II期提案已准备就绪。第二阶段的里程碑也与潜在的公司合作伙伴和风险投资者进行了讨论。这项研究的成功完成预计将导致投资者对支持ind临床试验开发的重大兴趣。

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 80 0C, 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 candidates to test in hypoxic tissues and tumors for their capacity to raise oxygen levels and enhance RT and chemotherapy. Phase I studies successfully identified a lead candidate that penetrates deep into tumors and raises oxygen levels in hypoxic zones. Phase II studies will focus on determining the degree of RT enhancement by lead H-NOX candidates, and refining them for optimal biodistribution, tumor oxygenation, RT enhancement and safety. A lead H-NOX candidate that meets this profile will be eligible for IND-enabling studies in preparation for clinical trials. This Phase II proposal has been prepared in accordance with guidelines for developing radiation enhancement therapies as published by the NCI's Radiation Modifier Working Group. The Phase II milestones have also been discussed with potential corporate partners and venture investors. Successful completion of this study is expected to result in significant investor interest in supporting IND-enabling development for clinical trials. 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 receive minimal benefit from RT. This project aims to use a breakthrough, oxygen-delivery technology that is tunable, stable, and modular, to revolutionize RT for cancer patients.