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

描述(申请人提供)：实体肿瘤中常见的低氧条件(缺氧)被认为是通过放射治疗(放射治疗，RT)进行癌症临床治疗的主要障碍。此外，肿瘤明显缺氧的癌症患者的生存预后往往很差。鉴于缺氧的临床相关性，实验性RT研究的一个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(氧)是一种天然而有效的放射增敏剂，因此，通过放射治疗有效治疗低氧肿瘤的一个策略是人为地增加它们的氧合。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/氧结合蛋白--来彻底改变癌症患者的放射治疗。H-NOx技术在氧气输送疗法领域体现了四个主要改进：(1)氧结合的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多个H-NOx候选化合物，每个候选H-NOx具有特定的氧气亲和力；整个载体面板显示出1000万倍的氧气亲和力；(3)H-NOx载体的结构在80摄氏度以上稳定，在室温下化学稳定数周；(4)H-NOX车辆是模块化的，可以对其进行表面修饰，以改变大小、致瘤性或组织靶向性。简而言之，H-NOX技术提供了一个供氧输送的工具箱，用于在低氧组织和肿瘤中测试其提高氧气水平、增强放疗和化疗的能力。第一阶段研究成功地确定了一种能够深入肿瘤并提高缺氧区氧气水平的候选铅。第二阶段的研究将集中于确定主要的H-NOX候选者的RT增强程度，并对其进行提炼，以实现最佳的生物分布、肿瘤氧合、RT增强和安全性。符合这一条件的主要H-NOX候选将有资格参加IND-Enabling研究，为临床试验做准备。这份第二阶段的提案是根据美国国家癌症研究所辐射调节剂工作组发布的辐射增强疗法开发指南编写的。第二阶段的里程碑也已经与潜在的企业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临床试验的IND开发产生极大的兴趣。 公共卫生相关性：实体肿瘤中常见的低氧条件(缺氧)被认为是通过放射治疗(RT)进行癌症临床治疗的主要障碍。在每年接受RT治疗的500,000名癌症患者中，超过50%的患者患有缺氧性肿瘤，从RT中获得的好处微乎其微。该项目旨在使用一种突破性的、可调的、稳定的和模块化的氧气输送技术，来彻底改变癌症患者的放射治疗。

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.