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

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;整个飞行器板显示出超过1000万倍范围的氧亲和力;（3）H-NOX飞行器在80 ℃以上结构稳定，并且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候选工具箱，用于在缺氧组织和肿瘤中测试其提高氧气水平并增强RT和化疗的能力。I期研究成功地确定了一种主要候选药物，它可以深入肿瘤并提高缺氧区的氧气水平。第二阶段研究将重点确定主要H-NOX候选物的RT增强程度，并对其进行改进，以实现最佳生物分布、肿瘤氧合、RT增强和安全性。符合这一条件的主要H-NOX候选者将有资格参加IND使能研究，为临床试验做准备。本第二阶段提案是根据NCI放射改性剂工作组发布的放射增强疗法开发指南编制的。还与潜在的企业伙伴和风险投资者讨论了第二阶段的里程碑。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。 公共卫生相关性：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。对于每年接受RT治疗的500，000名癌症患者，超过50%的患者患有缺氧肿瘤，并且从RT中获得的益处很少。该项目旨在使用可调，稳定和模块化的突破性氧气输送技术，彻底改变癌症患者的RT。

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.