6 MeV/amu ion linac for deep-penetration microbeam and millimeter-beam charged-particle irradiations in small animals and biological tissues

摘要：申请资金用于6 MeV/amu直线加速器，将用于产生 离子束跨越宽范围的辐射质量，在组织中具有高达1 mm的穿透。这些 然后将光束聚焦成微光束（几微米的光束直径）或毫米尺寸的光束， 允许系统地研究肿瘤反应和正常组织反应， 当代重离子束放射治疗。直线加速器将促进的研究是机械上的- 动机，并没有明确地集中在特定的协议，重离子癌症放疗。直线加速器将会 位于哥伦比亚大学的放射性研究加速器设施（RARAF），该设施是NIH的一部分， 国家生物医学技术资源中心致力于了解放射生物学 不同类型的辐射影响生物的机制。最近人们越来越关注 从放射治疗和重带电粒子放射治疗中的放射生物学社区， 特别是碳离子，用于治疗难以治疗的高危肿瘤，特别是那些已经扩散的肿瘤 在主站点之外。这些粒子以比X更空间密集的方式（“高LET”）沉积能量（存款） 射线或质子。已在临床上显示受益于高LET放射治疗的肿瘤实例 是局部晚期胰腺肿瘤、晚期前列腺肿瘤和局部复发性直肠肿瘤。基于 关于它们在治疗已经扩散到原发部位以外的肿瘤中的疗效，可以合理地假设， 高LET辐射引发了一种长距离的反应，通过旁观者，远距离或免疫反应， 机制，这可能不是由传统的放射治疗引起的类型。总之，有一个伟大的 放射治疗/放射生物学社区对试图理解潜在机制的兴趣 这种重离子高LET诱导的长程信号转导，特别是在难以治疗的背景下， 肿瘤的这反映在本申请的项目范围内，包括高LET机制研究 用于胰腺（Olive）、黑色素瘤（Guha）、前列腺（Shen）、乳腺（Demaria）以及正常组织保留 （Fornace）和旁观者效应范围估计（Brenner）。微束和毫米大小的光束， 在RARAF生产，允许能量沉积高度局部化，因此代表了一种理想的工具， 研究远程损伤信号机制。使用目前在RARAF的2.5 MeV/amu加速器， 可以产生的颗粒的空间范围仅足以照射细胞单层， 非常薄的组织。然而，当代感兴趣的长程损伤信号转导终点 这里需要用体内模型和3-D组织模型来研究，这些模型太厚而不能被2.5 MeV/amu离子。因此，带电粒子的空间穿透力需要通过增加电荷密度来增加。 粒子加速器的能量为了满足用户的需要，高LET充电器的可用范围 粒子需要增加3至4倍-需要RARAAF下的离子能量为6 MeV/amu。

Summary: Funds are requested for a 6 MeV/amu linear accelerator (linac), which will be used to generate ion beams spanning a wide range of radiation qualities having penetrations of up to 1 mm in tissue. These beams will then be focused into microbeams (beam diameter of a few microns) or millimeter-sized beams, allowing systematic mechanistic studies of tumor responses and normal-tissue responses relating to contemporary heavy-ion beam radiotherapy. The studies that will be facilitated by the linac are mechanistically- motivated and do not focus explicitly on specific protocols for heavy-ion cancer radiotherapy. The linac will be located at the Radiological Research Accelerator Facility (RARAF) at Columbia University which is an NIH- funded National Biomedical Technology Resource Center dedicated to understanding the radiobiological mechanisms by which different types of radiation affect living matter. There has been increasing recent interest from the radiation therapy and the radiation biology communities in heavy charged-particle radiotherapy, particularly carbon ions, to treat hard-to-treat high-risk tumors, particularly those that have already spread beyond the primary site. These particles deposit energy in a more spatially-dense way (“high LET”) than do X rays or protons. Examples of tumors that have been shown clinically to benefit from high-LET radiation therapy are locally advanced pancreatic tumors, late-stage prostate tumors, and locally recurrent rectal tumors. Based on their efficacy in treating tumors that have spread beyond the primary site, it is reasonable to assume that that the high-LET radiations are eliciting a long-range response, through bystander, abscopal or immunological mechanisms, of a type that may not be induced by conventional radiotherapy. In summary, there is a great deal of interest in the radiotherapy / radiobiology community in trying to understand the mechanisms underlying this heavy-ion high-LET induced long-range signal transduction, particularly in the context of hard-to treat tumors. This is reflected in the range of projects in this application, that include high-LET mechanistic studies for pancreas (Olive), melanoma (Guha), prostate (Shen), breast (Demaria), as well as normal tissue sparing (Fornace), and bystander-effect range estimation (Brenner). Microbeams and millimeter-sized beams, which are produced at RARAF, allow the energy deposition to be highly localized, and so represent an ideal tool to study long-range damage signaling mechanisms. Using the current 2.5 MeV/amu accelerator at RARAF, the spatial range of the particles that can be produced is sufficient only to irradiate cellular monolayers or extremely thin tissues. However the long-range damage signal transduction endpoints of contemporary interest here need to be studied with in-vivo models and 3-D tissue models, which are too thick to be penetrated by 2.5 MeV/amu ions. Thus the spatial penetration of the charged particles needs to be increased, by increasing the energy the particle accelerator. To meet the needs of the users, the available range of the high-LET charged particles needs to be increased by factors of 3 to 4 - requiring ion energies at RARAF of 6 MeV/amu.