Core 1: Animal Models, Pathology and Tissue

项目摘要 α粒子发射体放射性药物治疗（αRPT）是一种新的和快速发展的治疗方式 它可以将高效的α粒子输送到扩散的癌症转移灶， 辐射轨迹，并且对患者的毒性较小。由于αRPT中使用的几乎所有放射性核素都会发射光子， 提供了有价值的药物动力学和解剖学数据。精确 以癌症为目标而不对正常组织产生副作用将是病人护理的一个突破。所有患者 虽然不同，但每例患者可能需要αRPT剂量调整，但目前实施的αRPT 协议无法实现这一目标。为了解决这一未满足的需求，在本申请中概述的实验中， 由核心B、剂量学驱动的治疗计划以及对放射生物学的理解促进 吸收剂量如何转化为生物效应，将减少人体实验的范围（成本和 时间轴）进行临床优化。为了实现这些目标和测试项目假设，项目1-4 解决改善αRPT的多个步骤，并依靠动物模型、病理学和组织核心来促进 所有项目都使用动物模型或基于人体组织的分析。核心B分子组织技术将 在项目4中阐述αRPT和DNA修复途径抑制剂对DNA损伤的作用。总体假设 αRPT是一种全身性癌症治疗方式，特别适用于靶向 转移性癌症;并且对常规耐药机制的敏感性要低得多;然而， 剂量学驱动的治疗计划。在所提出的实验中，S值测量可以被完善 以将α粒子递送剂量集中在癌症上并消除外周侧支 器官损伤动物模型、病理学和组织核心由经验丰富的兽医领导 病理学家/毒理学家和约翰霍普金斯大学的医学博士病理学家，他们长期致力于癌症 在这个机构进行治疗研究核心小组的工作重点是在三个方面协助四个项目的主要负责人， 不同区域，（1）动物模型（2）尸检、组织采样、处理和αRPT组织病理学 图像相关和（3）对人和动物组织进行原位测定以评估DNA损伤和修复。 生物标本核心标准操作规程纳入了2011年 修订的NCI生物标本资源最佳实践。严格性和可重复性，以及性别作为一种生物学 将在实验设计中说明可变和适当的动物数量。此核心的PI具有 为使用人体标本提供病理学咨询所需的专业知识和方法 和动物组织的拟议研究与30年的合作，与成员， 计划项目和JHU研究社区。这些宝贵的知识和经验被应用于改善 患者癌症αRPT疗法，降低毒性，对公共卫生和患者护理产生重大影响。

Project Summary Alpha-particle -emitter radiopharmaceutical therapy (αRPT) is a new and rapidly evolving therapeutic modality that can deliver highly potent, alpha-particles to disseminated cancer metastases, with 100 micron precise radiation trajectory, and less toxicity in patients. Since almost all of the radionuclides used in αRPT emit photons that can be imaged non-invasively, valuable pharmacokinetic and anatomical data is provided. Precisely targeting the cancer without side effects to normal tissues would be a breakthrough for patient care. All patients are different though and each patient may need αRPT dose adjustments but current implemented αRPT protocols don’t achieve this goal. To address this unmet need, in experiments outlined in the application, facilitated by Core B, dosimetry-driven treatment planning, in combination with a radiobiologic understanding of how absorbed dose translates to biologic effect, will reduce the scope of human experimentation (costs and timeline) needed to clinically optimize αRPT. To achieve these goals and test project hypotheses, Projects 1-4 address multiple steps to improve αRPT and rely on the Animal Models, Pathology and Tissue Core to facilitate all projects using animal models or human tissue-based analyses. Core B molecular tissue techniques will address the role of DNA damage by αRPT and DNA repair pathway inhibitors in project 4. The overall hypothesis of this PPG is that αRPT is a systemic cancer therapy modality that is particularly applicable to targeting metastatic cancer; and far less susceptible to conventional resistance mechanisms; yet it is amenable to dosimetry-driven treatment planning. In the experiments proposed, S values measurements can be perfected down to a microscale to focus the alpha-particle delivered dose on cancer and eliminate peripheral collateral organ damage. The Animal models, Pathology and Tissue Core are led by an experienced veterinary pathologist/toxicologist and a MD pathologist at Johns Hopkins University who have long contributed to cancer therapeutic research at this institution. The emphasis of the Core is to assist PIs of the four projects in three different areas, (1) animal models (2) necropsy, tissue sampling, processing, and histopathology with αRPT image correlation and (3) in situ assays on human and animal tissues to assess DNA damage and repair. Standard operating procedures of the Core for biospecimens incorporate the guidelines as outlined by the 2011 Revised NCI Best Practices for Biospecimen Resources. Rigor and reproducibility, as well as sex as a biological variable and appropriate animal numbers will be addressed in experimental design. The PIs of this Core have the necessary expertise and methodologies to provide pathology consultation for use of the human specimens and animal tissues for the proposed studies with a combined 30 years of collaboration with members of this program project and JHU research community. This valued knowledge and experience is applied to improving patient cancer αRPT therapeutics, reducing toxicity resulting in a high impact on public health and patient care.