Core 1: Animal Models, Pathology and Tissue

核心 1：动物模型、病理学和组织

• 批准号: 10713715
• 负责人: KATHLEEN Louise GABRIELSON
• 金额: $ 22.74万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713715
• 关键词: Address; Alpha Particle Emitter; Alpha Particles; Anatomy; Animal Experiments; Animal Model; Animals; Area; Autopsy; Biodistribution; Biological; Biological Assay; Biological Markers; Cancer Patient; Cell Line; Clinical; Clinical Trials; Collaborations; Collection; Communities; Consultations; DNA Damage; DNA Repair; DNA Repair Pathway; Data; Data Analyses; Data Storage and Retrieval; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Experimental Designs; Goals; Guidelines; Healthcare; Histopathology; Human; Human Experimentation; Image; In Situ; Institution; Knock-out; Knowledge; Malignant Neoplasms; Measurement; Methodology; Modality; Molecular; Monitor; Neoplasm Metastasis; Normal tissue morphology; Organ; Pathologic; Pathologist; Pathology; Patient Care; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Photons; Predisposition; Procedures; Process; Protocols documentation; Public Health; Radiation; Radiobiology; Radioisotopes; Radiopharmaceuticals; Reproducibility; Research; Research Personnel; Resources; Retrieval; Role; Services; Specimen; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Research; Therapeutic procedure; Tissue Sample; Tissues; Toxic effect; Translating; Tumor Tissue; Universities; Work; absorption; animal tissue; cancer therapy; cost; data management; design; digital imaging; dosimetry; experience; experimental study; human tissue; improved; inhibitor; member; model design; non-invasive imaging; programs; prospective; resistance mechanism; sample collection; sex; side effect; single photon emission computed tomography; success; timeline; treatment planning

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.

项目摘要 α粒子 - 发射极分药疗法（αRPT）是一种新的，快速发展的治疗方式 可以将高潜力的α粒子传播到散布癌症转移的情况下，具有100微米的精度 辐射轨迹，患者的毒性较小。由于几乎所有用于αRPT中使用的放射线 可以提供非侵入性，有价值的药代动力学和解剖学数据的成像。恰恰 靶向无副作用到正常组织的癌症将是患者护理的突破。所有患者 虽然不同，但每个患者可能需要αRPT剂量调整，但电流实施了αRPT 协议无法实现此目标。为了满足这种未满足的需求，在应用程序中概述的实验中 由Core B，剂量驱动的治疗计划促进，结合了放射性生物学的理解 吸收剂量如何转化为生物学作用，将降低人类实验的范围（成本和成本和 时间轴）需要临床优化αRPT。为了实现这些目标并测试项目假设，项目1-4 解决改善αRPT并依赖动物模型，病理和组织核心的多个步骤以促进 使用动物模型或基于人体组织的分析的所有项目。核B分子组织技术将 解决项目4中αRPT和DNA修复途径抑制剂DNA损伤的作用。总体假设 该ppg的是αRPT是一种系统性癌症治疗方式，特别适用于靶向 转移性癌；并且不太容易受到常规抗性机制的影响；但是它可以 剂量驱动的治疗计划。在提出的实验中，可以完善S值测量值 向下到微观，以将α颗粒剂量送到癌症上并消除外周抵押品 器官损坏。动物模型，病理和组织核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MD病理学家，他们长期为癌症做出了贡献 该机构的治疗研究。核心的重点是在三个项目中协助四个项目的PI 不同的区域，（1）动物模型（2）尸检，组织采样，加工和组织病理学与αRPT 图像相关性和（3）对人类和动物组织的原位评估，以评估DNA损伤和修复。 Bioscimens核心的标准操作程序纳入了2011年概述的指南 修订了NCI的生物测量资源的最佳实践。严格和可重复性以及性别为生物学 实验设计将解决可变和适当的动物数量。该核心的PI有 提供用于使用人类标本的病理咨询的必要专业知识和方法 和动物组织进行拟议的研究，共有30年的合作与其中的成员合作 计划项目和JHU研究社区。这种有价值的知识和经验用于改善 患者癌症αRPT疗法，降低毒性，从而对公共卫生和患者护理产生高影响。