Core 1: Animal Models, Pathology and Tissue

核心 1：动物模型、病理学和组织

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 α粒子发射放射性药物治疗（αRPT）是一种快速发展的新型治疗方式可以以 100 微米的精度向播散性癌症转移提供高效的 α 粒子由于 αRPT 中使用的几乎所有放射性核素都会发射光子，因此放射轨迹良好，对患者的毒性较小。可以非侵入性地成像，提供精确的有价值的药代动力学和解剖学数据。针对癌症而不对正常组织产生副作用将是患者护理的一个突破。虽然不同，每个患者可能需要调整 αRPT 剂量，但目前已实施 αRPT 协议无法实现这一目标，为了解决这一未满足的需求，在申请中概述的实验中，由核心 B、剂量测定驱动的治疗计划以及对放射生物学的理解相结合来促进吸收剂量如何转化为生物效应，将缩小人体实验的范围（成本和临床优化 αRPT 所需的时间表）为了实现这些目标并测试项目假设，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使用动物模型或基于人体组织的分析的项目都将。解决项目 4 中 αRPT 和 DNA 修复途径抑制剂对 DNA 损伤的作用。总体假设该 PPG 的要点是 αRPT 是一种全身性癌症治疗方式，特别适用于靶向治疗转移性癌症；并且不太容易受到传统耐药机制的影响；在提出的实验中，可以完善剂量测定驱动的治疗计划。缩小到微米尺度，将α粒子传递的剂量集中在癌症上并消除周围的抵押品动物模型、病理学和组织核心由经验丰富的兽医领导。约翰·霍普金斯大学的病理学家/毒理学家和医学博士病理学家，长期以来对癌症做出了贡献该机构的治疗研究的重点是协助三个项目的 PI。不同领域，(1) 动物模型 (2) 使用 αRPT 进行尸检、组织取样、处理和组织病理学图像相关性和 (3) 对人类和动物组织进行原位分析以评估 DNA 损伤和修复。生物样本核心的标准操作程序纳入了 2011 年概述的指南修订了 NCI 生物样本资源最佳实践，以及生物样本资源的严谨性和可重复性。该核心的 PI 将在实验设计中解决可变和适当的动物数量问题。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用于拟议的研究，与该组织成员合作了 30 年计划项目和 JHU 研究界将这些宝贵的知识和经验应用于改进。患者癌症 αRPT 疗法，减少毒性，对公共健康和患者护理产生重大影响。