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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.

项目总结