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Detection, Radiosensitization and Theranostic Targeting of Metastatic Breast Cancer by PTPmu

PTPmu 转移性乳腺癌的检测、放射增敏和治疗诊断靶向

基本信息

批准号：
10594178
负责人：
SUSANN M BRADY-KALNAY
金额：
$ 66.81万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594178
关键词：
3-Dimensional Adhesions Affinity Architecture Area Binding Biological Markers Biology Brain Brain Neoplasms Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast cancer metastasis Carcinoma Cell Adhesion Cell Adhesion Molecules Cell-Adhesion Molecule Receptors Cell-Cell Adhesion Cells Central Nervous System Complex Cues Detection Development Diagnostic Imaging Disparate Drug Delivery Systems Engineering Exhibits Gold Growth Growth Factor Human Image Image Analysis Individual Invaded Invasive Lesion Knowledge Label Ligands Malignant Neoplasms Mammary Neoplasms Mediating Metastatic breast cancer Metastatic malignant neoplasm to brain Modeling Molecular Multimodal Imaging Mus Neoplasm Metastasis Nerve Nervous System Neural Crest Cell Neurites Neurons Neurosciences Patient-Focused Outcomes Patient-derived xenograft models of breast cancer Peptide Hydrolases Peripheral Nervous System Post-Translational Protein Processing Process Prognosis Protein Tyrosine Phosphatase Proteolysis Radiation Radiation Dose Unit Radiation therapy Radiosensitization Regulation Research Resistance Resolution Route Signal Transduction Solid Neoplasm Structure Testing Therapeutic Tissues Treatment Efficacy Tumor Cell Invasion Tumor Cell Migration Tumor Markers Tumor Promotion Tumor Tissue X-Ray Computed Tomography Xenograft Model axon guidance brain tissue cancer cell cell motility chemokine effective therapy extracellular fluorescence imaging fluorophore imaging biomarker imaging capabilities imaging modality imaging system improved in vivo insight malignant breast neoplasm migration mouse model nanoGold nanoparticle neoplastic cell neural neurodevelopment novel novel marker orthotopic breast cancer patient derived xenograft model perineural receptor standard of care stem targeted agent targeted biomarker targeted treatment theranostics therapy outcome tumor tumor growth tumor microenvironment white matter

项目摘要

Both inside the central nervous system and outside in the peripheral nervous system, cancer cells grow along nerves as routes of invasion and metastasis called neural invasion. This growth is common in several carcinomas including breast cancer and is associated with poor prognosis. Proteolysis of cell adhesion molecules (CAMs) occurs in development, and growing evidence suggests this post-translational modification may promote tumor migration and invasion on nerves that ultimately leads to metastasis to the brain in various tumor types including breast cancer. The receptor protein tyrosine phosphatase PTPµ is a CAM that is proteolyzed in cancer cells to generate an extracellular fragment that is a unique imaging biomarker of the tumor microenvironment. The PTPµ- targeted agents we developed bind to this biomarker and recognize human brain tumors as well as invasive primary breast cancer and breast cancer that has metastasized to the brain. Systemic delivery of the PTPµ- targeted agent results in binding to tumor cells within minutes in xenograft models. Using a 3D cryo-imaging system we analyzed the extent of cell migration and dispersal within the brain. We found that the PTPµ-targeted agent labels 99% of all dispersing tumor cells far away from the main tumor mass on nerves in mouse models. This proposal represents the convergence of our expertise in neuroscience, cell adhesion, imaging and cancer to test if the PTPµ biomarker can be used to detect tumor growth along nerves leading to brain metastases. Gold nanoparticles (AuNPs) have shown outstanding versatility in biomedical applications including imaging diagnostics, drug delivery, and radiation therapy. In this proposal, we describe the development of theranostic AuNPs for the detection and treatment of breast cancer metastases. We will achieve more sensitive detection and treatment of invasive and metastatic lesions through the use of a three component theranostic nanoparticle containing: 1) a highly specific targeting agent of the PTPµ biomarker in the tumor microenvironment; 2) a protease-sensitive quenched near infrared fluorophore for fluorescent imaging; and 3) a gold nanoparticle (AuNP) for sensitization to radiotherapy. We will test whether the PTPµ-targeted agents detects nerve associated growth using 3D single cell resolution cryo-imaging that precisely tracks migration of individual cancer cells on nerves. We will utilize our established human patient-derived xenograft models of metastatic breast cancer and models that metastasize from the breast to the brain. Metastatic tumors are resistant to almost all chemotherapeutics so “physical” killing strategies like radiation must be improved and employed for better therapeutic outcomes. By delivering PTPµ-targeted conjugated AuNPs directly to primary and metastatic breast cancer we will exploit the radiosensitization of AuNP to reduce the required dose of radiation needed for radiotherapy thereby reducing collateral damage to normal surrounding tissues. We expect that these studies will yield targeted nanoparticles that detect and treat nerve associated tumor growth while implicating CAM proteolysis as a generalizable mechanism for detecting and treating tumor invasion on nerves.

在中枢神经系统内部和周围神经系统外部，癌细胞都在生长