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Development of novel CXCR5 PET Imaging probe for Angioimmunoblastic T-cell Lymphoma

开发用于血管免疫母细胞 T 细胞淋巴瘤的新型 CXCR5 PET 成像探针

基本信息

批准号：
10044485
负责人：
Zhengxin Cai
金额：
$ 43.07万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-08 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044485
关键词：
Affinity Agonist Autoradiography B-Cell Lymphomas BLR1 gene Binding Binding Sites Biodistribution Biological Assay Breast CXC Chemokines CXCL13 gene CXCR4 gene Cancer cell line Cells Clinical Trials Colon Colon Carcinoma Crystallization Data Dermatology Development Diagnosis Disease Dissociation Doctor of Philosophy Dose Drug Kinetics Equilibrium Evaluation Genetic Grant Growth Helper-Inducer T-Lymphocyte Human Imaging ligands Imaging technology Immobilization Immunoblastic Lymphadenopathy Immunohistochemistry In Vitro Label Lead Legal patent Ligands Lung Lymphoma Lymphoma cell Lymphomagenesis Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Mediating Medicine Metabolic Methods Modeling Molecular Biology Monitor Monoclonal Antibodies Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Pathway interactions Patients Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Play Positron-Emission Tomography Precision therapeutics Preparation Progression-Free Survivals Property Prostate Proteins Radioisotopes Radiolabeled Reporting Research Research Personnel Resources Role Series Signal Transduction Slice Specificity Structure Surface Surface Plasmon Resonance Survival Rate T-Cell Lymphoma Therapeutic Effect Tissues Toxic effect Toxicology Tracer Transgenic Mice Western Blotting Xenograft Model Yale Cancer Center accurate diagnosis base cancer type chemokine chemokine receptor chemotherapy clinically relevant density drug candidate effective therapy first-in-human genetic analysis human disease imaging agent imaging probe improved in vivo in vivo evaluation innovation lipophilicity malignant breast neoplasm metabolic abnormality assessment mouse model mutant nanomolar new therapeutic target novel novel therapeutics objective response rate outcome forecast overexpression pharmacokinetics and pharmacodynamics pre-clinical preclinical study professor public health relevance radiotracer response screening sensor small molecule targeted treatment therapeutic target tumor tumor xenograft tumorigenesis

项目摘要

Abstract Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive type of peripheral T-cell lymphoma. The majority of patients with AITL are diagnosed at an advanced stage, and have poor prognosis, even with aggressive chemotherapies. Because there has been no improvement in the survival rate of AITL patients over the past two decades ever since the disease was first characterized, there is an urgent need for the discovery and development of an effective treatment. A novel therapeutic target for AITL is the CXCR5-CXCL13 signaling axis, which plays a prominent role in AITL lymphomagenesis, proliferation, and metastasis. By antagonizing CXCR5, Dr. Lolis (PhD, Professor of Pharmacology) and Dr. Foss (MD, Professor of Medicine and of Dermatology) are developing novel therapeutics to treat AITL. They have identified a promising CXCR5 antagonist with decent potency, toxicity profile, and pharmacokinetics for clinical trial in AITL patients. This project is to develop a CXCR5-specific Positron Emission Tomography (PET) imaging probe to explore the pharmacokinetics and pharmacodynamics of the experimental drug. Our research team comprises investigators from Yale PET Center and Yale Cancer Center, and will harness the unique research resources in these centers. Successful completion of this project will set the stage for the clinical trial of the experimental CXCR5 antagonist in AITL patients with the right dose range. Furthermore, as CXCR5 is overexpressed in other types of cancers, i.e., B-cell lymphoma, other T follicular helper cell-mediated lymphomas, prostate cancer, breast cancer, colon cancer, and non-small cell lung carcinoma, the CXCR5 PET imaging probe will also be instrumental in the study of these human diseases.

摘要血管免疫母细胞T细胞淋巴瘤(AITL)是一种罕见的侵袭性外周T细胞淋巴瘤。大多数AITL患者诊断为晚期，预后较差，即使是激进的化疗。因为AITL患者的存活率并没有比自从这种疾病首次被描述以来的过去20年里，人们迫切需要发现这种疾病并开发出一种有效的治疗方法。治疗AITL的新靶点是CXCR5-CXCL13 信号轴，在AITL淋巴肿瘤的发生、增殖和转移中起重要作用。通过对抗CXCR5，洛里斯博士(博士，药理学教授)和福斯博士(医学博士，医学教授) 和皮肤科)正在开发治疗AITL的新疗法。他们已经确定了一个很有前途的CXCR5 在AITL患者中进行临床试验的具有良好效力、毒性和药代动力学的拮抗剂。这该项目是开发一种CXCR5特异性正电子发射断层扫描(PET)成像探针，以探索实验药物的药代动力学和药效学。我们的研究团队包括来自耶鲁PET中心和耶鲁癌症中心的研究人员，并将利用独特的研究资源在这些中心。该项目的成功完成将为实验的临床试验奠定基础 CXCR5拮抗剂在AITL患者中的正确剂量范围。此外，由于CXCR5在其他类型的癌症，即B细胞淋巴瘤、其他T滤泡辅助细胞介导的淋巴瘤、前列腺癌癌症、乳腺癌、结肠癌和非小细胞肺癌，CXCR5 PET成像探针将对这些人类疾病的研究也是有帮助的。