A FEASIBILITY PET STUDY OF HER2 RECEPTORS IN BREAST CANCER USING 89ZR-TRASTUZUMAB

使用 89ZR-曲妥珠单抗对乳腺癌 HER2 受体进行可行性宠物研究

基本信息

批准号：
8635832
负责人：
FARROKH DEHDASHTI
金额：
$ 31.54万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635832
关键词：
Address Adverse effects Animals Antigen Targeting Behavior Binding Biodistribution Biological Biopsy Cancer Etiology Cancer Patient Clinical Data Country Detection Development Diagnostic Disease Dose ERBB2 gene Evaluation Extracellular Domain Feasibility Studies Fluorescent in Situ Hybridization Goals Growth Half-Life Heterogeneity Human Image Image Analysis Imaging Device Immunohistochemistry Immunotherapy In Vitro Individual Label Lesion Malignant Neoplasms Measurable Metastatic Lesion Methods Molecular and Cellular Biology Monoclonal Antibodies Morbidity - disease rate Mutation Neoplasm Metastasis Patients Pilot Projects Positron Positron-Emission Tomography Primary Lesion Property Radioimmunoconjugate Radioisotopes Radiolabeled Radiopharmaceuticals Recurrence Resistance Resolution Risk Safety Sampling Errors Site Staining method Stains Therapeutic Monoclonal Antibodies Time Tracer Trastuzumab Treatment Effectiveness Tumor Burden Visual Woman Xenograft procedure Zirconium base burden of illness chemotherapy cost dosimetry improved in vitro Assay in vivo malignant breast neoplasm mortality novel outcome forecast pre-clinical public health relevance radiotracer receptor receptor expression response tumor tumor xenograft uptake zirconium oxide

项目摘要

Title A Feasibility PET Study of HER2 Receptors in Breast Cancer Using 89Zr-Trastuzumab Project Summary The use of monoclonal antibodies (MAbs) for treatment of oncologic patients is rapidly expanding while the imaging tools for evaluation of the specific tumor antigens targeted by these therapies lagged behind. Breast cancer remains the leading cause of cancer mortality among women in Western countries. HER2-amplified breast cancers, which consist of 20-30% of breast cancers, are associated with a more aggressive growth rate, increased risk of metastasis and worse overall survival compared with HER2-negative breast cancers. The identification of HER2 amplification as the driver mutation in these cancers and the subsequent development of trastuzumab, a MAb directed against the extracellular domain of the HER2 receptor, have dramatically improved the prognosis in these patients. However, only half of HER2-positive patients receiving first-line trastuzumab and chemotherapy for metastatic disease have objective responses. This suggests that the presence of HER2 positivity by current in vitro assays is not an accurate predictor of response to therapy, possibly related to within-patient tumor heterogeneity. PET using radiolabeled antibodies (Immuno-PET) is a novel option for non-invasive identification of the presence of specific targets throughout the body, tracing and quantification of monoclonal antibodies binding to the target and ultimately helping in better understanding of in vivo behavior and effectiveness of treatment with MAbs in individual patients. In this application, we are proposing a feasibility study using Zirconium-89 (89Zr) labeled trastuzumab in breast cancer. Because of its longer physical half-life that matches the biological half-life of a MAb (i.e., the mean half-life of trastuzumab is 5.8 days), 89Zr is preferred to 68Ga- (t1/2 = 1.13 h) and 64Cu- (t1/2 = 12.7 h) for radiolabeling of MAbs. In studies with tumor xenografts, significantly greater 89Zr-trastuzumab uptake has been detected in HER2- positive than in HER2-negative tumor sites. In a small study of patients with HER2-positive breast cancer, high image quality with optimal biodistribution and excellent tumor uptake have been demonstrated with 89Zr- trastuzumab-PET. We are proposing to perform a pilot study with goals of demonstrating the feasibility of imaging breast cancer patients with 89Zr-trastuzumab-PET, evaluating the relationship between tumor 89Zr- trastuzumab uptake and in vitro status of HER2, assessing the safety of 89Zr-trastuzumab and determining the human dosimetry of this radiopharmaceutical.

标题使用 89Zr-曲妥珠单抗对乳腺癌 HER2 受体进行可行性 PET 研究项目概要单克隆抗体（MAb）用于治疗肿瘤患者的用途正在迅速扩大，而用于评估这些疗法针对的特定肿瘤抗原的成像工具滞后。胸部癌症仍然是西方国家女性癌症死亡的主要原因。 HER2 扩增乳腺癌占乳腺癌的 20-30%，其生长速度更快，与 HER2 阴性乳腺癌相比，转移风险增加，总体生存率较差。这 HER2 扩增被鉴定为这些癌症的驱动突变，以及随后的发展曲妥珠单抗是一种针对 HER2 受体胞外域的单克隆抗体，具有显着的疗效改善了这些患者的预后。然而，只有一半的 HER2 阳性患者接受一线治疗曲妥珠单抗和化疗对转移性疾病有客观反应。这表明目前体外检测显示 HER2 阳性并不能准确预测治疗反应，可能与患者体内肿瘤的异质性有关。使用放射性标记抗体的 PET (Immuno-PET) 是一种用于非侵入性识别全身特定目标的存在、追踪和量化与靶标结合的单克隆抗体，最终有助于更好地理解单克隆抗体在个体患者中的体内行为和治疗效果。在这个应用程序中，我们是提出使用锆 89 (89Zr) 标记的曲妥珠单抗治疗乳腺癌的可行性研究。由于其更长的物理半衰期，与 MAb 的生物半衰期相匹配（即曲妥珠单抗的平均半衰期为对于 MAb 的放射性标记，89Zr 优于 68Ga- (t1/2 = 1.13 h) 和 64Cu- (t1/2 = 12.7 h)。在肿瘤异种移植物研究发现，HER2- 中 89Zr-曲妥珠单抗的摄取显着增加 HER2 阴性肿瘤部位呈阳性。在一项针对 HER2 阳性乳腺癌患者的小型研究中， 89Zr- 已证明具有最佳生物分布和出色的肿瘤摄取的图像质量曲妥珠单抗-PET。我们建议进行一项试点研究，目的是证明可行性使用 89Zr-trastuzumab-PET 对乳腺癌患者进行成像，评估肿瘤 89Zr- 之间的关系曲妥珠单抗的摄取和 HER2 的体外状态，评估 89Zr-曲妥珠单抗的安全性并确定这种放射性药物的人体剂量测定。