EphB4 as Novel Target for Breast Cancer Imaging

EphB4 作为乳腺癌成像的新靶点

基本信息

批准号：
8245791
负责人：
Peter Stephen Conti
金额：
$ 20.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245791
关键词：
Advanced Malignant Neoplasm Affinity Animals Antibodies Area Binding Biological Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Diseases Cancer Patient Cancer cell line Cell surface Clinical Clinical Trials Colon Carcinoma Data Diagnosis Disease Doctor of Philosophy Dose Drug Kinetics Eph Family Receptors Ephrins Exploratory/Developmental Grant Exposure to Follow-Up Studies Human Image Immunofluorescence Immunologic Immunohistochemistry In Vitro Individual Intervention Label Lead Ligand Binding MCF7 cell Malignant neoplasm of lung Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Mesothelioma Methods Modeling Monitor Mus Nature Patients Peptides Pharmaceutical Preparations Pharmacodynamics Play Positron-Emission Tomography Primates Principal Investigator Proteins Radiation Radiolabeled Research SKBR3 Scanning Screening procedure Series Specificity Specimen Staining method Stains Stratification T47D Testing Therapeutic Therapeutic Intervention Tissues Toxic effect Translations Tumor-Derived Up-Regulation Uterine Cancer Western Blotting Woman Xenograft Model Xenograft procedure base cancer diagnosis cancer imaging cancer therapy cancer type design imaging probe in vivo inhibitor/antagonist malignant breast neoplasm melanoma novel novel diagnostics novel therapeutics osteosarcoma public health relevance radiotracer receptor research study response small molecule subcutaneous success treatment strategy tumor tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): It is estimated that 192,370 women were diagnosed with breast cancer in 2009 and 40,170 women died as a result of incurable metastatic breast disease. There is clearly a need to develop new diagnostic and therapeutic methods targeting both primary and metastatic breast cancer. Accumulating evidence suggests that Eph receptor tyrosine kinases and their cell-surface bound ligands, the Ephrins, play key roles in cancer progression. In particular, up-regulation of EphB4 expression has been found in mouse mammary tumor models and in more than half of the human breast cancer specimens examined. EphB4 is also widely expressed in human breast cancer cell lines, and has been found to correlate with survival in breast cancer patients. Based on the extremely important function of EphB4, therapies focusing on EphB4 have become potentially important components of breast cancer treatment strategies. However, tumor sensitivity to EphB4 suppression may not be uniform for all breast cancers, including primary v. metastatic disease. There is an urgent need to better predict which patients and individual tumors are likely to respond to such novel interventions, as well as monitor the therapeutic response. In this proposal, we plan to develop EphB4 specific PET probes, to quantify EphB4 expression in breast cancer xenografts. We hypothesize here that the EphB4 expression level is a determinant factor for predicting a tumor's response to EphB4 suppression therapy. Thus, PET imaging with suitably radiolabeled EphB4 antibodies, EphB4 inhibitors, or EphB4 binding peptides, will be highly valuable in assessing EphB4 suppression non-invasively and repetitively. The success of this novel imaging approach could lead to novel diagnosis method for breast cancer, help us better predict which patients and individual tumors are likely to respond to novel interventions targeting EphB4, and make it possible to direct monitor the responses towards therapeutic interventions. At the conclusion of this project, we will have accumulated sufficient animal-based translational data for submission of a clinically-based proposal. In addition to breast cancer, EphB4 is also significantly over-expressed in melanoma, prostate cancer, colon cancer, bladder cancer, lung cancer, mesothelioma, uterine cancer, and osteosarcoma. These newly developed PET probes could also have important applications in these other cancer types, and thus have a significant clinical impact on a very large number of cancer patients. PUBLIC HEALTH RELEVANCE: Breast cancer is the most frequently diagnosed cancer in women. It is estimated that 192,370 women were diagnosed with breast cancer in 2009 and 40,170 women died as a result of incurable metastatic breast disease. There is clearly a need to develop new diagnostic and therapeutic methods targeting both primary and metastatic breast cancer. The proposed research will develop EphB4 specific PET probes, which would be able to examine the breast cancer onset and progression by quantifying EphB4 expression non-invasively and repetitively. The data obtained from this project will help in many aspects of anti-EphB4 breast cancer therapy, particularly for patient stratification (e.g., selecting EphB4-positive cancer patients for new anti-EphB4 clinical trials while sparing EphB4-negative patients for other treatments), treatment monitoring, and dose optimization. The same probes developed in this project may also have important applications in many other cancer types, and thus have a significant clinical impact on a very large number of cancer patients.

描述（申请人提供）：据估计，2009 年有 192,370 名女性被诊断患有乳腺癌，40,170 名女性死于无法治愈的转移性乳腺疾病。显然需要开发针对原发性和转移性乳腺癌的新诊断和治疗方法。越来越多的证据表明，Eph 受体酪氨酸激酶及其细胞表面结合配体 Ephrins 在癌症进展中发挥着关键作用。特别是，在小鼠乳腺肿瘤模型和超过一半的人类乳腺癌样本中发现了 EphB4 表达的上调。 EphB4 也在人类乳腺癌细胞系中广泛表达，并且已被发现与乳腺癌患者的生存相关。基于EphB4极其重要的功能，针对EphB4的治疗已成为乳腺癌治疗策略的潜在重要组成部分。然而，所有乳腺癌（包括原发性乳腺癌和转移性乳腺癌）对 EphB4 抑制的肿瘤敏感性可能并不相同。迫切需要更好地预测哪些患者和个体肿瘤可能对此类新颖的干预措施产生反应，并监测治疗反应。在本提案中，我们计划开发 EphB4 特异性 PET 探针，以量化乳腺癌异种移植物中的 EphB4 表达。我们在此假设 EphB4 表达水平是预测肿瘤对 EphB4 抑制治疗反应的决定因素。因此，使用适当放射性标记的 EphB4 抗体、EphB4 抑制剂或 EphB4 结合肽进行 PET 成像对于非侵入性和重复性评估 EphB4 抑制非常有价值。这种新型成像方法的成功可能会带来新的乳腺癌诊断方法，帮助我们更好地预测哪些患者和个体肿瘤可能对针对 EphB4 的新型干预措施产生反应，并使直接监测对治疗干预措施的反应成为可能。在该项目结束时，我们将积累足够的基于动物的转化数据，用于提交基于临床的提案。除乳腺癌外，EphB4在黑色素瘤、前列腺癌、结肠癌、膀胱癌、肺癌、间皮瘤、子宫癌和骨肉瘤中也显着过度表达。这些新开发的 PET 探针也可能在其他癌症类型中具有重要的应用，从而对大量癌症患者产生重大的临床影响。公共卫生相关性：乳腺癌是女性中最常诊断出的癌症。据估计，2009 年有 192,370 名女性被诊断患有乳腺癌，40,170 名女性死于无法治愈的转移性乳腺疾病。显然需要开发针对原发性和转移性乳腺癌的新诊断和治疗方法。拟议的研究将开发 EphB4 特异性 PET 探针，该探针将能够通过非侵入性和重复性地量化 EphB4 表达来检查乳腺癌的发病和进展。从该项目获得的数据将有助于抗EphB4乳腺癌治疗的许多方面，特别是患者分层（例如，选择EphB4阳性癌症患者进行新的抗EphB4临床试验，同时保留EphB4阴性患者进行其他治疗），治疗监测和剂量优化。该项目中开发的相同探针也可能在许多其他癌症类型中具有重要应用，从而对大量癌症患者产生重大临床影响。