EphB4 as Novel Target for Breast Cancer Imaging

描述(申请人提供)：据估计，2009年有192,370名妇女被诊断为乳腺癌，40,170名妇女死于无法治愈的转移性乳房疾病。显然有必要开发针对原发和转移性乳腺癌的新的诊断和治疗方法。越来越多的证据表明，Eph受体酪氨酸激酶及其与细胞表面结合的配体--肾上腺素在癌症进展中发挥着关键作用。特别是，在小鼠乳腺癌模型和超过一半的人类乳腺癌标本中发现了EphB4的表达上调。EphB4在人类乳腺癌细胞系中也广泛表达，并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，对于所有乳腺癌，肿瘤对EphB4抑制的敏感性可能并不是一致的，包括原发和转移性疾病。迫切需要更好地预测哪些患者和单个肿瘤可能对这种新的干预措施产生反应，并监测治疗反应。在这项计划中，我们计划开发EphB4特异性的PET探针，以定量EphB4在乳腺癌移植瘤中的表达。我们假设EphB4的表达水平是预测肿瘤对EphB4抑制治疗反应的决定性因素。因此，用合适的放射性标记的EphB4抗体、EphB4抑制剂或EphB4结合肽进行PET成像，将在非侵入性和重复性评估EphB4抑制方面具有很高的价值。这种新的成像方法的成功可能导致新的乳腺癌诊断方法，帮助我们更好地预测哪些患者和单个肿瘤可能对针对EphB4的新干预措施产生反应，并使直接监测对治疗干预措施的反应成为可能。在这个项目结束时，我们将积累足够的基于动物的翻译数据来提交基于临床的建议。除了乳腺癌，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著过度表达。这些新开发的PET探针也可以在这些其他类型的癌症中有重要的应用，从而对非常大量的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被诊断出的癌症。据估计，2009年有192,370名妇女被诊断患有乳腺癌，40,170名妇女死于无法治愈的转移性乳房疾病。显然有必要开发针对原发和转移性乳腺癌的新的诊断和治疗方法。这项拟议的研究将开发EphB4特异的PET探针，它将能够通过非侵入性和重复地定量EphB4的表达来检测乳腺癌的发生和发展。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，而不选择EphB4阴性患者进行其他治疗)、治疗监测和剂量优化。在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，从而对非常大量的癌症患者产生重大的临床影响。

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.