Mechanisms of tumor resistance to anti-HER/ErbB therapeutics

肿瘤对抗 HER/ErbB 治疗的耐药机制

基本信息

批准号：
7466654
负责人：
Zhen Fan
金额：
$ 31.96万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-02 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7466654
关键词：
1-Phosphatidylinositol 3-Kinase Adaptor Signaling Protein Adverse effects Anemia Antineoplastic Agents Binding Binding Sites Bone Marrow Breast Cancer Cell Cancer Cell Growth Cancer Patient Cancer cell line Cardiac Case Study Cell Surface Receptors Cells Cessation of life Clinical Conditioned Culture Media Cytokine Receptors Cytoprotection Docking Epidermal Growth Factor Receptor Erythrocytes Erythroid Progenitor Cells Erythropoiesis Erythropoietin Erythropoietin Receptor Family Fatigue Frequencies Goals Homodimerization Human Interleukin-3 Investigation Janus kinase 2 Kidney Knowledge Laboratories Link MEKs Malignant Neoplasms Mammary Neoplasms Mediating Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Monoclonal Antibodies Neurons Numbers Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Production Protein Overexpression Public Health Rate Receptor Activation Receptor Cell Receptor Signaling Recombinants Relapse Renal Tissue Research Resistance Retinal Risk Roche brand of trastuzumab Role STAT protein Signal Pathway Signal Transduction Specimen Standards of Weights and Measures Testing Therapeutic Thinking Tissues Trastuzumab Treatment-Related Cancer Tyrosine Validation Xenograft procedure autocrine base cancer cell chemotherapy clinically relevant cytokine exposed human population malignant breast neoplasm member novel paracrine prevent receptor receptor expression recombinant human erythropoietin response src Homology Region 2 Domain tumor

项目摘要

DESCRIPTION (provided by applicant): Trastuzumab (Herceptin), a humanized anti-HER2 monoclonal antibody, has been demonstrated to confer a clear survival benefit when it is added to standard chemotherapy for HER2-overexpressing breast cancer. Unfortunately, however, only 30-40% of HER2-positive breast tumors respond to trastuzumab. In this proposal, we will explore whether erythropoietin (EPO)-induced cell signaling plays a role in breast cancer resistance to trastuzumab. EPO is a prime hematopoietic cytokine produced mainly by a group of specialized cells in the kidney and acts on erythroid progenitor cells in the bone marrow, leading to erythropoiesis. Recombinant human EPO (rHuEPO) is frequently used in cancer patients to prevent and alleviate cancer- and cancer treatment-related anemia and fatigue. Recent studies have shown that EPO has remarkable cytoprotective activity in nonhematopoietic tissues via activation of the EPO receptor (EpoR) found in these tissues. Interestingly, EpoR is also present in some clinical tumor specimens, particularly tumor specimens from breast cancer patients. As a member of the type I cytokine receptor family, EpoR homodimerizes upon EPO binding, triggering activation of the receptor-associated kinase Jak2, subsequent phosphorylation of STAT5, and a signal transduction cascade mediated by SH2 domain-containing adaptors that overlaps substantially with HER2-mediated signaling pathways. We found in our preliminary studies that EpoR is co-expressed with HER2 in a significant number of established breast cancer cell lines and breast cancer tissue specimens from patients. Exposure of breast cancer cells to rHuEPO activated cell signaling in an EpoR expression-dependent manner, and concurrent treatment of HER2/EpoR dual-positive breast cancer cells with trastuzumab and rHuEPO reduced the therapeutic response to trastuzumab treatment. We hypothesize that cell signaling in response to concurrent administration of rHuEPO constitutes a clinically relevant mechanism of breast cancer resistance to trastuzumab. We plan to test this hypothesis in four specific aims: 1) to confirm the cytoprotective effect of rHuEPO against trastuzumab in HER2/EpoR dual-positive breast cancer cells; 2) to determine the extent to which concurrent administration of rHuEPO counteracts the antitumor activity of trastuzumab in HER2/EpoR dual-positive breast cancer xenografts; 3) to elucidate the EpoR downstream signaling pathways through activation of which rHuEPO mediates cytoprotection against trastuzumab; and 4) to confirm the presence of HER2 and EpoR co-expression and to determine its frequency in tumor specimens from breast cancer patients. Attainment of these aims will reveal whether EPO/EpoR signaling contributes to trastuzumab resistance. A positive finding will warrant further investigation of whether rHuEPO should continue to be administered concurrently with trastuzumab in breast cancer patients. PUBLIC HEALTH RELEVANCE: The drug erythropoietin (EPO) is often given to breast cancer patients to help prevent or lessen treatment-related anemia and fatigue; however, some evidence from our laboratory and others suggests that EPO might make breast cancer resistant to the anti-breast cancer drug trastuzumab. We will investigate this possibility. Our findings may indicate that EPO should not be administered to breast cancer patients who are being treated with trastuzumab.

描述（由申请人提供）：曲妥珠单抗（Herceptin）是一种人源化的抗HER2单克隆抗体，当将其添加到标准化学疗法中以用于过表达HER2过表达乳腺癌时，已证明可以赋予明显的生存益处。然而，不幸的是，只有30-40％的HER2阳性乳腺肿瘤对曲妥珠单抗反应。在此提案中，我们将探讨促红细胞生成素（EPO）诱导的细胞信号传导在乳腺癌对曲妥珠单抗的耐药性中起作用。 EPO是一种主要的造血细胞因子，主要由肾脏中的一组专门细胞产生，并作用于骨髓中的红细胞祖细胞，导致促红细胞生成。重组人EPO（Rhuepo）经常用于癌症患者，以预防和减轻与癌症和癌症治疗相关的贫血和疲劳。最近的研究表明，通过在这些组织中发现的EPO受体（EPOR）激活，EPO在非杂造组织中具有显着的细胞保护活性。有趣的是，EPOR也存在于某些临床肿瘤标本中，尤其是来自乳腺癌患者的肿瘤标本。作为I型细胞因子受体家族的成员，EPOR在EPO结合后同构二聚体，触发与受体相关激酶JAK2的激活，STAT5的随后磷酸化以及由SH2域域介导的信号传输cascacade介导的，由SH2域域介导的适配器，与Her2介导的信号介导的途径重叠相关。我们在初步研究中发现，EPOR与HER2共表达，来自患者的大量已建立的乳腺癌细胞系和乳腺癌组织标本。乳腺癌细胞暴露于Rhuepo以Epor表达依赖性的方式激活细胞信号传导，并以曲妥珠单抗和Rhuepo的同时处理HER2/EPOR双阳性乳腺癌细胞，从而降低了对曲妥珠单抗治疗的治疗反应。我们假设对Rhuepo的并发施用响应细胞信号构成了乳腺癌对曲妥珠单抗的抗性机制。我们计划在四个特定目的中检验这一假设：1）确认Rhuepo对曲妥珠单抗在HER2/EPOR双重阳性乳腺癌细胞中的细胞保护作用； 2）确定Rhuepo并发施用曲妥珠单抗在HER2/EPOR双阳性乳腺癌异种移植物中的抗肿瘤活性的程度； 3）通过激活将EPOR下游信号通路阐明，Rhuepo介导了针对曲妥珠单抗的细胞保护作用； 4）确认HER2和EPOR共表达的存在，并确定其在乳腺癌患者的肿瘤标本中的频率。实现这些目标将揭示EPO/EPOR信号是否有助于曲妥珠单抗耐药性。一个积极的发现将有必要进一步研究是否应继续在乳腺癌患者中与曲妥珠单抗同时服用Rhuepo。公共卫生相关性：通常将药物红细胞生成素（EPO）提供给乳腺癌患者，以帮助预防或减轻与治疗有关的贫血和疲劳；但是，我们实验室和其他一些证据表明，EPO可能会使抗乳腺癌对抗胸腺抗癌药物抗议曲妥珠单抗具有抗药性。我们将调查这种可能性。我们的发现可能表明不应将EPO用于接受曲妥珠单抗治疗的乳腺癌患者。