Novel Anti-HER3 Strategy for Pancreatic Cancer

治疗胰腺癌的新型抗 HER3 策略

基本信息

批准号：
8512478
负责人：
TONG ZHOU
金额：
$ 19.12万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512478
关键词：
Address Antibodies Biological Assay Biological Process Cancer cell line Cells Combined Modality Therapy Data Development Drug resistance EGFR gene EGFR inhibition ERBB2 gene ERBB3 gene Epidermal Growth Factor Receptor Erlotinib Evaluation Extracellular Domain Family Feasibility Studies Goals Human In Vitro Lead Ligand Binding Ligands Malignant neoplasm of pancreas Measurement Mediating Modeling Molecular Pancreas Pathway interactions Phase Phosphorylation Pilot Projects Play Property Regulation Resistance Resistance development Role Signal Transduction System Testing Therapeutic Tissues Treatment Efficacy base cancer therapy extracellular gemcitabine in vivo inhibiting antibody inhibitor/antagonist lapatinib novel pancreatic cancer cells pancreatic neoplasm public health relevance receptor research clinical testing response treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a novel combination therapeutic strategy for treatment of pancreatic cancer using our newly developed anti-HER3 antibodies, which target both ligand-dependent and -independent pathways of HER3 activation. The central hypotheses are: (1) the extracellular domain of HER3 has at least two critical functional domains responsible for activation of HER3: one is responsible for the ligand binding and mediates HER3 activation in a ligand-dependent fashion, and another mediates and maintains HER3 activation in a ligand-independent fashion; (2) the activation of HER3 via both ligand-dependent and independent pathways are equally important for the development of resistance of pancreatic cells to EGFR and/or HER2 targeted therapies; and (3) the blockade of both pathways is required for a complete inactivation of HER3, which further would greatly enhance the efficacy of other targeted therapies such as erlotinib and lapatinib. The hypotheses were raised and have been supported by identification and characterization of a novel monoclonal anti-HER3 antibody, clone: 1A5, which primarily inhibits phosphorylation of HER3 in a ligand-independent fashion. The importance of the ligand-independent activation of HER3 was demonstrated by in vitro and in vivo anti-tumor efficacy of 1A5 alone and in combination with erlotinib or lapatinib. Furthermore, both HER3 activation pathways exist in most HER3+ pancreatic cancer cell lines we have tested, which appear to be associated with HER2 activation, and the resistance to erlotinib and lapatinib. As several anti-HER3 antibodies targeting ligand-dependent activation are under early phase clinical evaluation, our preliminary data raise a concern that only inhibition of the ligand-dependent activation of HER3 is not sufficient to override its agonistic activity to other receptors in the ERBB family, particularly, EGFR and HER2. The feasibility of this study is supported by the availability of both anti-HER3 antibodies and a novel assay system for quantitative measurement of the expression and function of the three major ERBB receptors: EGFR, HER2 and HER3, which allows us to determine the biological functions of interaction among the three receptors and the molecular mechanisms of the proposed combination therapy. Two Specific Aims will be addressed: AIM 1 will determine the role of the ligand-independent activation of HER3 in the activation of EGFR and HER2 in a panel of human pancreatic cancer cell lines and fresh pancreatic cancer tissues; and AIM 2 will determine the therapeutic efficacy of anti-HER3 in combination with erlotinib/lapatinib and gemcitabine.

描述（由申请人提供）：该提案的总体目标是使用我们新开发的抗 HER3 抗体开发一种治疗胰腺癌的新型联合治疗策略，该抗体针对 HER3 激活的配体依赖性和非配体依赖性途径。中心假设是：（1）HER3的胞外结构域至少有两个负责HER3激活的关键功能域：一个负责配体结合并以配体依赖性方式介导HER3激活，另一个介导和维持HER3以不依赖配体的方式激活； (2) 通过配体依赖性和独立途径激活 HER3 对于胰腺细胞对 EGFR 和/或 HER2 靶向治疗产生耐药性同样重要； (3) HER3完全失活需要阻断这两种途径，这将进一步大大增强其他靶向治疗如厄洛替尼和拉帕替尼的疗效。这些假设得到了新型单克隆抗 HER3 抗体（克隆：1A5）的鉴定和表征的支持，该抗体主要以不依赖配体的方式抑制 HER3 的磷酸化。 1A5 单独使用以及与厄洛替尼或拉帕替尼联合使用的体外和体内抗肿瘤功效证明了 HER3 的配体依赖性激活的重要性。此外，这两种 HER3 激活途径都存在于我们测试的大多数 HER3+ 胰腺癌细胞系中，这似乎与 HER2 激活以及对厄洛替尼和拉帕替尼的耐药性相关。由于几种针对配体依赖性激活的抗 HER3 抗体正处于早期临床评估阶段，我们的初步数据引起了人们的担忧，即仅抑制 HER3 的配体依赖性激活不足以覆盖其对 ERBB 家族其他受体的激动活性，特别是 EGFR 和 HER2。这项研究的可行性得到了抗 HER3 抗体和定量测量三种主要 ERBB 受体（EGFR、HER2 和 HER3）表达和功能的新型测定系统的可用性的支持，这使我们能够确定生物学功能三种受体之间的相互作用以及所提出的联合疗法的分子机制。将解决两个具体目标： AIM 1 将确定 HER3 的配体独立激活在一组人胰腺癌细胞系和新鲜胰腺癌组织中 EGFR 和 HER2 激活中的作用； AIM 2将确定抗HER3联合厄洛替尼/拉帕替尼和吉西他滨的治疗效果。