Novel Anti-HER3 Strategy for Pancreatic Cancer

治疗胰腺癌的新型抗 HER3 策略

• 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
• 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

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抗体制定一种新型的组合治疗策略来治疗胰腺癌，该抗体旨在靶向HER3激活的配体依赖性和独立的途径。中心假设是：（1）HER3的细胞外结构域至少有两个关键功能域负责激活HER3：一个是负责配体结合并介导HER3激活配体依赖性的方式，而另一种则以与配体无关的方式介导并保持HER3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靶向疗法的耐药性的发展同样重要； （3）两种途径的封锁是完全失活Her3所必需的，这将进一步增强其他靶向疗法（例如Erlotinib和Lapatinib）的疗效。提出了假设，并得到了新型单克隆抗HER3抗体克隆：1A5的识别和表征，该假设主要以独立于配体的方式抑制HER3的磷酸化。单独的1a5的体外和体内抗肿瘤疗效证明了HER3的配体非依赖性激活的重要性，并与Erlotinib或Lapatinib结合使用。此外，我们已经测试过的大多数HER3+胰腺癌细胞系中都存在两个HER3激活途径，这似乎与HER2激活有关，并且对Erlotinib和Lapatinib的耐药性。由于靶向配体依赖性激活的几种抗HER3抗体在早期临床评估下，我们的初步数据引起了人们的关注，即只有抑制HER3的配体依赖性激活HER3不足以使其对ERBB家族中其他受体的激动剂活性覆盖其激动剂活性，尤其是EGFR和HER2。这项研究的可行性得到了抗HER3抗体的可用性和一种新颖的测定系统，用于定量测量三个主要ERBB受体的表达和功能：EGFR，HER2和HER3，这使我们能够确定三种受体和拟议的组合疗法分子机制之间相互作用的生物学功能。将解决两个具体目标：AIM 1将决定HER3在人类胰腺癌细胞系和新鲜的胰腺癌组织中，HER3非配体非依赖性激活的作用； AIM 2将确定抗HER3与Erlotinib/Lapatinib和吉西他滨联合使用的治疗功效。