Novel Anti-HER3 Strategy for Pancreatic Cancer

描述（由申请人提供）：本提案的总体目标是开发一种新型联合治疗策略，用于使用我们新开发的抗HER 3抗体治疗胰腺癌，其靶向HER 3活化的配体依赖性和非依赖性途径。核心假设是：（1）HER 3的胞外结构域具有至少两个负责HER 3活化的关键功能结构域：一个负责配体结合并以配体依赖性方式介导HER 3活化，另一个以配体非依赖性方式介导并维持HER 3活化;（2）HER 3通过配体依赖性和非依赖性途径的活化对于胰腺细胞对EGFR和/或EGFR受体的抗性的发展同样重要。或HER 2靶向治疗;和（3）阻断两种途径是HER 3完全失活所必需的，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功效。提出了这些假设，并得到了一种新型单克隆抗HER 3抗体（克隆：1A 5）的鉴定和表征的支持，该抗体主要以配体非依赖性方式抑制HER 3磷酸化。HER 3的配体非依赖性活化的重要性通过单独的1A 5和与厄洛替尼或拉帕替尼组合的1A 5的体外和体内抗肿瘤功效证明。此外，我们测试的大多数HER 3+胰腺癌细胞系中存在两种HER 3激活途径，这似乎与HER 2激活以及对厄洛替尼和拉帕替尼的耐药性相关。由于几种靶向配体依赖性活化的抗HER 3抗体正在进行早期临床评价，我们的初步数据提出了一个问题，即仅抑制HER 3的配体依赖性活化不足以超越其对ERBB家族中其他受体（特别是EGFR和HER 2）的激动活性。本研究的可行性得到了抗HER 3抗体和用于定量测量三种主要ERBB受体（EGFR、HER 2和HER 3）的表达和功能的新型测定系统的支持，这使我们能够确定三种受体之间相互作用的生物学功能和拟议联合治疗的分子机制。将解决两个特定目的：AIM 1将确定HER 3的配体非依赖性活化在一组人胰腺癌细胞系和新鲜胰腺癌组织中EGFR和HER 2活化中的作用; AIM 2将确定抗HER 3与厄洛替尼/拉帕替尼和吉西他滨联合治疗的疗效。

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.