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的联合治疗策略，用于使用我们新开发的抗HER3抗体治疗胰腺癌，该抗体针对HER3激活的配体依赖性和非依赖性途径。主要假设是：(1)HER3的细胞外结构域至少有两个关键功能域负责HER3的激活：一个负责配体结合并以配体依赖的方式介导HER3的激活，另一个以配体独立的方式介导和维持HER3的激活；(2)通过配体依赖途径和独立途径激活HER3对于胰腺细胞对EGFR和/或HER2靶向治疗的耐药性的发展同样重要；(3)阻断这两种通路是HER3完全失活的必要条件，这将进一步大大增强厄洛替尼和拉帕替尼等其他靶向治疗的疗效。这些假设被提出，并被一种新的单克隆抗HER3抗体克隆：1A5的鉴定和表征所支持，该抗体主要以不依赖配体的方式抑制HER3的磷酸化。通过1A5单独使用和与厄洛替尼或拉帕替尼联合使用的体外和体内抗肿瘤效果，证明了HER3的配体非依赖性激活的重要性。此外，我们所测试的大多数HER3+胰腺癌细胞系中都存在HER3激活途径，这似乎与HER2激活以及对厄洛替尼和拉帕替尼的耐药性有关。由于一些靶向配体依赖性激活的抗HER3抗体处于早期临床评估阶段，我们的初步数据引起了人们的关注，即仅抑制HER3的配体依赖性激活不足以覆盖其对ERBB家族中其他受体的激动性活性，特别是EGFR和HER2。抗HER3抗体的可用性以及用于定量测量三种主要ERBB受体（EGFR、HER2和HER3）表达和功能的新型检测系统支持了本研究的可行性，这使我们能够确定三种受体之间相互作用的生物学功能以及拟议联合治疗的分子机制。两个特定目标将被解决：AIM 1将确定HER3的配体非依赖性激活在人类胰腺癌细胞系和新鲜胰腺癌组织中EGFR和HER2激活中的作用；和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。

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.