Breast cancer response markers to a dual HER1/2 blocker

描述(申请人提供)：针对乳腺癌HER2的治疗建立了一个成功的范例，表明其他分子靶向治疗可能被证明对这种疾病有用。尽管它们的功能重叠，但实验室数据表明，HER2/HER3异源二聚体主要激活Akt/PI3-激酶途径，而HER1/HER2异源二聚体主要通过ERK1，2 MAP-激酶途径激活细胞增殖。曲妥珠单抗是一种人源化的抗HER2的单抗，对乳腺癌有很高的疗效。我们在新佐剂曲妥珠单抗临床研究中获得的人乳腺癌活检组织的初步数据表明，曲妥珠单抗的主要作用机制是通过影响Akt/PI3-K的生存途径，从而诱导细胞凋亡，而对细胞增殖没有明显的影响(Ki67和p27)。我们和其他人的实验室数据表明，在人类乳腺癌中，旨在同时阻断HER1/HER2和HER2/HER3途径的治疗方法可能比单独使用这两种方法中的任何一种都要好。我们假设像GW572016这样的小分子通过阻断HER1和HER2来抑制Akt/PI3-Kinase细胞的存活和ERK-1，2 MAP-Kinase细胞的增殖途径。因此，作为双重作用机制，诱导细胞凋亡和减少细胞增殖，将是治疗HER1/HER2过表达乳腺癌的有效单药，可能优于仅影响其中任何一条途径的治疗方法(1)。为了验证这一假设，我们建议使用GW572016进行一项新辅助临床试验，在该试验中，将获得一系列癌症组织样本，用于与肿瘤反应相关的分子研究。建议的具体目标如下：(1)通过一项新辅助试验，评估GW572016在未接受治疗的患者中的临床有效率和毒性，并在不同时间点获得系列原发乳腺癌标本，以论证GW572016对HER1/HER2过表达的局部晚期乳腺癌患者的临床疗效，并通过新辅助试验评估GW572016对未接受治疗的患者的临床疗效。(2)确定GW572016在这些连续的核心活检中是否在体内抑制HER1和HER2信号转导，通过评估细胞生存途径(裂解caspase 3和磷酸化Akt诱导的细胞凋亡)，细胞周期停滞(ERK1，2 MAP-Kinase，Ki67和p27)，以及下调总的和磷酸化的HER1和HER2来确定GW572016是否抑制HER1和HER2的信号转导。(3)通过对预处理样本的基因表达谱芯片分析，筛选出对GW572016敏感和耐药的预测标记。在正常的血管和周围间质环境下，这些人类乳腺癌的系列样本将为GW572016的体内作用机制提供重要信息，GW572016是一种有希望的新型小分子，具有抗HER1和HER2的双重特异性，以及可能预测对该药物的反应和耐药性的分子标记。

DESCRIPTION (provided by applicant): Therapies directed at HER2 in breast cancer establish a successful paradigm that suggests other molecular-targeted treatments may prove useful in this disease. Though their functions overlap, laboratory data suggest that HER2/HER3 heterodimers predominantly activate the Akt/PI3-kinase cell survival pathway, while HER1/HER2 heterodimers mainly activate cell proliferation by the ERK1,2 MAP-kinase pathway. Trastuzumab, a humanized monoclonal antibody against HER2, is highly efficacious in breast cancer. Our preliminary data in human breast cancer biopsies obtained from a neoadjuvant trastuzumab clinical study indicates that the main mechanism of action of trastuzumab is by affecting Akt/PI3-kinase survival pathways, thereby inducing apoptosis, without significant changes in cell proliferation (Ki67 and p27). We and others have laboratory data suggesting that therapies designed to block both HER1/HER2 and HER2/HER3 pathways might be superior to either strategy alone in human breast cancers. We hypothesize that a small molecule like GW572016 which inhibits both Akt/PI3-kinase cell survival and ERK 1,2 MAP-kinase cell proliferation pathways by blocking HER1 and HER2. thereby inducing apoptosis and decreasing cell proliferation as dual mechanisms of action, will be an effective single agent in HER1/HER2 over-expressing breast cancer, and may be superior to therapies that affect either pathway alone (1). To test this hypothesis, we propose to perform a neoadjuvant clinical trial with GW572016, in which serial cancer tissue samples will be obtained for molecular studies in relation to tumor response. The following specific aims are proposed: (1) To demonstrate the clinical efficacy of GW572016 in patients with HER1/HER2-overexpressing locally advanced breast cancer, with and without gross concomitant metastatic disease, by assessing in a neoadjuvant trial the clinical response rate and toxicity of GW572016 in treatment-naive patients, and to obtain serial specimens from primary breast cancers at different time-points. (2) To determine if GW572016 inhibits HER1 and HER2 signaling in vivo in these sequential core biopsies by assessing cell survival pathways (apoptosis by cleaved caspase 3, and phosphorylated Akt), cell cycle arrest (ERK1,2 MAP-kinase, Ki67, and p27), and down-regulation of total and phosphorylated HER1 and HER2. (3) To identify predictive markers for sensitivity and resistance to GW572016 by gene expression array analysis of pretreatment samples. With normal vasculature and surrounding stromal milieu, these serial samples of human breast cancer will provide important information on the in vivo mechanisms of action of GW572016, a promising novel small molecule with dual specificity against HER1 and HER2, together with molecular signatures that may predict response and resistance to this agent.