Breast cancer response markers to a dual HER1/2 blocker

描述（由申请人提供）：针对乳腺癌中HER 2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证明对这种疾病有用。虽然它们的功能重叠，实验室数据表明，HER 2/HER 3异二聚体主要激活Akt/PI 3-激酶细胞存活途径，而HER 1/HER 2异二聚体主要通过ERK 1，2 MAP-激酶途径激活细胞增殖。曲妥珠单抗是一种抗HER 2的人源化单克隆抗体，在乳腺癌中非常有效。我们从一项新辅助曲妥珠单抗临床研究中获得的人乳腺癌活检的初步数据表明，曲妥珠单抗的主要作用机制是通过影响Akt/PI 3-激酶存活通路，从而诱导细胞凋亡，而不会显著改变细胞增殖（Ki 67和p27）。我们和其他人的实验室数据表明，设计用于阻断HER 1/HER 2和HER 2/HER 3通路的疗法可能上级人类乳腺癌中单独使用的任何一种策略。我们假设，像GW 572016这样的小分子通过阻断HER 1和HER 2来抑制Akt/PI 3激酶细胞存活和ERK 1，2 MAP激酶细胞增殖途径。从而作为双重作用机制诱导细胞凋亡和降低细胞增殖，将是治疗HER 1/HER 2过表达乳腺癌的有效单一药物，并且可能上级单独影响任一途径的疗法（1）。为了验证这一假设，我们建议使用GW 572016进行新辅助临床试验，其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）通过在新辅助治疗试验中评估GW 572016在未经治疗的患者中的临床应答率和毒性，证明GW 572016在患有HER 1/HER 2过表达的局部晚期乳腺癌（伴或不伴肉眼可见的伴随转移性疾病）的患者中的临床疗效，并在不同时间点获得原发性乳腺癌的系列标本。(2)通过评估细胞存活途径（通过裂解的半胱天冬酶3和磷酸化Akt引起的细胞凋亡）、细胞周期阻滞（ERK 1，2 MAP-激酶、Ki 67和p27）以及总HER 1和磷酸化HER 2的下调，确定GW 572016是否在这些连续核心活检中抑制体内HER 1和HER 2信号传导。(3)通过预处理样品的基因表达阵列分析来鉴定对GW 572016的敏感性和抗性的预测标记。在正常血管系统和周围基质环境下，这些人乳腺癌的系列样本将提供有关GW 572016体内作用机制的重要信息，GW 572016是一种有前途的新型小分子，对HER 1和HER 2具有双重特异性，以及可以预测对该药物的反应和耐药性的分子特征。

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.