Targeted Combinations for Her2- Positive Breast Cancer Biology

针对HER2阳性乳腺癌生物学的靶向组合 受体酪氨酸激酶HER(ErbB2/Neu)的过度表达在乳腺中起重要作用 癌症的发生和治疗的反应。人源化抗HER2单抗曲妥珠单抗 (Herceptin@)与化疗相结合，可延长HER2+乳腺癌患者的生存期。 不幸的是，癌症经常在这样的治疗方案下复发，目前的治疗方法不太可能治愈大多数 病人。曲妥兹单抗治疗的新组合方法将会有很大的临床益处。 HER2+肿瘤可能由于其他生长因子或细胞因子信号的激活而抵抗曲妥珠单抗治疗 小路。这项提案的目标是开发一种三层“管道”方法来描述新的 曲妥珠单抗和其他靶向信号转导抑制剂的组合。在目标1中，我们使用微阵列 和免疫组织化学技术描绘生物标志物，以早期检测最佳反应 曲妥珠单抗单独在“短暂暴露”环境中。曲妥珠单抗联合雷帕明类似物的1期临床试验 CCI-779将在转移性患者中进行评估，如果发现组合是安全的，则将其转移到 短暂的曝光设置。从Trastzumab暴露研究中获得的知识将用于评估 这个组合和其他组合的价值。 在目标2中，我们将测试曲妥珠单抗和新型信号转导抑制剂在药物中的组合。 开发管道(Akt、MEK、PI3K、JNK)。我们还将确定联合治疗是否可以 将曲妥珠单抗的治疗范围扩大到低水平表达HER2的乳腺肿瘤细胞。在《目标3》中我们 将进行一种、高通量的siRNA筛选激酶靶点，即增强曲妥珠单抗的作用，以及一种高 HER2+病中ErbB家族成员的吞吐量突变筛查我们预计这条管道将 产生新的靶点(目标3)，这将进展到有前景的药物的临床前测试和优先排序 候选人(目标2)，然后转移到快速和有效的临床测试(目标1)。具有这些互补性 方法，我们的研究结果可能会对HER2+乳腺癌的治疗产生影响 病人。

TARGETED COMBINATIONS FOR HER2 POSITIVE BREAST CANCER BIOLOGY Over-expression of the receptor tyrosine kinase HER (ErbB2/Neu) plays an important role in breast carcinogenesis and response to therapy. The humanized monoclonal anti-HER2 antibody trastuzumab (Herceptin@), in combination with chemotherapy, extends survival of HER2+ breast cancer patients. Unfortunately, cancer often recurs following such regimens, and current treatment is unlikely to cure most patients. New combination approaches to trastuzmab therapy would be of substantial clinical benefit. HER2+ tumors may resist trastuzumab therapy due to activation of other growth factor or cytokine signaling pathways. The goal of this proposal is to develop a three-tiered "pipeline" approach for delineating new combinations of trastuzumab and other targeted signal transduetion inhibitors. In Aim 1, we use microarray and immunohistochemical techniques to delineate biomarkers for the early detection of optimal response to trastuzumab alone in a "brief exposure" setting. A Phase 1 trial of trastuzumab plus the rapamyein analog CCI-779 will be evaluated in metastatic patients, and if the combination is found to be safe, moved to the brief exposure setting. Knowledge gained from the trastzumab exposure study will be used to assess the value of this and other combinations. In Aim 2, we will test combinations of trastuzumab and novel signal transduetion inhibitors in the drug development pipeline (Akt, Mek, PI3K, Jnk). We will also determine whether combination therapy can extend the therapeutic range of trastuzumab to breast tumor cells expressing low levels of HER2. In Aim 3 we will carry out a, high throughput siRNA screen kinase targets that enhance trastuzumab action, and a high throughput mutation screen for ErbB family members in HER2+ disease. We envision this pipeline will produce novel targets (Aim 3) that would progress to pre-clinical testing and prioritization of promising drug candidates (Aim 2) that then move to rapid and efficient clinical testing (Aim 1). With these complementary approaches, the results of our research are likely to have impact on the treatment of HER2+ breast cancer patients.