P-2: Target Combinations for HER2 - Positive Breast Cancer

P-2：HER2 的目标组合 - 阳性乳腺癌

• 批准号: 7550394
• 负责人: Lyndsay Norine Harris
• 金额: $ 13.32万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7550394
• 关键词: Antibodies; Antineoplastic Agents; Biological Markers; Breast; Breast Cancer Cell; CCI-779; Cancer Patient; Cancer cell line; Cell Death; Cell Proliferation; Class; Clinic; Clinical; Clinical assessments; Code; Combined Modality Therapy; DNA Sequence; Development; Disease; Disease-Free Survival; Drug Combinations; Drug Delivery Systems; ERBB2 gene; Early Diagnosis; Evaluation; Family; Family member; Genetic Polymorphism; Goals; Growth Factor; HER2 inhibition; Human; Kinase Family Gene; Knowledge; Lead; MAPK8 gene; Malignant Neoplasms; Mammary Neoplasms; Methods; Molecular; Mutation; Outcome; P-2; PIK3CG gene; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Range; Receptor Protein-Tyrosine Kinases; Research; Resistance; Roche brand of trastuzumab; Role; Screening procedure; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Signal Transduction Pathway; Sirolimus; Small Interfering RNA; Surrogate Markers; Techniques; Testing; Therapeutic; Translations; Trastuzumab; Treatment Protocols; analog; base; cancer cell; carcinogenesis; chemotherapy; drug development; high throughput screening; improved; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; member; neoplastic cell; novel; pre-clinical; receptor; receptor expression; research clinical testing; response; tumor

PROVIDED. 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 beneiii. HER2+ tumors may resist trastuzumab therapy due to activation of other growth factor or cytokinesignaling 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 1trial 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 prioritizationof 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 likelyto have impact on the treatment of HER2+ breast cancer patients.

提供了 受体酪氨酸激酶HER（ErbB 2/Neu）的过度表达在乳腺癌中起重要作用。 致癌作用和对治疗的反应。人源化抗HER 2单克隆抗体曲妥珠单抗 （Herceptin）与化疗联合，延长了HER 2+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后复发，目前的治疗方法不太可能治愈大多数人。 患者曲妥珠单抗治疗的新组合方法将具有实质性临床益处。 HER 2+肿瘤可能由于其他生长因子或精氨酸信号传导的激活而抵抗曲妥珠单抗治疗 路径。本提案的目标是制定一个三层“管道”方法， 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来描绘生物标志物，用于早期检测对 曲妥珠单抗单药在“短暂暴露”环境中。曲妥珠单抗联合雷帕霉素类似物的1期试验 CCI-779将在转移性患者中进行评估，如果发现该组合是安全的，则将其移至 短暂曝光设置。从曲妥珠单抗暴露研究中获得的知识将用于评估 这个和其他组合的价值。 在目标2中，我们将测试药物中曲妥珠单抗和新型信号转导抑制剂的组合。 开发管道（Akt、Mek、PI 3 K、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展至表达低水平HER 2的乳腺肿瘤细胞。在目标3中， 将进行高通量siRNA筛选增强曲妥珠单抗作用的激酶靶点，并进行高通量siRNA筛选， HER 2+疾病中ErbB家族成员的通量突变筛选。我们设想这条管道将 产生新的目标（目标3），将进展到临床前测试和优先考虑有前途的药物 候选人（目标2），然后转向快速有效的临床测试（目标1）。与这些互补 方法，我们的研究结果很可能对HER 2+乳腺癌的治疗产生影响 患者