Breast CancerTherapeutic Subtype Therapeutic Responses: Eval. of Chemo. and Bio.

乳腺癌治疗亚型治疗反应：评估。

• 批准号: 7558846
• 负责人: CHARLES M. PEROU
• 金额: $ 50.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/7558846
• 关键词: 2-methoxyestradiol; Alternative Therapies; Animal Model; Biological Assay; Biological Models; Biological Response Modifier Therapy; Bortezomib; Breast; Breast Carcinoma; Carboplatin; Carboplatin/Paclitaxel; Caring; Cell Line; Cetuximab; Chemotherapy-Oncologic Procedure; Clinical Trials; Combined Modality Therapy; Correlative Study; DNA Microarray Chip; DNA Microarray format; Dasatinib; Data; Data Set; Development; Doctor of Medicine; Doxorubicin Hydrochloride Liposome; Drug Delivery Systems; ERBB2 gene; End Point; Epidermal Growth Factor Receptor; Gene Expression; Genomics; Head; Human; Image; Literature; Mammary Neoplasms; Mammary gland; Measures; Modeling; Molecular; Molecular Profiling; Mus; NF-kappa B; Neoadjuvant Therapy; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Primary Neoplasm; Protein Analysis; Proteins; Reproduction spores; Research Personnel; Sampling; Science; Standards of Weights and Measures; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Mice; Treatment Protocols; Tumor Subtype; Tumor-Derived; Ultrasonography; Xenograft procedure; base; chemotherapy; cyclophosphamide/doxorubicin protocol; design; inhibitor/antagonist; malignant breast neoplasm; next generation; pre-clinical; response; small molecule; tumor; tumor xenograft

Gene expression profiles have identified five major molecular subtypes of breast cancer (Luminal A, Luminal B, Basal-like, HER2+/ER-, Normal Breast-like) that show significant differences in survival. Mounting evidence also suggests that these subtypes vary in their responsiveness to chemotherapeutics and biologic agents. In fact, specific drug targets, like HER1 and HER2, within different subtypes suggests that logical combinations of chemotherapeutics and biologic agents may be subtype-specific, which must be empirically evaluated. Nonetheless, picking the right chemotherapeutic(s) and biologic agent combination for each subtype has yet to be experimentally or clinically determined. Therefore, we propose here to identify efficacious combination therapies for the tumor subtypes by testing at least 8 different regimens on a preclinical animal models system composed of primary human tumor xenografts, breast tumor-derived cell lines grown as xenografts, and transgenic mice that develop mammary carcinomas with known molecular subtypes. These experimental results will be augmented with human clinical trial data from several different trials that test a variety of chemotherapy and biologic therapy combinations, which should ultimately allow us to develop genomic assays that could be used to select patients for specific chemotherapy regimens, and to identify tumor subtype sensitivities that will be prospectively tested in the next generation of clinical trials.

基因表达谱已经鉴定了乳腺癌的五种主要分子亚型（Luminal A，Luminal B，Luminal C）。 B、基底细胞样、HER 2 +/ER-、正常乳腺样），其显示出存活率的显著差异。安装 证据还表明，这些亚型对化疗药物和生物制剂的反应性不同， 剂.事实上，不同亚型中的特定药物靶点，如HER 1和HER 2，表明逻辑上 化学治疗剂和生物制剂的组合可以是亚型特异性的，这必须根据经验确定。 评估。尽管如此，选择正确的化疗药物和生物制剂组合， 亚型还有待实验或临床确定。因此，我们建议在此确定 通过对至少8种不同的方案进行测试， 由原代人肿瘤异种移植物、乳腺肿瘤来源的细胞 作为异种移植物生长的细胞系，以及发生具有已知分子标记的乳腺癌的转基因小鼠。 亚型。这些实验结果将得到来自几个不同的人类临床试验数据的补充。 这些试验测试了各种化疗和生物治疗的组合，最终应该让我们 开发可用于选择特定化疗方案的患者的基因组测定， 确定肿瘤亚型敏感性，将在下一代临床试验中进行前瞻性测试。