Targeted Combinations for Her2- Positive Breast Cancer Biology

Her2 阳性乳腺癌生物学的靶向组合

• 批准号: 7729484
• 负责人: Lyndsay Norine Harris
• 金额: $ 8.08万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729484
• 关键词: Antibodies; Biological Markers; Breast; CCI-779; Cancer Biology; Cancer Patient; Clinical; Combined Modality Therapy; Cytokine Signaling; Disease; ERBB2 gene; Early Diagnosis; Family member; Goals; Growth Factor; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mutation; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Play; Range; Receptor Protein-Tyrosine Kinases; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Techniques; Testing; Therapeutic; Trastuzumab; Treatment Protocols; analog; carcinogenesis; chemotherapy; drug development; inhibitor/antagonist; malignant breast neoplasm; neoplastic cell; novel; pre-clinical; receptor expression; research clinical testing; response; tumor

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.

her2阳性乳腺癌生物学的靶向组合