Deguelin in therapy of triple negative breast cancer

德桂林治疗三阴性乳腺癌

• 批准号: 8403823
• 负责人: RAJENDRA G MEHTA
• 金额: $ 43.88万
• 依托单位: IIT RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403823
• 关键词: Affect; African; Apoptosis; Aromatase Inhibitors; Biological Assay; Breast; Breast Cancer Cell; Cancer Patient; Cancer cell line; Cell Line; Cells; Classification; Clinical Trials; Development; ERBB2 gene; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Event; Exhibits; Fractionation; Gene Proteins; Genes; In Vitro; Investigation; Laboratories; Lesion; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Tumorigenesis; Mammary gland; Mediating; Metabolism; Methylnitrosourea; Modeling; Molecular; Mus; Organ Culture Techniques; Ornithine Decarboxylase; Papilloma; Pathway interactions; Patients; Phytochemical; Plants; Premalignant; Proto-Oncogene Proteins c-akt; Regimen; Roche brand of trastuzumab; Role; Signal Transduction; Skin Carcinogenesis; Staging; Steroid Receptors; Transplantation; WNT Signaling Pathway; Woman; base; beta catenin; carcinogenesis inhibitor; deguelin; in vivo; malignant breast neoplasm; progesterone receptor negative; programs; public health relevance; research study; response; triple-negative invasive breast carcinoma; tumor

DESCRIPTION (provided by applicant): Treatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) has been successfully used for steroid receptor positive breast cancers. More recently herceptin has become treatment of choice for patients exhibiting HER2/neu. However, breast cancer patients expressing estrogen and progesterone receptor negative status as well as are negative for HER2/neu only have a few chemotherapeutic options available. As a result, searching for appropriate therapy regimen for these triple negative breast cancers has become a major focus of investigations for many laboratories. During our program for identifying natural inhibitors of carcinogenesis, we isolated deguelin, a phytochemical present in an African plant Mundulea sericea (Leguminossae) via an activity guided fractionation based on mechanistically regulated bioassays. Deguelin induced apoptosis in many cancer cell lines, inhibited development of precancerous lesions in mammary glands in organ cultures, inhibited development of papilloma in two-stage skin carcinogenesis, suppressed tumor multiplicity in MNU-induced mammary carcinogenesis and suppressed ornithine decarboxylase activity. More recently we observed that it selectively inhibited proliferation of four cell lines characterized as triple negative breast cancer cells. Preliminary experiment evaluating microarray profile indicated differential expression of two independent pathways including clusters of apoptosis and Wnt/beta- catenin signaling genes in cells as a result of deguelin treatment. More importantly, deguelin has been considered for clinical trials for lung cancer patients. The proposed studies in this application will provide an immediate opportunity for translational application of deguelin for triple negative breast cancer patients. The overall objective is to understand role of deguelin for ER, PR and Her2/neu negative breast cancer cells in vitro and in vivo and to see if deguelin can be used as a targeted therapy for Triple Negative Breast Cancer (TNBC) patients. The specific objectives are: 1aTo evaluate the efficacy of deguelin using twelve commercially available breast cancer cell lines representing the three major classifications of breast cancers: ER and PR positive, HER-2 amplified, and Triple (ER, PR, Her2/neu) Negative. 1. To identify deguelin mediated molecular events during the development of steroid receptor positive and negative preneoplastic lesions in mouse mammary gland organ culture (MMOC). 2. To determine the effects of deguelin and its metabolism by TNBC cells in vivo using orthotopic transplantation model. 3. To delineate the target(s) of deguelin action. The results will provide an opportunity for TNBC patients to a new targeted selective therapy.

描述（由申请人提供）：用抗雌激素和芳香酶抑制剂治疗乳腺癌患者已成功用于类固醇受体阳性乳腺癌。最近，赫赛汀已成为 HER2/neu 患者的首选治疗方法。然而，表达雌激素和孕激素受体阴性以及 HER2/neu 阴性的乳腺癌患者只有几种可用的化疗选择。因此，寻找针对这些三阴性乳腺癌的合适治疗方案已成为许多实验室研究的主要焦点。在我们识别致癌天然抑制剂的计划中，我们通过基于机械调节生物测定的活性引导分馏分离了德桂林，这是非洲植物 Mundulea sericea（豆科）中存在的一种植物化学物质。 Deguelin 诱导许多癌细胞系凋亡，抑制器官培养中乳腺癌前病变的发展，抑制两阶段皮肤癌发生中乳头状瘤的发展，抑制 MNU 诱导的乳腺癌发生中的肿瘤多样性，并抑制鸟氨酸脱羧酶活性。最近，我们观察到它选择性抑制四种三阴性乳腺癌细胞系的增殖。评估微阵列图谱的初步实验表明，由于九角豆素处理，细胞中两个独立途径的差异表达，包括细胞凋亡和 Wnt/β-连环蛋白信号基因簇。更重要的是，德桂林已被考虑用于肺癌患者的临床试验。本申请中拟议的研究将为三阴性乳腺癌患者转化应用德桂林提供直接机会。总体目标是了解德桂林在体外和体内对 ER、PR 和 Her2/neu 阴性乳腺癌细胞的作用，并了解德桂林是否可以用作三阴性乳腺癌 (TNBC) 患者的靶向治疗。具体目标是： 1a 使用代表乳腺癌三大类的 12 种市售乳腺癌细胞系来评估德桂林的功效：ER 和 PR 阳性、HER-2 扩增和三重（ER、PR、Her2/neu）阴性。 1. 鉴定小鼠乳腺器官培养物（MMOC）中类固醇受体阳性和阴性癌前病变发展过程中九角茴香素介导的分子事件。 2.利用原位移植模型确定九十皮素及其在TNBC细胞体内代谢的作用。 3. 确定九角茴香行动的目标。该结果将为TNBC患者提供新的靶向选择性治疗的机会。