New Leads for Triple Negative Breast Cancer from Diverse Natural Sources

来自不同天然来源的三阴性乳腺癌的新线索

基本信息

批准号：
8761726
负责人：
Robert Henry Cichewicz
金额：
$ 47.15万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8761726
关键词：
Affect African American Biodiversity Biological Biological Assay Biological Factors Biology Breast Cancer Cell Breast Cancer Treatment Cancer Patient Cancer cell line Cell Line Cells Characteristics Chemicals Clinical Collection Coupled Crude Extracts Data Defect Development Dose Doxorubicin Drug Kinetics Drug Targeting Drug usage ERBB2 gene Environment Estrogen Receptors Estrogens Fractionation Genomics Goals Hispanics Human Cell Line Hybrids In Vitro Ixabepilone Lead Libraries Malignant Neoplasms Metabolic Modeling Molecular Molecular Analysis Molecular Mechanisms of Action Molecular Profiling Molecular Target Mus Natural Products Chemistry Nature Oncogenic Organism Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Plant Extracts Plant Preparations Plants Predisposition Progesterone Progesterone Receptors Recording of previous events Research Sampling Signal Pathway Sirolimus Source Structure Texas Time Validation Vascular Plant base biological systems cancer therapy cellular targeting cytotoxic cytotoxicity density disorder control docetaxel drug discovery effective therapy erbB-2 Receptor fungus improved in vitro activity in vivo innovation killings mTOR protein malignant breast neoplasm novel novel strategies outcome forecast overexpression public health relevance receptor response scale up screening small molecule small molecule libraries therapeutic target tool triple-negative invasive breast carcinoma tumor young woman

项目摘要

DESCRIPTION (provided by applicant): Triple negative breast cancers (TNBCs) are those devoid of estrogen and progesterone receptors and HER2 overexpression. They are heterogeneous cancers that disproportionately affect young women, African Americans and Hispanics. The prognosis for patients with metastatic TNBC is poor with only 30% surviving 5 years. There is an unmet need for more effective therapies for these breast cancers. Recent molecular profiling of TNBC tumors revealed 6 distinct subtypes with different molecular defects and identified cell lines representative of each of these subtypes. This information allows for the first time the opportunity for targeted drug discovery for each of the different subtypes of TNBC. The goal of this effort is to identify targeted therapies for the subtypes of TNBC. Many of the most successful drugs used to treat cancer are derived or modeled after compounds identified from nature. Natural products occupy a unique region of chemical space that overlaps extensively with pharmaceuticals and is not found in synthetic chemical libraries. Natural product extracts derived from diverse source organisms will be evaluated for the ability to selectively target cells representing the different subtypes of TNBC. An unprecedented collection of fungal extracts has been assembled from highly diverse environments ranging from deep lake sediments to road kill. The extensive biodiversity coupled with innovative culture conditions has yielded an exceptionally large collection of fungal extracts. A second source of chemical diversity will be obtained with extracts made from understudied Texas plants. Preliminary data from fungal and plant extracts show that lead extracts with greater than 100-fold selectivity against one TNBC subtype can be identified using high-content screening and secondary validation assays. Bioassay-guided fractionation of the active compounds will be conducted and those with selective activity will be identified. The pure compounds will be evaluated for in vitro efficacy and potency against multiple cell lines within a specific subtype o TNBC. The most promising compounds will be evaluated for chemical and metabolic stability, pharmacokinetic parameters and in vivo antitumor efficacy. Mechanism of action studies will be conducted to determine how these agents selectively target one subtype of TNBC and the pathways disrupted leading to selective cytotoxicity. These studies will discover new drug leads for consideration for clinical development and novel chemical probes that can identify signaling pathways of susceptibility for the distinct subtypes of TNBC. The ultimate goal of this effort is t identify effective molecularly targeted therapies with the potential to provide long-term disease control and overall survival for patients with TNBC.

描述（由申请人提供）：三重负乳腺癌（TNBC）是没有雌激素和孕激素受体和HER2过表达的乳腺癌（TNBC）。它们是异质的癌症，对年轻妇女，非裔美国人和西班牙裔的影响不成比例。转移性TNBC患者的预后很差，只有30％的5年存活。对于这些乳腺癌，对更有效的疗法有未满足的需求。 TNBC肿瘤的最新分子分析显示了6种不同的亚型，具有不同的分子缺损，并鉴定出代表这些亚型的细胞系。此信息允许第一次为TNBC的每种不同亚型的靶向药物发现机会。这项工作的目的是确定针对TNBC亚型的靶向疗法。许多用于治疗癌症的最成功的药物是在自然界鉴定出的化合物后得出或建模的。天然产品占据了一个独特的化学空间区域，该区域与药品广泛重叠，在合成化学文库中找不到。将评估源自不同源生物的天然产物提取物，以选择性地靶向代表TNBC不同亚型的细胞的能力。从深湖沉积物到道路杀人的高度多样化的环境中，已经组装了一个空前的真菌提取物。广泛的生物多样性以及创新的培养条件产生了大量的真菌提取物。第二种化学多样性的来源将通过从德克萨斯州植物进行研究的提取物获得。来自真菌和植物提取物的初步数据表明，可以使用高含量筛选和二级验证测定法鉴定出具有大于100倍选择性的铅提取物。将进行活性化合物的生物测定引导分馏，并确定具有选择性活性的人。将评估纯化合物在特定亚型O TNBC中针对多个细胞系的体外功效和效力。最有希望的化合物将用于化学和代谢稳定性，药代动力学参数以及体内抗肿瘤功效。将进行作用研究机理，以确定这些试剂如何选择性地靶向TNBC的一种亚型，并破坏导致选择性细胞毒性的途径。这些研究将发现新的药物铅用于考虑临床发育和新型化学探针，这些探针可以鉴定出对TNBC不同亚型易感性的信号传导途径。这项工作的最终目的是t鉴定有效的分子靶向疗法，具有为TNBC患者提供长期疾病控制和总体存活的潜力。