New Leads for Triple Negative Breast Cancer from Diverse Natural Sources

描述（由申请人提供）：三阴性乳腺癌（TNBC）是缺乏雌激素和孕激素受体以及HER2过表达的乳腺癌。它们是异质性癌症，不成比例地影响年轻女性，非洲裔美国人和西班牙裔美国人。转移性TNBC患者的预后较差，仅30%存活5年。对于这些乳腺癌的更有效疗法存在未满足的需求。TNBC肿瘤的最新分子分析揭示了具有不同分子缺陷的6种不同亚型，并鉴定了代表这些亚型中每一种的细胞系。该信息允许 第一次有机会为TNBC的每一种不同亚型发现靶向药物。这项工作的目标是确定TNBC亚型的靶向治疗。许多用于治疗癌症的最成功的药物都是从自然界中鉴定的化合物衍生或模仿的。天然产物占据了化学空间的一个独特区域，与药物广泛重叠，在合成化学图书馆中找不到。将评价来源于不同来源生物体的天然产物提取物选择性靶向代表不同TNBC亚型的细胞的能力。一个前所未有的收集真菌提取物已组装从高度多样化的环境，从深湖沉积物到道路杀死。广泛的生物多样性加上创新的培养条件产生了非常大的真菌提取物的集合。化学多样性的第二个来源将从未充分研究的德克萨斯州植物中提取。来自真菌和植物提取物的初步数据显示，可以使用高含量筛选和二次验证测定来鉴定对一种TNBC亚型具有大于100倍选择性的铅提取物。将对活性化合物进行生物测定指导的分级分离，并鉴定具有选择性活性的化合物。将评估纯化合物针对特定亚型TNBC内的多种细胞系的体外功效和效力。最有前途的化合物将进行评估的化学和代谢稳定性，药代动力学参数和体内抗肿瘤疗效。将进行作用机制研究，以确定这些药物如何选择性靶向TNBC的一种亚型，以及导致选择性细胞毒性的破坏途径。这些研究将发现可供临床开发考虑的新药线索和新型化学探针，这些探针可以识别TNBC不同亚型的易感性信号通路。这项工作的最终目标是确定有效的分子靶向治疗，有可能为TNBC患者提供长期疾病控制和总生存率。

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.