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）是指缺乏雌激素和孕激素受体和HER2过表达的乳腺癌。它们是异质癌症，对年轻女性、非洲裔美国人和西班牙裔美国人的影响尤为严重。转移性TNBC患者的预后很差，只有30%的患者能存活5年。对这些乳腺癌更有效的治疗方法的需求尚未得到满足。最近对TNBC肿瘤的分子分析揭示了具有不同分子缺陷的6种不同亚型，并鉴定了代表每种亚型的细胞系。这个信息允许

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.