Abstract P5-04-18: Extracts derived from fungi and plants demonstrate specificity for subtyptes of triple negative breast cancer
Authors: CV Shaffer, S Cai, A Perez, AL Risinger, L Du, BR O'Keefe, RH Cichewicz, SL Mooberry
Journal: Cancer Research (2016)

Abstract New effective therapies are needed for patients with triple negative breast cancers (TNBC). The identification by Lehmann and Bauer1 of distinct subtypes of TNBC and representative cell lines that are driven by different defects and signaling pathways provided the opportunity, for the first time, to screen for selective activities against these subtypes of TNBC. Using this knowledge, we initiated a screen of diverse natural product extract libraries with the goal of identifying extracts selective for subtypes of TNBC. The compounds with this selective activity will then be purified using bioassay-guided fractionation. Drugs derived from plants and fungi have provided some of the most important pharmaceuticals used today, including numerous anticancer agents.2 Natural products occupy a biologically validated chemical space that does not overlap with compounds found in most synthetic chemical libraries.3 Additionally, there are differences in chemical space between plant and fungal-derived compounds4 and different compound classes are expected to be isolated from these two sources. A total of 1,953 extracts of fungi collected from diverse environments, including Great Lakes sediments and 2,200 plant extracts from tropical environments have been screened for selective cytotoxic activities against cell lines representing 5 subtypes of TNBC. These subtypes are the basal-like 1 and 2 (BL1, BL2), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). The initial screening using one concentration, 2 µg/ml for fungal extracts and 20 µg/ml for plant extracts, identified many extracts with selective activity against the TNBC subtypes. Detailed dose response curves were then generated with these extracts in each of the TNBC cell lines. A total of 4 fungal extracts and 7 plant extracts with selective cytotoxic activities were identified with selectivity up to 100-fold for 3 of the extracts. Bioassay-guided fractionation is ongoing to identify the active constituents. These results demonstrate that natural product extracts can yield selective actions against TNBC subtypes. We expect that these plant and fungal extracts will yield compounds that target molecular drivers specific to the TNBC subtypes. It is our expectation that compounds with selective, targeted activities will continue to be isolated from these extract collections. 1. Lehman BD and Bauer JA et al. J Clin Invest: 121, 2750-2767, 2011. 2. Newman DJ and Cragg GM. J Nat Prod: 75, 311-335, 2012. 3. Feher M and Schmidt JM. J Chem Inf Comput Sci: 43, 218-227, 2003. 4. El-Elimat, T et al. ACS Med Chem Lett: 3, 645-649, 2012. Citation Format: Shaffer CV, Cai S, Perez A, Risinger AL, Du L, O'Keefe BR, Cichewicz RH, Mooberry SL. Extracts derived from fungi and plants demonstrate specificity for subtyptes of triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-04-18.