Abstract A01: Application of patient-derived models from understudied patient populations to discover therapeutically targetable pathways in triple-negative breast cancer systems
Authors: Matossian Margarite , Burks Hope , Chang Tiffany , Bowles Annie , Sabol Rachel , Hoang Van , Bunnell Bruce , Alfortish Alex , Moroz Krzysztof , Zea Arnold , Riker Adam , Jones Steven , Bilyeu Ayse D. Ucar , Hossain Fokhrul , Miller Kristin , Martin Elizabeth , O’Donnell Benjamen , Pashos Nicholas , Miele Lucio , Burow Matthew , Collins-Burow Bridgette 
Published: August 2018

Triple-negative breast cancers (TNBCs) constitute approximately 12% of all breast cancers, and are approximately twice more prevalent in African-American populations. Louisiana has a high proportion of African-American residents (32.5% in 2015), and among the highest incidences of TNBC in the country. Louisiana patients also have a high incidence of comorbidities that affect breast cancer biology and outcomes, including type 2 diabetes and obesity. TNBCs have an aggressive clinical presentation due to high rates of metastasis, recurrence, and chemoresistance, and targeted therapy remains elusive. Discovery of novel therapeutic targets, including a subset of previously uncharacterized kinases in TNBC could provide important insights into future targeted therapies. However, current models utilized in target discovery research are limited by the inability to accurately recapitulate the complex architecture and heterogenous genetic and molecular composition of breast cancer. Furthermore, immortalized cell lines have been selected in a two-dimensional environment and may have lost important epigenetic features of original tumors they derived from. Recently, our laboratory has successfully established four TNBC patient-derived xenograft (PDX) models representing different patient ethnicities, responsiveness to chemotherapies, and different TNBC molecular subtypes and metastatic behavior. Our primary objective was to dissect and evaluate the various individual components (tumor cell biology, stroma, immune, extracellular matrix) that drive complex interactions within TNBC tumors. We utilize these models in vivo, ex vivo, and in vitro to examine how unique kinases and small molecule inhibitors affect the distinct tumor characteristics. In addition to in vivo treatment studies we generated cell lines and mammospheres (TU-BcX-2K1, TU-BcX-2O0, TU-BcX-49S, TU-BcX-4IC), and we utilize novel techniques such as tissue decellularization to examine extracellular matrix components. We also analyze mechanistically relevant transcript (qRT-PCR) and protein (Western blot, immunohistochemistry) expression patterns that are unique to each PDX model to evaluate the effect of small-molecule inhibitors on these transcripts and proteins. Our aim is to leverage novel patient-derived models from understudied patients with a range of clinical presentations to guide the selection of therapeutically targetable pathways and molecules in specific molecular subtypes of TNBC.

Citation Format: Margarite Matossian, Hope Burks, Tiffany Chang, Annie Bowles, Rachel Sabol, Van Hoang, Bruce Bunnell, Alex Alfortish, Krzysztof Moroz, Arnold Zea, Adam Riker, Steven Jones, Ayse D. Ucar Bilyeu, Fokhrul Hossain, Kristin Miller, Elizabeth Martin, Benjamen O’Donnell, Nicholas Pashos, Lucio Miele, Matthew Burow, Bridgette Collins-Burow. Application of patient-derived models from understudied patient populations to discover therapeutically targetable pathways in triple-negative breast cancer systems [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A01.