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Abstract C110: Applications of patient-derived triple-negative breast cancer xenografts that represent understudied patients in Louisiana in targeted therapeutic research
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Cancer epidemiology, biomarkers & prevention, 2020-06, Vol.29 (6_Supplement_1), p.C110-C110
Abstract
Triple-negative breast cancers (TNBCs) constitute approximately 12% of all breast cancer cases and are approximately twice as prevalent in African-American populations. Louisiana has a high proportion of African-American residents (32.3% in 2017), and New Orleans has among the highest incidences of TNBC in the country. Louisiana patients also have a high incidence of co-morbidities 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. There are currently no clinically approved targeted therapies for TNBC; cytotoxic chemotherapy is the first-line treatment for TNBC, and recurrent, chemoresistant cancers are usually fatal. TNBCs are molecularly heterogeneous, consisting of at least four molecular subgroups, and immunologically heterogeneous. Both molecular and immunologic properties are associated with clinical outcomes and are seriously understudied in patients under-represented in biomedical research. Patient-derived xenografts (PDXs), as well as patient-derived organoids (PDO), are currently the best model for translational oncology therapeutic research because they accurately recapitulate the complex architecture and heterogenous genetic and molecular composition of solid cancers. To date, the majority of TNBC research has been based on Caucasian patients, although incidence rates of TNBC are higher in African-American cohorts. Our collaborative team aims to overcome this obstacle by establishing and characterizing TNBC PDX models that represent this understudied cohort. We currently have ten TNBC PDX models representing different patient ethnicities, responsiveness to chemotherapies, as well as different TNBC molecular subtypes and metastatic behavior. We dissect and evaluate the various individual components (tumor cell biology, stroma, immune, extracellular matrix) of TNBC tumors. We utilize these models in vivo, ex vivo and in vitro to examine how unique kinases and targeted inhibitors affect the distinct tumor characteristics. In addition to in vivo treatment studies, we generated cell lines and PDOs 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 effects of targeted therapies. We work with surrounding laboratories in the greater New Orleans area (Tulane, LSU, Xavier) that are also focused on therapeutic discovery of TNBC in a collaborative effort to provide translational models for their projects. Our aim is to leverage novel PDX models from understudied patients with a range of clinical and molecular presentations to guide the selection of therapeutically targetable pathways and therapeutic agents in specific molecular subtypes of TNBC.
Citation Format: Margarite D. Matossian, Steven Elliott, Hope E. Burks, Maryl Wright, Rachel A. Sabol, Van T. Hoang, Deniz A. Ucar, Alex Alfortish, Jovanny Zabaleta, Fokhrul Hossain, Tiffany Chang, Henri Wathieu, Nicholas Pashos, Bruce Bunnell, Krzysztof Moroz, Arnold Zea, Adam Riker, Steven D. Jones, Elizabeth C. Martin, Lucio Miele, Bridgette M. Collins-Burow, Matthew E. Burow. Applications of patient-derived triple-negative breast cancer xenografts that represent understudied patients in Louisiana in targeted therapeutic research [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C110.