Abstract 3337: A racially/ethnically diverse 3D PDX model of prostate cancer

Abstract

Abstract Prostate cancer (PCa) incidence and mortality rates in African American men are double that of any other race/ethnicity in the United States. Thorough understanding of the biological factors that contribute to this long-standing cancer health disparity (CHD) is required to improve the major public health concern and close this gap. However, few models exist that can compare racially-diverse specimens directly and provide a platform for dissecting the impact of ancestry-dependent factors on disease pathway selection and drug susceptibility. Both the conventional 2D culture of clonal human cell lines and the purely rodent-based in vivo models fail to reflect the heterogeneity of human tumors, often leading to inaccurate prediction of in vivo tumor response in patients, and confounding researchers’ ability to detect potentially subtle biological factors that may contribute to prostate CHD. PCa patient-derived xenografts (PDXs) offer substantially greater fidelity to original patient tumors but are non-adherent and ultimately non-viable in extended in vitro 2D culture. Therefore, a population-based PCa platform which accurately mimics the three-dimensional (3D) tumor microenvironment (TME) is urgently needed. We have employed MIMETAS’ OrganoPlate®, a high throughput microfluidic culture platform containing 40-96 individual tissue chips, for ex vivo 3D culture of multiple racially/ethnically diverse PCa PDXs (African American, Caucasian, Hispanic) developed at MD Anderson Cancer Center (the MDA PCa PDXs series). MDA PCa PDX tumors were reconstituted from single-cell digestates into multicellular clusters, suspended within HyStem® hyaluronic acid hydrogel precursor solutions, and loaded into the OrganoPlate®. PDXs were maintained in 3D either as monocultures, as cocultures with bone marrow-derived stromal fibroblasts, or as tricultures with endothelial cell blood vessel mimics under continuous perfusion. High-content fluorescence imaging identified retention of stable, viable cultures for at least 7 days. Positive immunofluorescent staining for human nuclear antigen (HNA) confirmed that nearly 100% of encapsulated PCa cells were of human origin. For each PCa model developed, appropriate expression of phenotypic prostate-specific antigen (PSA) and androgen receptor (AR) was maintained over the life of the culture. PCa cultures were treated with various chemotherapeutic drugs and viability was monitored to generate dose response curves for comparison to clinical data. This engineered “tumor-on-a-chip” will better predict patient responses and, by incorporating PCa cells from patients with diverse ancestries, support CHD research. Citation Format: Lindsey K. Sablatura, Kristin M. Bircsak, Peter Shepherd, Rick Kittles, Pamela E. Constantinou, Anthony D. Saleh, Nora M. Navone, Daniel A. Harrington. A racially/ethnically diverse 3D PDX model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3337.