Abstract 223: Generation of single cell-derived normal, benign and cancer mini-prostates from primary patient-derived tissues (2015)

Abstract Clinically effective next generation androgen deprivation therapy (ADT) and androgen receptor (AR)-directed therapies have been developed to treat castration-resistant prostate cancer (CRPC). However, disease progression inevitably occurs, and majority of relapsed tumors continue to overexpress AR. AR mutations and constitutively active AR splice variants (AR-Vs) are detected during ADT and may lead to drug resistance. Therefore, there is dire need to develop models that provide a better understanding of AR signaling and determine markers of ADT resistance in prostate cancer patient cells. Mouse models and existing human prostate cancer cell lines have inherent limitations for deciphering mechanisms of therapy resistance. Unlike the recently reported prostate tissue organoids that were derived at a low efficiency from 7/49 metastatic prostate cancer samples, we have developed a novel and exciting technology to generate normal, benign prostatic hyperplasia (BPH) and cancer “mini-prostates” from both early-stage and advanced prostate cancer patient samples. We have successfully rederived mini-prostates from 17 out of 19 primary prostatectomy tissues. We incorporated developmental epithelial and mesenchymal signals, stem-like cells and growth requirements in 3D cultures for maintaining primary normal, BPH and prostate cancer patient-derived cells as stem-like cell-derived organoids. Our preliminary data show the establishment of patient- single cell-derived normal, BPH and cancer mini-prostates comprised of organoids with glandular tissues that have a thick basement membrane, an outer mesenchymal and inner epithelial cells conveying AR signaling, expressing cytokeratins and secreting PSA. RNA sequencing, expression profiling and ADT revealed that mini-prostate cells maintain the genetic, chemoresistance, and growth rate features of the primary prostate. To model tumor heterogeneity, prostate cells from surgical tissues were isolated upon digital imaging and tissue mapping in mirror sections for AMACR, AR, AR-Vs, p63, Ki67, ERG expression and FISH analysis for TMPRSS2-ERG fusion. Living cells from mapped BPH and cancer clones are being utilized to derive single cells into mini-prostates. Our studies generated novel therapy sensitivity and drug discovery models that would allow for precision medicine and coclinical approaches to be enlisted to reveal chemo- or hormonal-resistance profiles in genetically defined mini-prostates, apply combinatory-targeted therapies and study therapy-induced clonal selection processes to ultimately guide future clinical trials. Citation Format: Monica Bartucci, Michele Patrizii, Eric Huselid, Shamila Yussuf, Nitu Bansal, Kathleen Flaherty, Denis Tolkunov, Hua Zhong, Mark N. Stein, Joseph Bertino, Robert DiPaola, Isaac Kim, Hatem E. Sabaawy. Generation of single cell-derived normal, benign and cancer mini-prostates from primary patient-derived tissues. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 223. doi:10.1158/1538-7445.AM2015-223