Abstract C36: Patient-derived organoids from high-risk prostate cancer identify different biological subtypes and responsiveness to therapy

Abstract

Abstract Clonal heterogeneity in primary prostate cancer (PC) is a well-established phenomenon from which rare subclones develop metastatic potential that seed distant sites. It is also well established that androgen deprivation increases clonal heterogeneity of PC foci, seeding between sites and progression to castration resistant (CR) disease that is poorly controlled by subsequent therapies. Genomic sequencing and expression profiling have revealed the complexity and variation of the molecular changes within foci and across patients. In spite of the heterogeneity, a number of gene/pathway alterations have been identified that discriminate molecular subtype and potential differences in response to therapies. To study the heterogeneity of locally advanced PC in high-risk patients, identify foci with metastatic potential and differences in biologic behavior, we generated patient-derived organoids. To this end, we isolated cells from PC foci and normal epithelial counterparts from histopathologically mapped radical prostatectomy specimens and developed a 3D culture system utilizing single cell-derived tumor initiating cells (TICs) and epithelial/mesenchymal growth factors. Organoid growth peaks at 2 weeks and serially passaged organoids can be maintained in culture for up to 6 months with no significant deviation from early passages. The organoids mirror the morphologic features (well-organized glandular structures with central E-Cad+ cells, peripheral Vimentin+ cells and a surrounding thick basement membrane), biomarker expression (AR and PSA) and molecular subtypes of the foci from which they were derived, including alterations in TMRSS2-Ets fusions, loss of PTEN, RB and CHD1, overexpression of Erg, BMI-1, AR and AR-Vs. To study the biology and responsiveness of these organoids to established therapies in the androgen sensitive and castration resistant stages of PC progression, we measured single-cell-derived organoid cell proliferation, viability and secondary organoid- forming potential in response to androgen deprivation, docetaxel, abiraterone, enzalutamide, BEZ325, BMS-345541 IKB/IKK inhibitor and a novel BMI-1 inhibitor. The results show that androgen deprivation decreases cellular growth compared to control untreated organoids, although they can be passaged for up to 4 additional weeks. Monotherapy with docetaxel, abiraterone or BEZ325 significantly reduced tumor cell viability in the absence of DHT but only abiraterone and docetaxel reduced the organoid-forming potential. The BMI-1 inhibitor selectively inhibited self-renewal, and combinations of the BMI-1 inhibitor with docetaxel rescued resistance to docetaxel in CRPC-derived cells. In conclusion, we developed a personalized and genetically defined patient-derived PC organoid model that can be utilized to identify clones with metastatic potential which may help planning systemic therapeutic interventions. Citation Format: Hatem E. Sabaawy, Monica Bartucci, Mark N. Stein, Isaac Yi Kim, Joseph R. Bertino, Robert S. DiPaola, Anna Ferrari. Patient-derived organoids from high-risk prostate cancer identify different biological subtypes and responsiveness to therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C36.