The role of the Organoid Core (Core E) is to generate a bank of state-of-the-art next-generation 3D in vitro organoid models of prostate cancer and provide them to the SPORE research projects for investigation. The study of castration-resistant prostate cancer (CRPC) has been limited by lack of in vitro models that represent the molecular and phenotypic diversity of the disease. We have developed optimized growth conditions for 3D prostate organoids from benign human and mouse prostate epithelial cells that can be engineered with defined genetic lesions using patient-derived CRPC biopsy specimens. The organoids maintain the histology and 3D architecture of the cancer tissue. We have generated 17 CRPC organoid lines over the past 2 years that harbor a number of genetic alterations not present in publicly available cell line models. Leveraging our program's commitment to collect, annotate, and sequence biopsy specimens from >2000 patients with CRPC, we plan to establish 20 clinically and molecularly annotated CRPC organoid lines annually. We will collaborate with each research project to engineer and study CRPC organoids that harbor specific genetic alterations or molecular phenotypes, including those with mutations in the DNA repair pathway (RP-1), mutations in the PI3K pathway (RP-2), mutations in TP35, silencing of RB1, and/or altered lineage specification (RP-3), and overexpression of different glucocorticoid receptor isoforms (RP-4). Working with the Animal Models Core (Core D), we will generate murine prostate organoids from genetically engineered mouse models harboring the specific genetic alterations of interest for the research projects. We will work with each project to develop protocols for in vitro drug treatment, in vivo xenograft studies, and genetic engineering of the organoid lines such as RNAi-mediated knockdown and CRISPR (clustered regularly interspaced palindromic repeats)-mediated somatic knockout. We will also conduct independent research aimed at improving services, including further optimization of organoid acquisition and growth protocols, identification of clinical and molecular determinants of successful organoid growth, and development of protocols to engineer genetic lesions into benign human prostate organoids.

Public Health Relevance

The study of castration-resistant prostate cancer (CRPC) has been limited by lack of tissue resources and in vitro models. The Organoid Core (Core E) will generate a bank of prostate cancer organoid lines from biopsy specimens of patients with CRPC and distribute them to each research project for study.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA092629-16
Application #
9148028
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2001-09-14
Project End
2021-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Rathkopf, Dana E; Antonarakis, Emmanuel S; Shore, Neal D et al. (2017) Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone. Clin Cancer Res 23:3544-3551
Vertosick, Emily A; Assel, Melissa; Vickers, Andrew J (2017) A systematic review of instrumental variable analyses using geographic region as an instrument. Cancer Epidemiol 51:49-55
Bose, Rohit; Karthaus, Wouter R; Armenia, Joshua et al. (2017) ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis. Nature 546:671-675
Yang, Zhaohui; Peng, Yu-Ching; Gopalan, Anuradha et al. (2017) Stromal hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer. Dis Model Mech 10:39-52
O'Rourke, Kevin P; Loizou, Evangelia; Livshits, Geulah et al. (2017) Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat Biotechnol 35:577-582
Ku, Sheng Yu; Rosario, Spencer; Wang, Yanqing et al. (2017) Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355:78-83
Blattner, Mirjam; Liu, Deli; Robinson, Brian D et al. (2017) SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling. Cancer Cell 31:436-451
Vickers, Andrew J; Van Calster, Ben; Steyerberg, Ewout (2017) Decision Curves, Calibration, and Subgroups. J Clin Oncol 35:472-473
Hyman, David M; Smyth, Lillian M; Donoghue, Mark T A et al. (2017) AKT Inhibition in Solid Tumors With AKT1 Mutations. J Clin Oncol 35:2251-2259
Zhang, Pingzhao; Wang, Dejie; Zhao, Yu et al. (2017) Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat Med 23:1055-1062

Showing the most recent 10 out of 460 publications