MP06-05: Urothelial Cancer Rapid Autopsy Program: Biospecimens and Patient-derived Preclinical Models

Jose Garcia*, Funda Vakar-Lopez, Martine Roudier, Petros Grivas, Evan Y. Yu, Heather Cheng, Michael T. Schweizer, Michael Haffner, John K. Lee, Eva Corey, Bruce Montgomery, Andrew Hsieh, Jonathan L. Wright, Hung-Ming Lam, Seattle, WA

Introduction: Understanding the biology of metastatic urothelial cancer (UC) has been historically difficult due to a paucity of biospecimens and models that recapitulate human disease. All existing bladder cancer patient-derived xenografts (PDX) were developed from the primary tumor, so preclinical models reflecting metastatic disease biology are needed. Rapid autopsies allow tissue biospecimens sampled across multiple metastatic locations. We established a UC rapid autopsy program to systematically acquire UC metastases and develop PDX and organoid models for biological and preclinical studies. We hypothesize that UC rapid autopsy allows the acquisition of viable metastatic specimens for preclinical model development.

Methods: Patients with metastatic UC were consented and rapid autopsies were performed 2-6 hours after death to allow acquisition of viable normal tissue and metastatic cancer biospecimens. Frozen and formalin-fixed, paraffin-embedded specimens were deposited into University of Washington genitourinary biorepository. Pathological evaluation of each biospecimen was performed. Additionally, fresh tumors were implanted subcutaneously into SCID mice to establish PDX models. Once PDX models were established, PDX tissue was dissociated for companion organoid culture.

Results: We have performed 20 UC rapid autopsies to date, including 13 bladder cancer and 7 upper tract UC.  We have acquired 243 metastatic and 97 normal specimens. The histological spectrum of the tumors includes conventional UC (7/20), squamous cell carcinoma (5/20), plasmacytoid variant of UC (5/10) and neuroendocrine carcinoma (2/10). Most common sites of metastases were liver (14/20), lymph node (13/20) and lung (11/20). We have implanted 55 metastatic tumors from 15 patients, in which 5 tumors (9%) from 2 bladder cancer patients (13%) resulted in establishment of PDX. The mean latency for PDX to take varies among histology, with 3.5 weeks for predominantly squamous and 25 weeks for urothelial. Organoids were successfully developed from PDX models from both patients, including two metastases (omentum and liver) from the same patient.

Conclusions: Simultaneous collection of multiple viable metastatic biospecimens was feasible through urothelial cancer rapid autopsy. The success rate for PDX development from metastatic bladder cancer was about 10%. Organoids can be reliably developed from established PDX allowing more detailed biology evaluation.

Source of Funding: Seattle Translational Tumor Research, Howard J Cohen Bladder Cancer Foundation, Kleberg Foundation.