Establishing functional models of peritoneal carcinomatosis using MicroOrganoSphere (MOS) technology.

Abstract

e16337 Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy according to best practices developed for colorectal cancer, despite clear evidence that the two cancers are distinctly different in their clinical behavior and molecular profiles. In this study, we created functional tumoroid models (MicroOrganoSpheres or MOS) of peritoneal carcinomatosis from appendix cancer and mesothelioma and used these MOS to test the efficacy of different chemotherapy treatments. Methods: After obtaining informed consent, fresh tumor samples were obtained from 5 patients with peritoneal carcinomatosis undergoing surgical resection at The University of Texas MD Anderson Cancer Center and 5 samples were obtained from previously established PDX models. Tissue was digested using xMRS solution and MOS culture was established. H&E was performed on tissue and paired MOS. Results: Five MOS models were successfully established, including four AA and one primary peritoneal mesothelioma (to our knowledge the first time this has been done from a peritoneal mesothelioma). Four (80%) of the 5 PDX models samples successfully generated MOS. Three out of five from the fresh samples generated p0 MOS, but only one continued to grow (20%). The MOS successfully established from fresh biopsy was a moderately differentiated mucinous adenocarcinoma with GNASR201C and KRASG12R mutation, to our knowledge the first time a Patient Derived Organoid (PDO) model of this disease has been created. Identified failure modes were delayed processing times (>48 hours after extraction in 3 out of 5 clinical samples) and low tumor content in samples. Histologically, the MOS recapitulated several important characteristics of the original patients’ tumors, including degree of differentiation, abundance of mucin, and presence of signet ring features. Response of AA MOS models to chemotherapeutic agents and regimes has been evaluated in one model thus far. AAPDX-13, derived from a low-grade mucinous adenocarcinoma, was tested against common CRC treatments: 5-FU (pIC50 5.90), Oxaliplatin (pIC50 4.51), SN-38 (pIC50 5.16). Relative to the mean from multiple CRC MOS, this was less sensitive to 5FU and more sensitive to irinotecan. Conclusions: Novel MOS models for AA and peritoneal mesothelioma were successfully established. MOS recapitulated key histologic features of AA and mesothelioma. Data acquired from this MOS system can aid in identifying appropriate chemotherapy treatments in select patients where there are no existing preclinical disease models.