Abstract 6040: Orthotopic patient-derived xenograft models of appendiceal adenocarcinoma identify intraperitoneal paclitaxel treatment as an active therapeutic agent

• Published in: Cancer research (Chicago, Ill.) Vol. 82; no. 12_Supplement; p. 6040
• Main Authors: Ito, Ichiaki, White, Michael G., Yousef, Abdelrahman M., Dickson, Princess N., Gu, Yue, Fournier, Keith F., Shen, John P.
• Format: Journal Article
• Language: English
• Published: 15-06-2022
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-6040

Abstract
Background Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which only few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy like those for colorectal cancer despite clear evidence that the two cancers are distinctly different in their clinical behavior and tumor molecular profiles. In this study, we created PDX models of appendix cancer and tested the efficacy of IP paclitaxel treatment.
Methods After obtaining informed consent, fresh tumor samples were obtained from 9 patients with AA cancer undergoing surgical resection at MD Anderson Cancer Center. Tumors were implanted in both the flank and peritoneum of NSG mice; from each patient 5 mice were implanted with approx. 0.5 cm3 tumor. Mice were evaluated after 6 months to assess for tumor formation. Additionally, 3 AA PDX models were obtained from collaborators and implanted. A PDX model was treated with paclitaxel (25 mg/kg, IP, 3 weekly treatments and 1 week off, for two cycles). Tumor size in MRI was evaluated by mucinous peritoneal Response Evaluation Criteria In Solid Tumors (mpRECIST) method.
Results None of 5 well differentiated (grade 1) tumors grew in either flank and peritoneum (0 of 10 mice and 0 of 15 mice). Two of 3 moderately differentiated (grade 2) tumors grew in the peritoneum [8 of 9 mice (89%) and 8 of 8 mice (100%)], while only 1 grew in the flank [2 of 4 mice (50%)]. Three poorly differentiated (grade 3) tumors grew in the peritoneum [13 of 13 mice (100%), 8 of 8 mice (100%), and 2 of 5 mice (40%)]. Two of these tumors also grew in the flank but with lower rate of formation [8 of 8 mice (100%), 2 of 4 mice (50%), and 0 of 1 mouse (0%)]. Overall, the tumor formation rate was greater in peritoneum vs flank (30.8% vs 16.7%). Although low-grade tumor didn’t grow, the formation rates of grade 2 and 3 tumors were 56% and 67% in the peritoneum. PMP-2 and PMCA-3 models grew as a mucinous ascites, MAd20-001 grew as solid tumors, while TM00351 formed a mix of solid tumor and mucinous ascites. Histologically, in MAd20-001, neoplastic cells were poorly differentiated and arranged in sheets with frequent mitoses. PMP-2 and PMCA-3, both with GNASR201C mutation, had a mucinous phenotype similar to GNAS mutant appendiceal tumors in humans. IP paclitaxel treatment of the TM00351 showed 77.9% reduction of tumor growth relative to no treatment control mice at 12 weeks. No significant side effect of the treatment was seen in any mice. IP paclitaxel treatment of additional models is ongoing.
Conclusion Interaction with the peritoneal microenvironment is important to promote growth of appendiceal tumors. Orthotopic PDX models recapitulate clinical, histologic, and molecular features of AA, including the indolent growth of low-grade and aggressive growth of high-grade tumors. Using this system we identify IP paclitaxel as an active agent for high-grade AA.
Citation Format: Ichiaki Ito, Michael G. White, Abdelrahman M. Yousef, Princess N. Dickson, Yue Gu, Keith F. Fournier, John P. Shen. Orthotopic patient-derived xenograft models of appendiceal adenocarcinoma identify intraperitoneal paclitaxel treatment as an active therapeutic agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6040.