Abstract B06: A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries
Authors: Veeranki Omkara , Tong Zhimin , Mejia Alicia , Verma Anuj , Katkhuda Riham , Bassett Roland , Kim Tae , Wang Jing , Lang Wenhua , Mino Barbara , Solis Luisa , Kingsley Charles , Norton William , Tailor Ramesh , Wu Ji , Krishnan Sunil , Lin Steven , Blum Mariela , Hofstetter Wayne , Ajani Jaffer , Kopetz Scott , Maru Dipen 
Published: June 2020

Background and Aims: Mouse models of GEJ cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain a therapeutic challenge due to a lack of reliable mouse model for preclinical drug testing.

Methods: A novel PDOX was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by H&E, immunohistochemistry, and next-generation sequencing. Treatment efficacy studies of radiotherapy were performed.

Results: Mechanical abrasion of mouse GEJ prior to surgical implantation of patient-derived tumor in situ promotes tumor engraftment (100%, n=6). Complete PDOX engraftment was observed with rapid intra- and extraluminal tumor growth as evidenced by magnetic resonance imaging. PDOXs contain fibroblasts, tumor-associated macrophages (TAMs), immune and inflammatory cells, and vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJs are recapitulated in GEJ-PDOX mouse model. PDOXs demonstrates tumor invasion into vasculature and perineural space. Next-generation sequencing revealed loss of heterozygosity (LOH) with very high allelic frequency in NOTCH3, TGFB1, EZH2, and KMT2C in the patient tumor, the subcutaneous PDX, and the PDOX. Immunohistochemical analysis of Her2/neu, p53, and p16 in PDX and PDOX demonstrated maintenance of protein expression found in patient tumors while membranous EGFR overexpression in patient tumor cells was absent in both xenografts. Targeted radiotherapy in this model suggested a decreased in size by 61% according to RECIST, indicating a partial response to radiation therapy.

Conclusions: A GEJ-PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture, facilitating it as a novel tool in translating findings from such studies. This model can be applied to study metastatic progression and to develop novel therapeutic approaches for the treatment of GEJ cancer.

Note: This abstract was not presented at the conference.

Citation Format: Omkara Veeranki, Zhimin Tong, Alicia Mejia, Anuj Verma, Riham Katkhuda, Roland Bassett, Tae Kim, Jing Wang, Wenhua Lang, Barbara Mino, Luisa Solis, Charles Kingsley, William Norton, Ramesh Tailor, Ji Wu, Sunil Krishnan, Steven Lin, Mariela Blum, Wayne Hofstetter, Jaffer Ajani, Scott Kopetz, Dipen Maru. A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B06.