Abstract 2789: Functional and molecular characteristics of 20 novel patient-derived xenografts of Asian gastric cancer.
Authors: Krumbach Rebekka , Kong Seong-Ho , Kim Woo Ho , Schüler Julia , Ackermann Andreas , Vuaroqueaux Vincent , Donoho Gregory P. , Aggarwal Amit , Reinhard Christoph , Yang Han-Kwang , Beckers Thomas , Fiebig Heiner 
Published: August 2014

Introduction: Asian and Caucasian populations are distinct regarding the prevalence of different tumor types due to differences in lifestyle and genetics. The molecular makeup of tumors of the same type can also vary. When developing drugs for the treatment of stomach cancer it is important to study tumors in both Asian and Caucasian backgrounds. In East Asia stomach cancer is the 2nd most common malignancy. The development of patient derived xenografts (PDX) from patients of East Asian origin is therefore critical. Oncotest established xenografts from stomach cancer patients who underwent surgery for the treatment of their cancer at the Seoul National University, South Korea. These Asian gastric cancer xenografts (GXA) were utilized for the investigation of molecular characteristics and sensitivity to anticancer agents.

Material and Methods: 78 gastric tumor samples from SNU were implanted subcutaneously in nude mice and sequentially passaged. Tumor material was collected for molecular profiling, including mutational analysis by Sanger sequencing and OncoCarta panels I, II, III. The efficacy of standard of care drugs 5-fluoruracil, cisplatin and taxol was tested in vivo.

Results: From the 78 implantations we were able to establish 21 Asian patient-derived gastric cancer xenografts, representing a take rate of 27%. The majority of tumors from which GXA xenografts were derived were poorly or moderately differentiated adenocarcinomas. The panel also includes mucinous adenocarcinomas and squamous cell carcinomas. The morphological features of the tumors (degree of differentiation) were preserved throughout serial passages.

Mutational analysis for 18 established models revealed that TP53 (13/18, 72%), PTEN (6/9, as well as one with PTEN RNA levels too low for RT-PCR), KRAS (5/18, 28%) and PIK3CA (4/18, 22%) were frequently mutated in these gastric cancers. Mutations in EGFR, MLH1 and APC were also detected, but no mutations in NRAS (0/18) or BRAF (0/17) were found.

Regarding sensitivity to anticancer agents, the response of the tumors varied strongly. Tumors were considered sensitive if the optimal treatment / control (T/C [%]) value was lower than 30%. 6 of 18 (33%) tumors were sensitive to 5-fluoruracil, 5 of 18 (28%) to paclitaxel and 3/18 (17 %) to cisplatin. Some gastric PDX were responsive to more than one chemotherapy, whereas 7 of 18 (39%) were not sensitive to any of these standard of care therapies.

These results demonstrate (i) that standard of care therapies are not the therapy of choice for a large proportion of these tumors and (ii) great heterogeneity within the 18 analyzed gastric Asian patient- derived xenografts.

Conclusion: In this study we developed a panel of Asian patient-derived gastric cancer xenografts with diverse molecular characteristics and responses to standard of care drugs.

Citation Format: Rebekka Krumbach, Seong-Ho Kong, Woo Ho Kim, Julia Schüler, Andreas Ackermann, Vincent Vuaroqueaux, Gregory P. Donoho, Amit Aggarwal, Christoph Reinhard, Han-Kwang Yang, Thomas Beckers, Heiner Fiebig. Functional and molecular characteristics of 20 novel patient-derived xenografts of Asian gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2789. doi:10.1158/1538-7445.AM2013-2789