Abstract A30: Comprehensive and serial analyses of tumor-stroma interactions in individual PDX/NOG models contribute to personalized chemotherapy
Authors: Chijiwa Tsuyoshi , Haraguchi Mizuha , Komura Daisuke , Noguchi Akira , Shiozawa Manabu , Katayama Makoto , Miyao Naoki , Matsui Naruaki , Tateishi Yuichi , Suemizu Hiroshi , Nakamura Yoshiyasu , Isagawa Takayuki , Katoh Hiroto , Ishikawa Shumpei , Nakamura Masato , Miyagi Yohei 
Published: December 2017

Abstract
Xenografts derived from engrafting fresh surgical specimens directly into immunodeficient mice have recently enabled the development of more relevant in vivo models of human cancers. These patient-derived xenograft (PDX) models, established by the direct transfer of tumor tissue, retain similar morphologies, heterogeneities, and molecular signatures as the original cancers and, thus, may be used in promising personalized medicine for cancer. We previously reported the rapid and efficient establishment of PDXs using super immunodeficient NOG mice (PDX/NOG models). In the present study, we compared the gene-expression and cancer-stroma interaction profiles of PDX pairs metachronously established from the same patient due to therapeutic advances and investigated whether characteristic changes in these PDX pairs are influenced by chemotherapy. We also discussed the possibility of individual PDX/NOG model simulations for personalized cancer chemotherapy. More than 100 lines of cancer xenografts were established in our previous studies. In these cases, two pairs of PDX/NOG were established from the same patient who had undergone multiple operations or samplings and provided their samples twice. Genome sequencing and comprehensive analyses of tumor-stroma interactions (CAncer-STromal INteractome analysis, CASTIN) were performed on mRNA from two pairs of PDX/NOG. CASTIN showed tumor-stroma interactions in PDX/NOG comprehensively and quantitatively at the gene expression level by distinguishing gene arrangements in human tissue (Cancer) from mouse tissue (Stroma) as signal strength (ligand dependency (%)/receptor dependency (%)).
Case 1: Sigmoid colonic cancer, adenocarcinoma, 58-year-old woman. She received chemotherapy with bevacizumab +FOLFOX and cetuximab+FOLFIRI between two operations. EGF (cancer)-EGFR (stroma) interaction strength was down-regulated from 7.3 (ligand dependency 59% / receptor dependency 81%) to 7.1 (37%/56%). VEGFA (cancer)-KDR (stroma) was up-regulated from 9.9 (77%/100%) to 121.6 (87%/100%).
Case 2: Lung cancer with malignant pleural effusion, adenocarcinoma, 71-year-old man. He received chemotherapy with docetaxel+bevacizumab during two samplings. EGF (cancer)-EGFR (stroma) was down-regulated from 11.2 (85%/79%) to 5.1 (31%/71%). VEGFA (cancer)-KDR (stroma) was up-regulated from 45.2 (78%/94%) to 128.4 (68%/93%). Interaction changes in EGF-EGFR or VEGFA-KDR in PDX/NOG closely reflected the clinical effectiveness of the EGFR inhibitor (cetuximab) or VEGF-A inhibitor (bevacizumab).
The CASTIN results of PDX/NOG appear to be reliable for clinical simulations of chemotherapy and will assist in the selection of the most sensitive anti-cancer drugs. Serial analyses of PDX/NOGs will disclose characteristic changes in cancer cells induced by the chemotherapy administered. It is considered suitable to establish serial PDX/NOGs for the same patients from malignant pleural effusion because these patients may repeatedly undergo therapeutic thoracentesis. The fast and efficient establishment of individual PDXs will contribute to personalized anti-cancer therapies.
Citation Format: Tsuyoshi Chijiwa, Mizuha Haraguchi, Daisuke Komura, Akira Noguchi, Manabu Shiozawa, Makoto Katayama, Naoki Miyao, Naruaki Matsui, Yuichi Tateishi, Hiroshi Suemizu, Yoshiyasu Nakamura, Takayuki Isagawa, Hiroto Katoh, Shumpei Ishikawa, Masato Nakamura, Yohei Miyagi. Comprehensive and serial analyses of tumor-stroma interactions in individual PDX/NOG models contribute to personalized chemotherapy [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A30.