Annual Report 2020
Division of Biomarker Discovery (Kashiwa Campus)
Atsushi Ochiai, Syuichi Mitsunaga, Tomofumi Miura, Yuki Iino, Yuka Nakamura, Aya Endo, Misato Ohasi, Teruo Komatsu, Mariko Yajima, Michiko Hamamoto, Takahiro Iimura, Sachiko Fukuda, Motoko Suzaki.
Introduction
In the translational research field for the exploration of biomarkers, we have been exploring biomarkers which enables the prediction of prognoses for cancer patients and biological nature of cancer, and constructing the companion diagnostics that relate to the clinical studies with an aim to achieve personalized (optimized) medicine.
The Team and What We Do
To achieve our goal to explore biomarkers which enables the prediction of prognoses of cancer patients and biological nature of cancer, we focus our efforts on developing new tumor markers and level of cachexia for pancreatic cancer patients.
Research activities
The research achievements of this year are summarized into the following five points:
1) The pathological diagnosis is the basis of cancer therapy, and the tissue classification has been achieved by pathologists from all over the world at the International Agency for Research on Cancer (IARC) in Lyon, France. The results have been published as the WHO Blue Books. We participated in this classification work as a member of the editorial board. As a result, we were able to publish “Soft Tissue and Bone Tumours 5th Edition” and “Gynecologic Oncology” in 2020.
2) The establishment of serum microRNA tests to detect pancreatic cancer (one of the representative intractable cancers) and biliary tract cancer (which affects a large number of people in Japan) has a high clinical significance, given that it can contribute to the comprehensive improvement of treatment results by providing opportunities for early treatment.
We commenced the “Study on the establishment of serum microRNA panel to detect pancreatic and biliary tract cancer with high accuracy and the performance to detect the diseases”, which included 50 healthy individuals and 50 patients with pancreatic and/or biliary tract cancer. In this study, we reused sera collected from 1225 participants enrolled in the prior study, the “Study on the establishment of the serum microRNA test for the detection of pancreatic and biliary tract cancer which is superior to the existing tumor marker performances”, which was conducted at 11 facilities in Japan to produce DNA chips using serum microRNA probes that have robust detection performance. The objective of the current study is to validate the detection performance of the novel DNA chip.
The aforementioned panel is currently the subject of the “Sakigake (Pioneer) Designation Scheme” of The Health, Labour and Welfare Ministry of Japan as an in vitro diagnosis kit. We are working hard to bring this system to the market.
3) Over 70% of patients with pancreatic cancer who are undergoing primary chemotherapy for the cancer will develop cachexia, and the condition is associated with non-response to chemotherapy, poor prognosis and deterioration of the QoL.
Interleukin 6 (IL-6) is considered to be one of the molecules that causes the cachexia. We are preparing to publish the results of phase I study in which the administration of anti-IL-6 receptor antibody was combined with the re-administration of gemcitabine/nab-paclitaxel (GnP). We confirmed an increase in the infiltration of the drugs and increased apoptosis and tumor immunity as intratumor changes occur. We filed a patent application on the novel therapy of pancreatic cancer with Chugai Pharmaceutical Co., Ltd and Technische Universität München (München Institute of Technology). Based on these results, Roche Diagnostics KK launched the phase I study in which GnP/IL-6 receptor antibody and PD-1 inhibitor were combined.
4) From 35 strains of patient-derived xenograft (PDX) from patients with gastric carcinoma, strains that were established in the Discovery and Establishment of new biomarkers For gastric cancer (DEF) study, we selected 16 strains that covered scores of 0 to +3 based on the results of immunostaining for Her2 gene expression. We prepared samples for distribution from these strains. The severely immunocompromised animals used for the transplantation were exchanged for nude mice, which have been more widely used, thereby simplifying and streamlining the resource for the experiment.
Furthermore, we advanced the establishment of the co-clinical trial system by which the results of the preclinical and clinical studies can be directly compared. We focused on the organoid, which might be the basic evaluation system for drugs, and investigated how to improve the method for stably producing the organoid, which is most suited to gastric carcinoma using the aforementioned PDX tissues.
5) In the Exploratory Oncology Research and Clinical Trial Center, we guided researchers on the methods for preparing PDX from pathological specimens, supported the pathological research at Tsuruoka Metabolomics Laboratory, and instructed the researchers in preparing sections from pathology specimens and immunostaining and evaluating the results at the Exploratory Oncology Research and Clinical Trial Center. We also supported the study using pathology specimens by helping the preparation of specimens shown in the table below.
Table 1. Slicing and staining (cumulative April 2020 to March 2021)
Future Prospects
We will advance the “Study on the establishment of serum microRNA panel to detect the pancreatic and biliary tract cancer with high accuracy and the performance to detect the diseases” with the goal of bringing this system to the market. We will also target the development of a novel technology based mainly on the evaluation method for cancerous cachexia.
List of papers published in 2020
Journal
1. Naruse M, Ochiai M, Sekine S, Taniguchi H, Yoshida T, Ichikawa H, Sakamoto H, Kubo T, Matsumoto K, Ochiai A, Imai T. Re-expression of REG family and DUOXs genes in CRC organoids by co-culturing with CAFs. Sci Rep, 11:2077, 2021
2. Amemiya R, Miyoshi T, Aokage K, Suzuki J, Hoshino H, Udagawa H, Tane K, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Goto K, Ikeda N, Tsuboi M, Ishii G. Prognostic impact of the tumor immune microenvironment in pulmonary pleomorphic carcinoma. Lung Cancer, 153:56-65, 2021
3. Suzuki J, Aokage K, Neri S, Sakai T, Hashimoto H, Su Y, Yamazaki S, Nakamura H, Tane K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Tsuboi M, Ishii G. Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma. Lung Cancer, 153:1-10, 2021
4. Su Y, Yamazaki S, Morisue R, Suzuki J, Yoshikawa T, Nakatsura T, Tsuboi M, Ochiai A, Ishii G. Tumor-Infiltrating T Cells Concurrently Overexpress CD200R with Immune Checkpoints PD-1, CTLA-4, and TIM-3 in Non-Small-Cell Lung Cancer. Pathobiology, 88:218-227, 2021
5. Amano K, Maeda I, Ishiki H, Miura T, Hatano Y, Tsukuura H, Taniyama T, Matsumoto Y, Matsuda Y, Kohara H, Morita T, Mori M. Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study. Clin Nutr, 40:1168-1175, 2021
6. Hattori K, Tago K, Memezawa S, Ochiai A, Sawaguchi S, Kato Y, Sato T, Tomizuka K, Ooizumi H, Ohbuchi K, Mizoguchi K, Miyamoto Y, Yamauchi J. The Infantile Leukoencephalopathy-Associated Mutation of C11ORF73/HIKESHI Proteins Generates de novo Interactive Activity with Filamin A, Inhibiting Oligodendroglial Cell Morphological Differentiation. Medicines (Basel), 8:2021
7. Tsumura R, Koga Y, Hamada A, Kuwata T, Sasaki H, Doi T, Aikawa K, Ohashi A, Katano I, Ikarashi Y, Ito M, Ochiai A. Report of the use of patient-derived xenograft models in the development of anticancer drugs in Japan. Cancer Sci, 111:3386-3394, 2020
8. Watanabe K, Mitsunaga S, Kojima M, Suzuki H, Irisawa A, Takahashi H, Sasaki M, Hashimoto Y, Imaoka H, Ohno I, Ikeda M, Akimoto T, Ochiai A. The "histological replacement growth pattern" represents aggressive invasive behavior in liver metastasis from pancreatic cancer. Cancer Med, 9:3130-3141, 2020
9. Kan M, Imaoka H, Watanabe K, Sasaki M, Takahashi H, Hashimoto Y, Ohno I, Mitsunaga S, Umemoto K, Kimura G, Suzuki Y, Eguchi H, Otsuru T, Goda K, Ikeda M. Chemotherapy-induced neutropenia as a prognostic factor in patients with pancreatic cancer treated with gemcitabine plus nab-paclitaxel: a retrospective cohort study. Cancer Chemother Pharmacol, 86:203-210, 2020
10. Koike Y, Aokage K, Ikeda K, Nakai T, Tane K, Miyoshi T, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Tanaka T, Suzuki K, Tsuboi M, Ishii G. Machine learning-based histological classification that predicts recurrence of peripheral lung squamous cell carcinoma. Lung Cancer, 147:252-258, 2020
11. Sato K, Mimaki S, Yamashita R, Togashi Y, Naito T, Udagawa H, Katsumata S, Nakasone S, Miyoshi T, Tane K, Aokage K, Sugano M, Kojima M, Fujii S, Kuwata T, Ochiai A, Goto K, Tsuboi M, Tsuchihara K, Ishii G. Association between the mutational smoking signature and the immune microenvironment in lung adenocarcinoma. Lung Cancer, 147:12-20, 2020
12. Yamazaki S, Su Y, Maruyama A, Makinoshima H, Suzuki J, Tsuboi M, Goto K, Ochiai A, Ishii G. Uptake of collagen type I via macropinocytosis cause mTOR activation and anti-cancer drug resistance. Biochem Biophys Res Commun, 526:191-198, 2020
13. Miyashita T, Neri S, Hashimoto H, Akutsu A, Sugano M, Fujii S, Ochiai A, Ishii G. Fibroblasts-dependent invasion of podoplanin-positive cancer stem cells in squamous cell carcinoma. J Cell Physiol, 235:7251-7260, 2020
14. Nishida Y, Nagatsuma AK, Kojima M, Gotohda N, Ochiai A. Novel stromal biomarker screening in pancreatic cancer patients using the in vitro cancer-stromal interaction model. BMC Gastroenterol, 20:411, 2020
15. Takahashi D, Kojima M, Morisue R, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Ikeda M, Ochiai A. Comparison of morphological features in lymph node metastasis between pancreatic neuroendocrine neoplasms and pancreatic ductal adenocarcinomas. Pancreatology, 20:936-943, 2020
16. Kojima M, Yamauchi C, Oyamada S, Hojo T, Iwase S, Naito A, Yamano K, Takahashi S, Ochiai A. Assessment of Upper Limb Physiological Features in Patients with Lymphedema After Breast Surgery Using Multiple Instruments. Lymphat Res Biol, 18:239-246, 2020
17. Tagami K, Kawaguchi T, Miura T, Yamaguchi T, Matsumoto Y, Watanabe YS, Uehara Y, Okizaki A, Inoue A, Morita T, Kinoshita H. The association between health-related quality of life and achievement of personalized symptom goal. Support Care Cancer, 28:4737-4743, 2020
18. Oda I, Shimizu Y, Yoshio T, Katada C, Yokoyama T, Yano T, Suzuki H, Abiko S, Takemura K, Koike T, Takizawa K, Hirao M, Okada H, Yoshii T, Katagiri A, Yamanouchi T, Matsuo Y, Kawakubo H, Kobayashi N, Shimoda T, Ochiai A, Ishikawa H, Yokoyama A, Muto M. Long-term outcome of endoscopic resection for intramucosal esophageal squamous cell cancer: a secondary analysis of the Japan Esophageal Cohort study. Endoscopy, 52:967-975, 2020
19. Quezada-Mar?n JI, Lam AK, Ochiai A, Odze RD, Washington KM, Fukayama M, Rugge M, Klimstra DS, Nagtegaal ID, Tan PH, Arends MJ, Goldblum JR, Cree IA, Salto-Tellez M. Gastrointestinal tissue-based molecular biomarkers: a practical categorisation based on the 2019 World Health Organization classification of epithelial digestive tumours. Histopathology, 77:340-350, 2020
20. Mimaki S, Watanabe M, Kinoshita M, Yamashita R, Haeno H, Takemura S, Tanaka S, Marubashi S, Totsuka Y, Shibata T, Nakagama H, Ochiai A, Nakamori S, Kubo S, Tsuchihara K. Multifocal origin of occupational cholangiocarcinoma revealed by comparison of multilesion mutational profiles. Carcinogenesis, 41:368-376, 2020
21. Mitsunaga S, Kasamatsu E, Machii K. Incidence and frequency of cancer cachexia during chemotherapy for advanced pancreatic ductal adenocarcinoma. Support Care Cancer, 28:5271-5279, 2020
22. Hojo H, Raturi V, Nakamura N, Arahira S, Akita T, Mitsunaga S, Nakamura M, Motegi A, Kageyama SI, Zenda S, Okumura M, Ikeda M, Akimoto T. Impact of Proton Beam Irradiation of an Anatomic Subsegment of the Liver for Hepatocellular Carcinoma. Pract Radiat Oncol, 10:e264-e271, 2020
23. Sugimoto M, Kobayashi T, Kobayashi S, Takahashi S, Konishi M, Mitsunaga S, Ikeda M, Gotohda N. Extrapancreatic Nerve Plexus Invasion on Imaging Predicts Poor Survival After Upfront Surgery for Anatomically Resectable Pancreatic Cancer. Pancreas, 49:675-682, 2020
Book
1. Ochiai A. In: WHO Classification of Tumours, 5th Editon, Vol.3. Soft Tissue & Bone Tumours, Switzerland, WHO, 2020