Annual Report 2018

Division of Rare Cancer Research

Tadashi Kondo, Rei Noguchi, Emi Hattori

Introduction

 The research goal of the Division of Rare Cancer Research is to create the innovative seeds for better clinical outcomes for rare cancer patients. A rare cancer is defined as a cancer with incidence of less than six per 100,000 annually. Rare cancer includes approximately 200 types, and despite the rarity of each rare cancer, they represent approximately 15% in total of all cancer cases in Japan. Thus, rare cancer research deals with wide-ranging subjects for a large number of cancer patients. We consider that the fundamental problem of rare cancer research is a lack of research resources such as cancer models, biobank materials and databases. Thus, we address these issues. The establishment of patient-derived cancer models, and the database for meta-analysis of genes are efforts to solve problems related to the limited amount of clinical material. Re-purposing of cancer drugs is a practical approach to rare cancers, and the experimental systems for re-purposing of cancer drugs were created in our laboratory. These include the high-throughput screening system and the application of a Connectivity Map and other bioinformatics modalities. Studies for individual rare cancer have also been conducted in our laboratory. Using global gene and protein data, we identified candidates of novel innovative seeds, e.g., predictive and prognostic biomarkers. To facilitate the research and development of novel medical seeds, we have developed proteogenomics software. Our experience and fundamental systems for rare cancer research will be applicable for major cancer research.

Research activities

1. Establishment of fundamental research system

• Patient-derived cancer models were created from the clinical materials of sarcoma patients.
• Screening system for the study of relocalization of cancer drugs was established and used for the cell panel.
• Platform of bioinformatics such as the original Connectivity Map was created and applied to the study of re-localization of cancer drugs.
• Database of gene status of rare cancer was created using bioinformatics approach.

2. Study of individual rare cancer

 The identification of therapeutic targets and biomarkers was undertaken using clinical materials and our original cell panel. The biomarker candidates to predict the resistance of molecular anti-cancer drugs and those to evaluate the invasion potentials of tumors were identified by a multi-omics approach. Their molecular backgrounds and validation using additional cases are under consideration.

3. Reverse innovation

 The research platforms were developed with the idea that they will be applicable to other malignancies.

Education

 Students and young medical doctors were trained.

Future prospects

 Our research activities will benefit patients with rare cancers. The fundamental system for rare cancer research will be applicable to the research of all cancers.

List of papers published in 2018

Journal

1. Oyama R, Kito F, Qiao Z, Sakumoto M, Shiozawa K, Toki S, Yoshida A, Kawai A, Kondo T. Establishment of novel patient-derived models of dermatofibrosarcoma protuberans: two cell lines, NCC-DFSP1-C1 and NCC-DFSP2-C1. In Vitro Cell Dev Biol Anim, 55:62-73, 2019

2. Patel N, Wang J, Shiozawa K, Jones KB, Zhang Y, Prokop JW, Davenport GG, Nihira NT, Hao Z, Wong D, Brandsmeier L, Meadows SK, Sampaio AV, Werff RV, Endo M, Capecchi MR, McNagny KM, Mak TW, Nielsen TO, Underhill TM, Myers RM, Kondo T, Su L. HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression. iScience, 13:43-54, 2019

3. Qiao Z, Kondo T. Identification of cantharidin as a drug candidate for glioblastoma by using a Connectivity Map-based approach. J Electrophoresis, 63:9-14, 2019

4. Qiao Z, Kondo T. Screening of a growth inhibitor library of sarcoma cell lines to identify potent anti-cancer drugs. J Electrophoresis, 63:1-7, 2019

5. Kondo T. Cancer biomarker development and two-dimensional difference gel electrophoresis (2D-DIGE). Biochim Biophys Acta Proteins Proteom, 1867:2-8, 2019

6. Hattori E, Oyama R, Kondo T. Systematic Review of the Current Status of Human Sarcoma Cell Lines. Cells, 8:2019

7. Oyama Rieko, Takahashi Mami, Kito Fusako, Sakumoto Marimu, Takai Yoko, Shiozawa Kumiko, Qiao Zhiwei, Toki Shunichi, Tanzawa Yoshikazu, Yoshida Akihiko, Kawai Akira, Kondo Tadashi. ESTABLISHMENT AND CHARACTERIZATION OF PATIENT-DERIVED PLEOMORPHIC RHABDOMYOSARCOMA MODELS. Tiss Cult Res Commun, 38:1-12, 2019

8. Kojima M, Chen Y, Ikeda K, Tsukada Y, Takahashi D, Kawano S, Amemiya K, Ito M, Ohki R, Ochiai A. Recommendation of longterm and systemic management according to the risk factors in rectal NETs patients. Sci Rep, 9:2404, 2019

9. Fujii K, Suzuki N, Jimura N, Idogawa M, Kondo T, Iwatsuki K, Kanekura T. HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors. J Dermatol Sci, 90:82-89, 2018

10. Oyama R, Kito F, Sakumoto M, Shiozawa K, Toki S, Endo M, Yoshida A, Kawai A, Kondo T. Establishment and proteomic characterization of a novel synovial sarcoma cell line, NCC-SS2-C1. In Vitro Cell Dev Biol Anim, 54:392-399, 2018

11. Kito F, Oyama R, Takai Y, Sakumoto M, Shiozawa K, Qiao Z, Uehara T, Yoshida A, Kawai A, Kondo T. Establishment and characterization of the NCC-SS1-C1 synovial sarcoma cell line. Hum Cell, 31:167-174, 2018

12. Qiao Z, Kondo T. Identification of cephalomannine as a drug candidate for glioblastoma via high-throughput drug screening. J Electrophoresis, 62:17-20, 2018

13. Shiozawa K, Yoshioka Y, Qiao Z, Shuting J, Ochiya T, Kondo T. Pazopanib-induced changes in protein expression signatures of extracellular vesicles in synovial sarcoma. Biochem Biophys Res Commun, 506:723-730, 2018

14. Qiao Zhiwei, Parlayan Cuneyd, Saito Shigeru, Kondo Tadashi. Meta-analysis of global gene-expression profiles identify molecular signatures for histological subtypes of sarcomas. J Electrophoresis, 62:21-29, 2018

15. Ohtsuka J, Oshima H, Ezawa I, Abe R, Oshima M, Ohki R. Functional loss of p53 cooperates with the in vivo microenvironment to promote malignant progression of gastric cancers. Sci Rep, 8:2291, 2018

16. Chen Y, Takikawa M, Tsutsumi S, Yamaguchi Y, Okabe A, Shimada M, Kawase T, Sada A, Ezawa I, Takano Y, Nagata K, Suzuki Y, Semba K, Aburatani H, Ohki R. PHLDA1, another PHLDA family protein that inhibits Akt. Cancer Sci, 109:3532-3542, 2018

17. Magi S, Iwamoto K, Yumoto N, Hiroshima M, Nagashima T, Ohki R, Garcia-Munoz A, Volinsky N, Von Kriegsheim A, Sako Y, Takahashi K, Kimura S, Kholodenko BN, Okada-Hatakeyama M. Transcriptionally inducible Pleckstrin homology-like domain, family A, member 1, attenuates ErbB receptor activity by inhibiting receptor oligomerization. J Biol Chem, 293:2206-2218, 2018

18. Wang X, Li G, Koul S, Ohki R, Maurer M, Borczuk A, Halmos B. PHLDA2 is a key oncogene-induced negative feedback inhibitor of EGFR/ErbB2 signaling via interference with AKT signaling. Oncotarget, 9:24914-24926, 2018

19. Kondo T. Mass Spectrometry and Proteomics 2018: the Mass Spectrometry Society of Japan, Japanese Proteomics Society, and Asia-Oceania Human Proteome Organization. Expert Rev Proteomics, 15:777-779, 2018

20. Oyama R, Takahashi M, Kito F, Sakumoto M, Shiozawa K, Qiao Z, Yoshida A, Endo M, Kawai A, Kondo T. Establishment and characterization of patient-derived xenograft and its cell line of primary leiomyosarcoma of bone. In Vitro Cell Dev Biol Anim, 54:458- 467, 2018

21. Kito F, Oyama R, Sakumoto M, Takahashi M, Shiozawa K, Qiao Z, Sakamoto H, Hirose T, Setsu N, Yoshida A, Kawai A, Kondo T. Establishment and characterization of novel patient-derived osteosarcoma xenograft and cell line. In Vitro Cell Dev Biol Anim, 54:528-536, 2018

22. Oyama R, Kito F, Qiao Z, Sakumoto M, Noguchi R, Takahashi M, Toki S, Tanzawa Y, Yoshida A, Kawai A, Kondo T. Establishment of a novel patient-derived Ewing's sarcoma cell line, NCCES1-C1. In Vitro Cell Dev Biol Anim, 54:770-778, 2018

23. Kito Fusako, Oyama Rieko, Takahashi Mami, Shiozawa Kumiko, Sakumoto Marimu, Yoshida Akihiko, Setsu Noritaka, Kobayashi Eisuke, Kawai Akira, Kondo Tadashi. ESTABLISHMENT AND CHARACTERIZATION OF A PATIENT-DERIVED CANCER MODEL OF UNDIFFERENTIATED PLEOMORPHIC SARCOMA. Tiss Cult Res Commun, 37:133-145, 2018

24. Hattori E, Kondo T. Current status of cancer proteogenomics: a brief introduction. J Electrophoresis, 63: 33-37, 2019