Annual Report 2017

Division of Rare Cancer Research

Tadashi Kondo, Xiaoqing Pan, Rieko Ohki

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 cancers include approximately 200 cancer 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 the 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 the efforts to solve problems of 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. Those include the high-throughput screening system and the application of Connectivity Map and other bioinformatics modalities. Studies for individual rare cancers 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 develop-ment of novel medical seeds, we have developed the 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.

The screening system for the study of re-localization 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. Biomarker candidates to predict the resistance of molecular anti-cancer drugs and those to evaluate 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

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

Education

 Students and young medical doctors were educated.

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 January 2017 - March 2018

Journal

1. Qiao Z, Shiozawa K, Kondo T. Proteomic approach toward determining the molecular background of pazopanib resistance in synovial sarcoma. Oncotarget, 8:109587-109595, 2017

2. Nakasuji T, Ogonuki N, Chiba T, Kato T, Shiozawa K, Yamatoya K, Tanaka H, Kondo T, Miyado K, Miyasaka N, Kubota T, Ogura A, Asahara H. Complementary Critical Functions of Zfy1 and Zfy2 in Mouse Spermatogenesis and Reproduction. PLoS Genet, 13:e1006578, 2017

3. Qiao Z, Kito F, Kondo T. Meta-analysis identifies endothelin-3 as a prognostic biomarker in gastrointestinal stromal tumors. J Sarcoma Res, 1:1001, 2017

4. Qiao Z, Tajima T, Kito F, Arai Y, Kawai A, Kondo T. Metastasis-associated gene signature in primary myxoid liposarcoma identified through a gene expression study. J Electrophoresis, 61:9-15, 2017

5. Qiao Z, Kito F, Takai Y, Oyama R, Kondo T. Secretomics identifies follistatin as a predictive biomarker for response to treatment with tyrosine kinase inhibitors in synovial sarcoma. J Electrophoresis, 61:1-7, 2017

6. Sakumoto M, Takahashi M, Oyama R, Takai Y, Kito F, Shiozawa K, Qiao Z, Yoshida A, Endo M, Kawai A, Kondo T. Establishment and proteomic characterization of NCC-LMS1-C1, a novel cell line of primary leiomyosarcoma of the bone. Jpn J Clin Oncol, 47:954-961, 2017

7. Kikuta K, Kubota D, Yoshida A, Qiao Z, Morioka H, Nakamura M, Matsumoto M, Chuman H, Kawai A, Kondo T. Discoidin, CUB and LCCL domain-containing protein 2 (DCBLD2) is a novel biomarker of myxofibrosarcoma invasion identified by global protein expression profiling. Biochim Biophys Acta, 1865:1160-1166, 2017

8. Oyama R, Takahashi M, Yoshida A, Sakumoto M, Takai Y, Kito F, Shiozawa K, Qiao Z, Arai Y, Shibata T, Araki Y, Endo M, Kawai A, Kondo T. Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines. Sci Rep, 7:4712, 2017

9. Asano N, Yoshida A, Mitani S, Kobayashi E, Shiotani B, Komiyama M, Fujimoto H, Chuman H, Morioka H, Matsumoto M, Nakamura M, Kubo T, Kato M, Kohno T, Kawai A, Kondo T, Ichikawa H. Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. Oncotarget, 8:12941-12952, 2017

10. Kondo T. Current status of proteomics of soft tissue sarcomas. Expert Rev Proteomics, 14:1131-1140, 2017

11. Takai Y, Oyama R, Kito F, Sakumoto M, Shiozawa K, Qiao Z, Nakajima K, Takahashi M, Yoshida A, Setsu N, Kobayashi E, Kawai A, Kondo T. Establishment and characterization of a patient-derived cancer model of undifferentiated pleomorphic sarcoma. Tiss Cult Res Commun, 36:41-48, 2017

12. 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

13. 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

14. Shiozawa K, Shuting J, Yoshioka Y, Ochiya T, Kondo T. Extracellular vesicle-encapsulated microRNA-761 enhances pazopanib resistance in synovial sarcoma. Biochem Biophys Res Commun, 495:1322-1327, 2018

15. Sakumoto M, Oyama R, Takahashi M, Takai Y, Kito F, Shiozawa K, Qiao Z, Endo M, Yoshida A, Kawai A, Kondo T. Establishment and proteomic characterization of patient-derived clear cell sarcoma xenografts and cell lines. In Vitro Cell Dev Biol Anim, 54:163-176, 2018

16. Oyama R, Kito F, Sakumoto M, Shiozawa K, Toki S, Yoshida A, Kawai A, Kondo T. Establishment and proteomic characterization of a novel cell line, NCC-UPS2-C1, derived from a patient with undifferentiated pleomorphic sarcoma. In Vitro Cell Dev Biol Anim, 54:257-263, 2018

Book

1. Kondo T. OMICS Approach for Identifying Predictive Biomarkers in Osteosarcoma. In: Honoki K, Weiss KR (eds), Osteosarcoma - Biology, Behavior and Mechanisms, InTech, 2017