Annual Report 2017

Department of Biomarker for Early Detection of Cancer

Kazufumi Honda, Nami Miura, Kaoru Onidani, Shinobu Okaya, Takako Sakamoto, Teru Hiroi, Keiko Takeuchi, Hideaki Shiraishi

Introduction

 Using innovative proteomic, metabolic, and genomic techniques, the Department of Biomarker for Early Detection of Cancer will focus its research interests on clarifying the molecular and cellular mechanisms of cancer promotion and progression. With the aim of discovering targets for early cancer detection, molecular therapy, and personalized medicine, we have undertaken comprehensive protein, metabolite, and gene expression profiling of various cancer cell lines and cancer tissues, as well as sera/plasma and tissue samples from cancer patients.

Our team and what we do

1) Practical implementation of effective blood biomarker-based pancreatic cancer screening

2) Practical application of predictive biomarkers for adjuvant chemotherapy

3) Elucidation of molecular mechanisms of cancer invasion and metastasis

Research activities

1) Development of an efficient screening system for pancreatic cancer, to reduce the mortality associated with this disease, is an urgent and unmet medical need. We recently identified unique alterations in apolipoprotein A2 isoforms (apoA2-is), in the form of different C-terminal amino acids, in pancreatic cancer and its precancerous lesions. The clinical utility of these findings was blindly validated by the National Cancer Institute Early Detection Research Network (NCI-EDRN). To demonstrate proof of concept for pancreatic cancer screening using biomarkers, we have started experimental screening for pancreatic cancer using apoA2-i in Japan, with international collaboration, to assess risk stratification of pancreatic cancer.

2) The National Cancer Institute Canadian Clinical Trial Group JBR.10 led to the adoption of adjuvant cisplatin-based chemotherapy for patients with resected stages-IB to IIIA non-small cell lung cancer (NSCLC). In the subgroup analysis using a JBR.10 database search, we demonstrated a significant clinical benefit of adjuvant chemotherapy in terms of overall survival only in the actinin-4 (ACTN4) high expression group. The data suggested that ACTN4 is a potential predictive biomarker of  the efficacy of adjuvant chemotherapy in early- stage NSCLC patients. We are in the process of preparing a test kit for confirming ACTN4 gene amplification and protein expression in surgical specimens.

3) The activities of kinases are tightly associated with the formation of malignant phenotypes in cancer cells. Inhibition of kinases, which are associated with driving malignant phenotypes, has recently garnered attention as a potential molecular-targeted therapy for cancer. Since there are only two molecular-targeted drugs approved for therapeutic use in head and neck cancers in Japan, the development of molecular-targeted therapy and companion diagnostic technology are urgently needed. To identify novel molecular targets for patients with stage I/II tongue cancer, we screened expression profiles for the kinome using  antibody-based proteomics.

Clinical trials

 Experimental screening for pancreatic cancer in Kagoshima and Hyogo prefectures

Education

1) Education for a PhD student (Kakuya T) at  Tokyo Dental College Graduate School of Dental Science in performing the research and writing of the thesis Kakuya T, Mori T, Yoshimoto S, Watabe Y,  Miura N, Shoji H, Onidani K, Shibahara T, Honda K*. Prognostic significance of gene amplification of ACTN4 in stage I and II oral tongue cancer. Int J Oral Maxillofac Surg. 2017 Apr 3. pii: S0901-5027(17)31345-0

2) Education for a PhD student (Shoji H) at  Juntendo University Graduate School of  Medicine in performing the research and writing of the thesis Shoji H, Tada K, Kitano S, Nishimura T,  Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Takashima A, Kato K, Boku N, Honda K, Yamada T, Heike Y, Hamaguchi T. The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy. Oncotarget 2017 May 30. doi: 10.18632/oncotarget.18297

3) Education for a PhD student (Shiraishi H) at Juntendo University Graduate School of Medicine in performing the research and writing of the thesis Shiraishi H, Fujiwara Y, Kakuya T, Tsuta K, Motoi N, Miura N, Watabe Y, Watanabe SI, Noro R, Nagashima K, Huang W, Yamada T, Asamura H, Ohe Y, Honda K*. Actinin-4 protein overexpression as a predictive biomarker in adjuvant chemotherapy for resected lung adenocarcinoma. Biomark Med. 2017 Jun 29. doi: 10.2217/bmm-2017-0150

4) Acquisition of funds for young research resident training for the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED (Japan)

Future prospects

1) In this study, we will enroll 8,000-20,000 subjects to obtain proof of concept for the use of blood tests as pancreatic cancer screening tools. The aim of the study is to develop efficient screening methods for pancreatic cancer.

2) To improve the mortality of non-small cell lung cancer (NSCLC), we are clinically developing in vitro diagnostics (IVD) to predict the efficacy of adjuvant chemotherapy in patients with completely resected stage-I NSCLC. It is expected that IVD will allow the efficient treatment selection for patients with stage-I NSCLC.

3) Novel therapeutic strategies for oral squamous cell carcinoma will be developed through the investigation of the expression profile of the kinome.

List of papers published in January 2017 - March 2018

Journal

1. Shoji H, Tada K, Kitano S, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Takashima A, Kato K, Boku N, Honda K, Yamada T, Heike Y, Hamaguchi T. The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy. Oncotarget, 8:95083-95094, 2017

2. Kakuya T, Mori T, Yoshimoto S, Watabe Y, Miura N, Shoji H, Onidani K, Shibahara T, Honda K. Prognostic significance of gene amplification of ACTN4 in stage I and II oral tongue cancer. Int J Oral Maxillofac Surg, 46:968-976, 2017

3. Yamaguchi H, Ito Y, Miura N, Nagamura Y, Nakabo A, Fukami K, Honda K, Sakai R. Actinin-1 and actinin-4 play essential but distinct roles in invadopodia formation by carcinoma cells. Eur J Cell Biol, 96:685-694, 2017

4. Hirata Y, Kobayashi T, Nishiumi S, Yamanaka K, Nakagawa T, Fujigaki S, Iemoto T, Kobayashi M, Okusaka T, Nakamori S, Shimahara M, Ueno T, Tsuchida A, Sata N, Ioka T, Yasunami Y, Kosuge T, Kaneda T, Kato T, Yagihara K, Fujita S, Yamada T, Honda K, Azuma T, Yoshida M. Identification of highly sensitive biomarkers that can aid the early detection of pancreatic cancer using GC/MS/MS-based targeted metabolomics. Clin Chim Acta, 468:98-104, 2017

5. Kobayashi T, Sato Y, Nishiumi S, Yagi Y, Sakai A, Shiomi H, Masuda A, Okaya S, Kutsumi H, Yoshida M, Honda K. Serum apolipoprotein A2 isoforms in autoimmune pancreatitis. Biochem Biophys Res Commun, 497:903-907, 2018