Precision medicine using circulating tumor cells of gastrointestinal cancer

• Project/Area Number: 19K08432
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Shoji Hirokazu 国立研究開発法人国立がん研究センター, 中央病院, 医員 (50765568)
• Co-Investigator(Kenkyū-buntansha): 本田 一文 国立研究開発法人国立がん研究センター, 研究所, 部門長 (10260936)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 末梢循環腫瘍細胞 / 胃癌 / tumor mutation burden / nivolumab / 胃がん / 免疫チェックポイント阻害薬 / 次世代シークエンス / リキッドバイオプシー / スフェロイド培養 / 消化管がん / オミクス解析 / 精密医療

Outline of Research at the Start

【研究目的】
消化管がんの個別化医療の確立を目的に消化管がんの末梢循環腫瘍細胞（circulating tumor cells, CTCs）の生物学的特性を理解し、有用な病態診断法を開発する。
【研究目標】
I.胃がんCTCsを用いたゲノム解析をはじめとしたオミクス解析技術を創出し、免疫チェックポイント阻害薬に対する精密医療を確立する。
II.消化管がんCTCsを用いた細胞培養技術を創出する。

Outline of Final Research Achievements

Circulating tumor cells (CTCs) could be isolated from peripheral blood of a total of 11 patients with advanced gastric cancer, prior to the start of nivolumab in the third line of therapy. Next-generation sequencing was performed from the amplified DNA, and oncogenes and cancer-promoting gene mutation profiles were successfully extracted from CTCs. The gene mutation profiles of CTCs and ctDNA from surgical specimens (FFPE) and liquid biopsy specimens obtained from the same patient were different. Therefore, the combined use of both CTCs and ctDNA profiles was expected to improve gene mutation detection compared to each assay alone; the TMBs of FFPE and CTCs were not consistent, and the TMB of CTCs tended to be lower than that of FFPE.

Academic Significance and Societal Importance of the Research Achievements

CTCs から消化管がんの「がんの個性診断法」を実現できれば、患者に対して最少侵襲で時々刻々変化するがん細胞に対して「適時・最適医療」を提示できるようになると考え、本研究を進めてきた。本研究の結果、進行胃がんCTCsからの遺伝子変異解析、TMB解析が可能でることを証明した。今後は本技術を用いて検討症例数を増やし、そして臨床試験への応用、CTCsの細胞培養が実現できれば、プロテオーム解析や薬剤感受性試験につながり、個々の患者に適した薬剤の提供につながる可能性があり、国内外へのインパクトが非常に高いと考える。

Research Products

• [Journal Article] Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer (2022)
  • Author(s): Hirano H, Abe Y, Nojima Y, Aoki M, Shoji H, Isoyama J, Honda K, Boku N, Mizuguchi K, Tomonaga T, Adachi J.
  • Journal Title: Sci Rep. Volume: 12(1) Issue: 1 Pages: 4419-4419
  • DOI: 10.1038/s41598-022-08430-7
  • Peer Reviewed / Open Access
• [Journal Article] Topical corticosteroid therapy for facial acneiform eruption due to EGFR inhibitors in metastatic colorectal cancer patients: a randomized controlled trial comparing starting with a very strong or a weak topical corticosteroid (FAEISS study, NCCH1512, colorectal part) (2022)
  • Author(s): Kikuchi K, Yamazaki N, Nozawa K, Fukuda H, Shibata T, Machida R, Hamaguchi T, Takashima A, Shoji H, Boku N, Takatsuka S, Takenouchi T, Nishina T, Yoshikawa S, Takahashi M, Hasegawa A, Kawazoe A, Masuishi T, Mizutani H, Kiyohara Y.
  • Journal Title: Support Care Cancer. Volume: 30(5) Issue: 5 Pages: 4497-4504
  • DOI: 10.1007/s00520-022-06874-1
  • Peer Reviewed
• [Journal Article] A Phase I study of pevonedistat plus capecitabine plus oxaliplatin in patients with advanced gastric cancer refractory to platinum (NCCH-1811) (2021)
  • Author(s): Shoji H, Takahari D, Hara H, Nagashima K, Adachi J, Boku N.
  • Journal Title: Future Sci OA. Volume: 7(7) Issue: 7 Pages: 721-721
  • DOI: 10.2144/fsoa-2021-0023
  • Peer Reviewed / Open Access
• [Journal Article] REVIVE study: a prospective observational study in chemotherapy after nivolumab therapy for advanced gastric cancer (2021)
  • Author(s): Narita Y, Shoji H, Kawai S, Mizukami T, Nakamura M, Moriwaki T, Yamanaka T, Sunakawa Y, Kawakami H, Nishina T, Misumi T, Muro K.
  • Journal Title: Future Oncol. Volume: 17(8) Issue: 8 Pages: 869-875
  • DOI: 10.2217/fon-2020-0621
  • Peer Reviewed / Open Access
• [Journal Article] Tumor growth rate during re-challenge chemotherapy with previously used agents as salvage treatment for metastatic colorectal cancer: A retrospective study (2021)
  • Author(s): Ishikawa M, Takashima A, Nagata Y, Sawada R, Aoki M, Imazeki H, Hirano H, Shoji H, Honma Y, Iwasa S, Okita N, Kato K, Saruta M, Boku N.
  • Journal Title: PLoS One. Volume: 16(9) Issue: 9 Pages: e0257551-e0257551
  • DOI: 10.1371/journal.pone.0257551
  • Peer Reviewed / Open Access
• [Journal Article] Panitumumab-Associated Drug-Induced Immune Thrombocytopenia in a Patient with Colorectal Cancer (2021)
  • Author(s): Takamizawa S, Shoji H, Hirano H, Izutsu K, Yamamoto S, Iwasa S, Honma Y, Okita N, Takashima A, Kato K, Boku N.
  • Journal Title: Case Rep Oncol. Volume: 14(1) Issue: 1 Pages: 85-89
  • DOI: 10.1159/000512821
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between cervical esophageal squamous cell carcinoma and human papilloma virus infection and gene mutations (2021)
  • Author(s): Fukahori M, Kato K, Taniguchi H, Ohtomo R, Takahashi N, Shoji H, Iwasa S, Honma Y, Takashima A, Hamaguchi T, Yamada Y, Shimada Y, Ito Y, Itami J, Hokamura N, Igaki H, Tachimori Y, Miwa K, Torimura T, Boku N.
  • Journal Title: Mol Clin Oncol. Volume: 14(2) Issue: 2 Pages: 41-41
  • DOI: 10.3892/mco.2020.2205
  • Peer Reviewed
• [Journal Article] Case report: potential treatment of metastatic amphicrine carcinoma of the rectum with FOLFOXIRI chemotherapy (2020)
  • Author(s): Tamura N, Honma Y, Sekine S, Tsukamoto S, Hirano H, Okita N, Shoji H, Iwasa S, Takashima A, Kato K, Boku N.
  • Journal Title: Oxf Med Case Reports. Volume: 2020(11) Issue: 11
  • DOI: 10.1093/omcr/omaa097
  • Peer Reviewed
• [Journal Article] Survival Outcomes of Resected BRAF V600E Mutant Colorectal Liver Metastases: A Multicenter Retrospective Cohort Study in Japan (2020)
  • Author(s): Kobayashi S, Takahashi S, Takahashi N, Masuishi T, Shoji H, Shinozaki E, Yamaguchi T, Kojima M, Gotohda N, Nomura S, Yoshino T, Taniguchi H.
  • Journal Title: Ann Surg Oncol. Volume: 27(9) Issue: 9 Pages: 3307-3315
  • DOI: 10.1245/s10434-020-08817-8
  • Peer Reviewed
• [Journal Article] Prospects for Comprehensive Analyses of Circulating Tumor Cells in Tumor Biology. (2020)
  • Author(s): Aoki M, Shoji H, Kashiro A, Takeuchi K, Shimizu Y, Honda K.
  • Journal Title: Cancers (Basel) Volume: 12（5） Issue: 5 Pages: 1135-1135
  • DOI: 10.3390/cancers12051135
  • Peer Reviewed / Open Access
• [Journal Article] Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in gastrointestinal cancer patients with massive ascites treated with systemic chemotherapy. (2020)
  • Author(s): Nagata Y, Kato K, Miyamoto T, Hirano H, Shoji H, Iwasa S, Honma Y, Takashima A, Hamaguchi T, Matsushita H, Nagashima K, Saruta M, Boku N.
  • Journal Title: Support Care Cancer Volume: Epub ahead of print Issue: 12 Pages: 5861-5869
  • DOI: 10.1007/s00520-020-05401-4
  • Peer Reviewed
• [Journal Article] Comparison of involved field radiotherapy and elective nodal irradiation in combination with concurrent chemotherapy for T1bN0M0 esophageal cancer. (2020)
  • Author(s): Nakatani Y, Kato K, Shoji H, Iwasa S, Honma Y, Takashima A, Ushijima T, Ito Y, Itami J, Boku N.
  • Journal Title: Int J Clin Oncol Volume: Epub ahead of print Issue: 6 Pages: 1098-1104
  • DOI: 10.1007/s10147-020-01652-7
  • Peer Reviewed
• [Journal Article] IL33 Is a Key Driver of Treatment Resistance of Cancer. (2020)
  • Author(s): Kudo-Saito C, Miyamoto T, Imazeki H, Shoji H, Aoki K, Boku N.
  • Journal Title: Cancer Res Volume: Epub ahead of print Issue: 10 Pages: 1981-1990
  • DOI: 10.1158/0008-5472.can-19-2235
• [Journal Article] Comprehensive characterization of the phosphoproteome of gastric cancer from endoscopic biopsy specimens. (2020)
  • Author(s): Abe Y, Hirano H, Shoji H, Tada A, Isoyama J, Kakudo A, Gunji D, Honda K, Boku N, Adachi J, Tomonaga T.
  • Journal Title: Theranostics Volume: 10（5） Issue: 5 Pages: 2115-2129
  • DOI: 10.7150/thno.37623
  • Peer Reviewed / Open Access
• [Journal Article] Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab. (2019)
  • Author(s): Masuda K, Shoji H, Nagashima K, Yamamoto S, Ishikawa M, Imazeki H, Aoki M, Miyamoto T, Hirano H, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Boku N.
  • Journal Title: BMC Cancer Volume: 19（1） Issue: 1 Pages: 974-974
  • DOI: 10.1186/s12885-019-6150-y
  • Peer Reviewed / Open Access
• [Journal Article] Hyperprogressive disease during nivolumab or irinotecan treatment in patients with advanced gastric cancer. (2019)
  • Author(s): Aoki M, Shoji H, Nagashima K, Imazeki H, Miyamoto T, Hirano H, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Higuchi K, Boku N.
  • Journal Title: ESMO Open Volume: 4（3） Issue: 3 Pages: e000488-e000488
  • DOI: 10.1136/esmoopen-2019-000488
  • Peer Reviewed / Open Access
• [Journal Article] Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA (2019)
  • Author(s): Onidani Kaoru、Shoji Hirokazu、Kakizaki Takahiko、Yoshimoto Seiichi、Okaya Shinobu、Miura Nami、Sekikawa Shoichi、Furuta Koh、Lim Chwee Teck、Shibahara Takahiko、Boku Narikazu、Kato Ken、Honda Kazufumi
  • Journal Title: Cancer Science Volume: 110 Issue: 8 Pages: 2590-2599
  • DOI: 10.1111/cas.14092
  • Peer Reviewed / Open Access
• [Presentation] Safety and early efficacy of nivolumab plus trastuzumab with FU plus oxaliplatin for HER2-positive gastric cancer (2022)
  • Author(s): Hirokazu Shoji, Daisuke Takahari, Keiko Minashi, Hiroki Hara, Keisho Chin, Akira Ooki, Mariko Ogura, Izuma Nakayama, Ken Kato, Satoru Iwasa, Hidekazu Hirano, Yusuke Amanuma, Naoki Ishizuka, Narikazu Boku,Kensei Yamaguchi
  • Organizer: JSMO
• [Presentation] Temporal dynamics of phosphoproteomics using endoscopic biopsy specimens in stage IV gastric cancer (2022)
  • Author(s): Hidekazu Hirano, Yuichi Abe, Yosui Nojima, Masahiko Aoki, Hirokazu Shoji, Junko Isoyama, Kazufumi Honda, Narikazu Boku, Kenji Mizuguchi, Takeshi Tomonaga, Jun Adachi
  • Organizer: JGCA
• [Presentation] Search of biomarkers and creation of innovative methods required for precision medicine for gastric cancer (2021)
  • Author(s): Shoji H, Adachi J, Hirano H, Honda K, Mizuguchi K, Tomonaga T, Boku N
  • Organizer: 第18回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] 血液検体を用いたリキッドバイオプシーの有用性 (2020)
  • Author(s): 庄司広和
  • Organizer: 第33回日本口腔診断学会 第30回日本口腔内科学会 第13回日本口腔検査学会 合同学術大会.
  • Invited
• [Presentation] Comprehensive phosphoproteomics using gastric cancer biopsy specimens. (2019)
  • Author(s): H. Shoji, Y. Abe, H. Hirano, J. Adachi, M. Aoki, K. Honda, N. Boku, T. Tomonaga
  • Organizer: 13th International Gastric Cancer Congress 2019 (IGCC 2019)
  • Int'l Joint Research