Prediction of drug efficacy by patients derived tumor organoids (PDOs) and early response markers (ERMs)

• Project/Area Number: 18H02631
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Oita University
• Principal Investigator: Tsukamoto Yoshiyuki 大分大学, 医学部, 助教 (00433053)
• Co-Investigator(Kenkyū-buntansha): 泥谷 直樹 大分大学, 医学部, 准教授 (80305036) ; 守山 正胤 大分大学, 医学部, 教授 (90239707) ; 平下 有香 大分大学, 医学部, 医員 (70771955)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2020: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2019: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 癌オルガノイド / 早期反応性マーカー / 抗癌剤 / オルガノイド / 胃癌 / 感受性試験 / 個別化医療 / 抗がん剤

Outline of Final Research Achievements

Prediction of therapy outcome is important to optimize therapeutic strategy for individual patients because drug efficacy varies widely among cancer patients. Patient derived tumor organoids (PDOs) are three-dimensional (3D) tumor cell cultures from primary tumors. PDOs potentially offer great benefits as a preclinical cancer model because they closely recapitulate morphological and genetic features in matched original tumor tissue. Furthermore, success rates for establishment of PDOs are generally higher than those of traditional 2D cell lines among various types of tumors. Previously, we suggested that early response after the drug treatment could predict an efficacy of the drug. Based on the data, we proposed diagnostic model using such biomarkers (ERM; Early Response Marker) to predict drug efficacies. Here, we aimed to establish the diagnostic system by using PDOs in combination with ERM.

Academic Significance and Societal Importance of the Research Achievements

本研究は抗癌剤効果予測法の確立を目指すものであり、癌化学療法適応患者が対象となる。例えば、国内で食道、胃、大腸、膵癌の化学療法適応患者は年間99,000人である（2016年度厚労省）。抗癌剤効果は患者により異なる。副作用の低減と高い治療効果のためには適した抗癌剤の選択、すなわち個別化医療が必須である。現行のがん個別化医療は遺伝子異常を標的とした分子病的薬が使われているため、遺伝子異常を標的としない抗癌剤の効果予測は困難である（細胞障害性抗癌剤など）。本研究はその課題を解決し、遺伝子異常では効果予測が困難な抗癌剤の効果予測法確立を目指しており、より多くの癌患者の個別化医療に貢献すると確信する。

Research Products

• [Int'l Joint Research] Hubrecht Institute (Clevers group)(オランダ)
• [Int'l Joint Research] Hubrecht Institute(オランダ)
• [Journal Article] Early response in phosphorylation of ribosomal protein S6 is associated with sensitivity to trametinib in colorectal cancer cells (2021)
  • Author(s): Hirashita Yuka、Tsukamoto Yoshiyuki、Kudo Y、Kakisako D、Kurogi S、Hijiya Naoki、Nakada C、Uchida T、Hirashita T、Hiratsuka T、Akagi T、Ueda Y、Shiroshita H、Etoh T、Mizukami K、Honda K、Okimoto T、Kodama M、Inomata M、Moriyama Masatsugu、Murakami K
  • Journal Title: Laboratory Investigation Volume: - Issue: 8 Pages: 1036-1047
  • DOI: 10.1038/s41374-021-00590-w
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of ZNF395 Drives Progression of Pancreatic Ductal Adenocarcinoma through Enhancement of Growth Potential. (2021)
  • Author(s): Kurogi S, Hijiya N, Hidano S, Sato S, Uchida T, Tsukamoto Y, Nakada C, Yada K, Hirashita T, Inomata M, Murakami K, Takahashi N, Kobayashi T, Moriyama M.
  • Journal Title: Pathobiology Volume: 2021 Issue: 5 Pages: 1-9
  • DOI: 10.1159/000514593
  • Peer Reviewed / Open Access
• [Journal Article] DUSP4 is involved in the enhanced proliferation and survival of DUSP4-overexpressing cancer cells. (2020)
  • Author(s): Ratsada P, Hijiya N, Hidano S, Tsukamoto Y, Nakada C, Uchida T, Kobayashi T, Moriyama M.
  • Journal Title: Biochem Biophys Res Commun Volume: 528 Issue: 3 Pages: 586-593
  • DOI: 10.1016/j.bbrc.2020.05.140
  • Peer Reviewed / Open Access
• [Journal Article] A transgenic mouse expressing miR-210 in proximal tubule cells shows mitochondrial alteration: possible association of miR-210 with a shift in energy metabolism. (2020)
  • Author(s): Nakada C, Hijiya N, Tsukamoto Y, Yano S, Kai T, Uchida T, Kimoto M, Takahashi M, Daa T, Matsuura K, Shin T, Mimata H, Moriyama M.
  • Journal Title: J Pathol. Volume: in press Issue: 1 Pages: 12-25
  • DOI: 10.1002/path.5394
  • Peer Reviewed
• [Journal Article] Invasive intraductal papillary mucinous neoplasms of the pancreas: relationships between mural nodules detected on thin-section contrast-enhanced MDCT and invasive components. (2019)
  • Author(s): Kamei N, Yamada Y, Hijiya N, Takaji R, Kiyonaga M, Hongo N, Ohta M, Hirashita T, Inomata M, Matsumoto S.
  • Journal Title: Abdom Radiol Volume: 44 Issue: 9 Pages: 3139-3147
  • DOI: 10.1007/s00261-019-02084-2
  • Peer Reviewed
• [Journal Article] Examine the Availability and Safety of Mucosal Cutting Biopsy Technique for Diagnosis of Gastric Submucosal Tumor. (2019)
  • Author(s): Mizukami K, Matsunari O, Ogawa R, Hirashita Y, Okamoto K, Fukuda K, Sonoda A, Akiyama H, Ozaka S, Kawahara Y, Okimoto T, Kodama M, Murakami K.
  • Journal Title: Gastroenterol Res Pract Volume: 3121695 Pages: 1-6
  • DOI: 10.1155/2019/3121695
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of a Novel Anti-H. pylori Antibody Detection Kit by Latex Turbidimetric Immunoassay. (2019)
  • Author(s): Kodama M, Okimoto T, Mizukami K, Fukuda K, Ogawa R, Okamoto K, Matsunari O, Wada Y, Hirashita Y, Murakami K.
  • Journal Title: Clin Lab Volume: 65 Issue: 06/2019 Pages: 929-936
  • DOI: 10.7754/clin.lab.2018.180918
  • Peer Reviewed / Open Access
• [Journal Article] Differences in <i>Helicobacter pylori</i> and CagA antibody changes after eradication between subjects developing and not developing gastric cancer (2019)
  • Author(s): Kodama M, Okimoto T, Mizukami K, Fukuda K, Ogawa R, Okamoto K, Matsunari O, Kawahara Y, Hirashita Y, Murakami K.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 65 Issue: 1 Pages: 71-75
  • DOI: 10.3164/jcbn.19-30
  • NAID: 130007672120
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic gastric mucosal atrophy as a predictor of colorectal polyps: a large scale case-control study (2019)
  • Author(s): Kawahara Y, Kodama M, Mizukami K, Saito T, Hirashita Y, Sonoda A, Fukuda K, Matsunari O, Okamoto K, Ogawa R, Okimoto T, Murakami K.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 65 Issue: 2 Pages: 153-159
  • DOI: 10.3164/jcbn.19-47
  • NAID: 130007700225
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Complete Sequences of the Human T-Cell Leukemia Virus Type 1 Proviral Genomes from Newly Established Adult T-Cell Leukemia Cell Lines in Oita Prefecture, Japan (2018)
  • Author(s): Fukumoto T, Ikebe E, Ogata M, Kohno K, Kuramitsu M, Sato Y, Fife N, Matsumoto T, Yahiro T, Ikeda M, Kusano S, Okayama A, Hori M, Hijiya N, Tsukamoto Y, Hirashita Y, Moriyama M, Ahmed K, Hasegawa H, Nishizono A, Saito M, Iha H
  • Journal Title: Genome Announcements Volume: 6 Issue: 25
  • DOI: 10.1128/genomea.00090-18
  • Peer Reviewed / Open Access
• [Journal Article] Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1 (2018)
  • Author(s): Iwasaki K, Ninomiya R, Shin T, Nomura T, Kajiwara T, Hijiya N, Moriyama M, Mimata H, Hamada F
  • Journal Title: Cancer Science Volume: 109 Issue: 10 Pages: 3159-3170
  • DOI: 10.1111/cas.13754
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic and Immunohistochemical Characteristics of Gastric Cancer with versus without <b><i>Helicobacter Pylori</i></b> Eradication (2018)
  • Author(s): Kodama Masaaki、Okimoto Tadayoshi、Mizukami Kazuhiro、Abe Hisanori、Ogawa Ryo、Okamoto Kazuhisa、Shuto Mitsutaka、Matsunari Osamu、Hirashita Yuka、Sato Ryugo、Abe Takashi、Nagai Takayuki、Arita Tsuyoshi、Murakami Kazunari
  • Journal Title: Digestion Volume: 97 Issue: 4 Pages: 288-297
  • DOI: 10.1159/000485504
  • Peer Reviewed / Open Access
• [Presentation] 食道扁平上皮癌及び腺癌の機能比較モデルの作製 (2020)
  • Author(s): 柴田 智隆, 塚本 善之, 黒木 秀作, 矢野 信次, 錦 耕平, 鈴木 浩輔, 麓 祥一, 衛藤 剛, 守山 正胤, 猪股 雅史
  • Organizer: 第58回日本癌治療学会学術集会
• [Presentation] ZNF395の発現低下は膵癌の増殖能亢進と進展に寄与する (2020)
  • Author(s): 黒木秀作, 泥谷直樹, 塚本善之, 中田知里, 猪股雅史, 小林隆志, 守山正胤
  • Organizer: 日本癌学会学術総会
• [Presentation] レナリドミドによるATL細胞増殖抑制効果の分子機序 (2020)
  • Author(s): 伊波英克, 池辺詠美, 下崎俊介, 山本淳一, 半田宏, 堀光雄, 長谷川寛雄, 泥谷直樹, 塚本善之, 守山正胤, 草野秀一, 菊池次郎, 古川雄祐, 萩原將太郎, 斎藤益満, 鈴木敦, 森下和広
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] RAS/BRAF 変異型進行大腸癌における 早期反応性マーカーを用い た trametinib 感受性予測法の検討 (2019)
  • Author(s): 平下由香
  • Organizer: 第27回 日本消化器関連学会週間
• [Presentation] 膵IPMNの癌化・浸潤におけるmTORC 1活性と糖の取り込みとの関係 (2019)
  • Author(s): 平下有香
  • Organizer: 日本消化器病学会九州支部例会
• [Remarks] 大分大学医学部分子病理学講座ホームページ
  • URL: http://www.med.oita-u.ac.jp/byori2/
• [Remarks] 大分大学医学部分子病理学講座
  • URL: http://www.med.oita-u.ac.jp/byori2/index.htm
• [Remarks] 大分大学医学部分子病理学講座ホームページ
  • URL: http://www.med.oita-u.ac.jp/byori2/index.htm
• [Patent(Industrial Property Rights)] 癌治療効果の有効性を予測する方法、予測装置及び予測プログラム (2020)
  • Inventor(s): 塚本善之
  • Industrial Property Rights Holder: 塚本善之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-143512
  • Filing Date: 2020