Establishment of prediction system for RTK/KRAS targeting therapy in gastric cancer using early response biomarker.

• Project/Area Number: 18K15283
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Oita University
• Principal Investigator: Hirashita Yuka 大分大学, 医学部, 医員 (70771955)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: バイオマーカー / 感受性予測 / 感受性マーカー / RTK/KRASシグナル / 胃癌 / 大腸癌 / 進行胃癌 / 感受性 / マーカー / 分子標的治療 / オルガノイド / RTK/KRAS / 分子標的薬

Outline of Final Research Achievements

Gastric cancer (GC) and is characterized by genomic alteration with RTK and KRAS signaling pathway, therefore, targeting of the RTK/KRAS downstream pathways could help to broaden the applicability of molecular targeted therapy for GC. We established patient-derived GC organoid (additionally CRC organoid) to analyze the sensitivities of organoids to MEK inhibitor treatment. Furthermore, we showed that the change in pS6 level after MEK inhibition was well correlated with responsiveness to trametinib. We proposed predict system with patient-derived organoids, the change in pS6 could be a useful biomarker for RTK/KRAS signal targeting therapy.

Academic Significance and Societal Importance of the Research Achievements

癌ゲノム時代を迎え、遺伝子異常を標的とした個別化医療が可能となった。しかし遺伝子異常だけでは、分子標的治療薬の感受性が完全に予測できずより精度の高いバイオマーカーが望まれている。
本研究では癌オルガノイドを用いて薬剤投与早期のタンパク質リン酸化レベルの変化による感受性予測法は、癌オルガノイドを用いた従来の感受性試験と比べ、少量の検体量でより早期に検出可能であった。またKRASなどの遺伝子変異だけでは予測不可能な耐性を示す症例も見つけることが可能であった。申請者の示す予測法は遺伝子異常と組み合わせることで、RTK/KRASシグナル標的治療において、より精度の高い感受性予測法の一助になると考える。

Research Products

• [Journal Article] Differences in Regression Patterns of Complete and Incomplete Intestinal Metaplasia at Ten Years after <i>Helicobacter pylori</i> Eradication (2021)
  • Author(s): Wada Yasuhiro、Kodama Masaaki、Mizukami Kazuhiro、Okimoto Tadayoshi、Fuchino Takafumi、Tsutsumi Koshiro、Fukuda Masahide、Hirashita Yuka、Fukuda Kensuke、Okamoto Kazuhisa、Ogawa Ryo、Kushima Ryoji、Murakami Kazunari
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 54 Issue: 6 Pages: 185-194
  • DOI: 10.1267/ahc.21-00069
  • NAID: 130008132648
  • ISSN: 0044-5991, 1347-5800
  • Year and Date: 2021-12-24
  • Peer Reviewed
• [Journal Article] Immunohistochemical differences in gastric mucosal damage between nodular and non-nodular gastritis caused by <i>Helicobacter pylori</i> infection (2021)
  • Author(s): Okamoto K, Kodama M, Mizukami K, Okimoto T, Abe H, Ogawa R, Fukuda F, Matsunari O, Hirashita Y, Wada Y, Fukuda M, Murakami K
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 69 Issue: 2 Pages: 216-221
  • DOI: 10.3164/jcbn.20-179
  • NAID: 130008082423
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Gastric mucosal changes, and sex differences therein, after Helicobacter pylori eradication: A long-term prospective follow-up study. (2021)
  • Author(s): Kodama M, Okimoto T, Mizukami K, Hirashita Y, Wada Y, Fukuda M, Matsunari O, Okamoto K, Ogawa R, Fukuda K, Kudo Y, Kawahara Y, Murakami K.
  • Journal Title: J Gastroenterol Hepatol Volume: - Issue: 8 Pages: 2210-2216
  • DOI: 10.1111/jgh.15477
  • Peer Reviewed / Open Access
• [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] Complex polypectomy in the sigmoid colon using a double-balloon endolumenal intervention platform (2021)
  • Author(s): Huang A.、Hirashita T.、Urakawa S.、Hirashita Y.、Alzghari T.、Milsom J. W.
  • Journal Title: Techniques in Coloproctology Volume: 25 Issue: 5 Pages: 599-600
  • DOI: 10.1007/s10151-020-02400-9
  • Peer Reviewed
• [Journal Article] α ‐Tocopherol suppresses hepatic steatosis by increasing CPT‐1 expression in a mouse model of diet‐induced nonalcoholic fatty liver disease (2020)
  • Author(s): Tokoro Masanori、Gotoh Koro、Kudo Yoko、Hirashita Yuka、Iwao Masao、Arakawa Mie、Endo Mizuki、Oribe Junya、Masaki Takayuki、Honda Koichi、Kakuma Tetsuya、Seike Masataka、Murakami Kazunari、Shibata Hirotaka
  • Journal Title: Obesity Science & Practice Volume: 7 Issue: 1 Pages: 91-99
  • DOI: 10.1002/osp4.460
  • Peer Reviewed / Open Access
• [Journal Article] S6 ribosomal protein phosphorylation is associated with malignancy of intraductal papillary mucinous neoplasm of the pancreas. (2020)
  • Author(s): Hirashita T, Hirashita Y, Iwashita Y, Endo Y, Kiyonaga M, Matsumoto S, Hijiya N, Moriyama M, Murakami K, Inomata M.
  • Journal Title: Ann Gastroenterol Surg Volume: 4 Issue: 5 Pages: 571-579
  • DOI: 10.1002/ags3.12367
  • Peer Reviewed / Open Access
• [Journal Article] Influence of acotiamide on ¹³C-urea breath test for <i>Helicobacter pylori</i> diagnosis (2020)
  • Author(s): Mizukami Kazuhiro、Katsuta Makoto、Okamoto Kazuhisa、Fukuda Kensuke、Ogawa Ryo、Kawahara Yoshinari、Hirashita Yuka、Sato Yuto、Fukuda Masahide、Okimoto Tadayoshi、Kodama Masaaki、Fujioka Toshio、Murakami Kazunari
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 67 Issue: 3 Pages: 332-337
  • DOI: 10.3164/jcbn.20-17
  • NAID: 130007934182
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [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
• [Presentation] 研究生活を通して感じること (2021)
  • Author(s): 平下 有香
  • Organizer: 第107回日本消化器病学会総会 キャリア支援委員会企画
• [Presentation] eEF1A dimethylation level in the basal area of Helicobacter pylori-eradicated gastric mucosa is associated with the risk of gastric cancer (2021)
  • Author(s): 平下有香 兒玉雅明 村上和成
  • Organizer: 2021年10月第80回癌学会学術総会
• [Presentation] 除菌後胃粘膜におけるeEF1Aジメチル化と胃癌発症との相関 (2020)
  • Author(s): 平下 有香
  • Organizer: 第92回日本胃癌学会総会
• [Presentation] Dimethylation level of eEF1A and the gastric mucosa after Helicobacter pylori (H. pylori) eradication therapy (2020)
  • Author(s): Yuka Hirashita
  • Organizer: American College of Gastroenterology 2020
  • Int'l Joint Research
• [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 有香
  • Organizer: 第27回日本消化器関連学会週間
• [Presentation] 膵IPMN癌化・浸潤過程におけるmTORC1活性と糖の取り込みとの相関 (2019)
  • Author(s): 平下 有香
  • Organizer: 第114回日本消化器病学会 九州支部例会