Establishment of novel anti-cancer concept overcoming drug resisitancies.

• Project/Area Number: 17H03597
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kyoto University
• Principal Investigator: Kamikubo Yasuhkiko 京都大学, 医学研究科, 特定教授 (60548527)
• Co-Investigator(Kenkyū-buntansha): 足立 壯一 京都大学, 医学研究科, 教授 (10273450)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2017: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: 人工遺伝子スイッチ法 / スパコンシミュレーション法 / RUNX / p300 / Ras Gene Module / RTK / 難治性白血病 / 肺癌 / 白血病 / 膵癌 / 大腸癌 / 脳腫瘍 / HAT / 悪性グリオブラストーマ / 前立腺癌 / スーパーエンハンサー / 遺伝子発現制御 / 癌増殖機構 / レセプターチロシンキナーゼ / シグナル伝達 / 人工知能 / マイクロ・ナノデバイス / 核酸 / 癌 / 発現制御

Outline of Final Research Achievements

A: Development of a common tumor growth mechanism (RGM: Ras Gene Module) control method using an artificial gene switch method
A RTK (Receptor Tyrosine Kinase) control method was discovered. The oncogene fusion control method was discovered. We have developed a novel solid tumor stem cell / tumor marker control method.
B: Simulation drug development using supercomputer K: Development of p300-RUNX1 inhibitor; Candidate inhibitors were extracted from various cancers (prostate cancer DNPC), TNBC lung cancer, Kras mutant colon cancer and pancreatic cancer. Through the construction of an innovative anti-tumor concept that overcomes the resistance of molecular target drugs by A.B, we have achieved a fusion development method of human-school gene switch method and supercomputer simulation method.

Academic Significance and Societal Importance of the Research Achievements

革新的な人工遺伝子スイッチ法によりRUNXを転写抑制することにより、RUNXのターゲット遺伝子を消失させることに成功した。これは世界には未だない方法である。スパコンシミュレーション法を用いて、RUNXとp300を同時に抑制できる低分子化合物を創薬計算し抽出した。この2つの方法を融合し、分子標的薬耐性を克服する革新的抗腫瘍コンセプトの構築を行ったことは学術的意義と社会的意義を有する。

Research Products

• [Journal Article] Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia (2018)
  • Author(s): Matsuo Hidemasa、Itonaga Hidehiro、et al.
  • Journal Title: Blood Advances Volume: 2 Issue: 21 Pages: 2879-2889
  • DOI: 10.1182/bloodadvances.2018019398
  • NAID: 120006534600
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification (2018)
  • Author(s): Uni Masahiro、Masamoto Yosuke、Sato Tomohiko、Kamikubo Yasuhiko、Arai Shunya、Hara Eiji、Kurokawa Mineo
  • Journal Title: Leukemia Volume: 33 Issue: 1 Pages: 191-204
  • DOI: 10.1038/s41375-018-0198-6
  • Peer Reviewed / Open Access
• [Journal Article] Genetic compensation of RUNX family transcription factors in leukemia. (2018)
  • Author(s): Kamikubo Y
  • Journal Title: Cancer Science Volume: Jun 8. Issue: 8 Pages: 123-134
  • DOI: 10.1111/cas.13664
  • Peer Reviewed / Open Access
• [Journal Article] RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells. (2018)
  • Author(s): Mitsuda Y, Morita K, Kashiwazaki G, Taniguchi J, Bando T, Obara M, Hirata M, Kataoka TR, Muto M, Kaneda Y, Nakahata T, Liu PP, Adachi S, Sugiyama H, Kamikubo Y.
  • Journal Title: Sci. Rep. Volume: 8 Issue: 1 Pages: 6423-6423
  • DOI: 10.1038/s41598-018-24969-w
  • NAID: 120006510275
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PAS positivity of erythroid precursor cells is associated with a poor prognosis in newly diagnosed myelodysplastic syndrome patients (2018)
  • Author(s): Masuda K, Shiga S, Kawabata H, Takaori-K A, Ichiyama S and Kamikubo Y
  • Journal Title: Int J Hematol. Volume: 108(1) Issue: 1 Pages: 30-38
  • DOI: 10.1007/s12185-018-2443-1
  • Peer Reviewed / Open Access
• [Presentation] Genetic regulation of RUNX2 induce apoptotic cell death through regulating the expression of SOX2 in CRPC-NE cells. (2018)
  • Author(s): Noguchi Y, Wariishi N, Iwai S, Kashiwazaki G, Taniguchi J, Bando T, Baba M, Adachi S, Sugiyama H and Kamikubo Y
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Paradoxical enhancement of AML through moderately attenuated RUNX1 expression. (2018)
  • Author(s): Okinaka E*, Kobayashi S*, Noguchi Y, Furuichi K, Suzuki Y, Iwai S, Shimada S, Iwai A, Sugiyama H, Adachi S and Kamikubo Y
  • Organizer: 第9回JSH国際シンポジウム（京都）
  • Int'l Joint Research
• [Presentation] Highly efficient elimination of p210-, p190-BCR-ABL protein through CROX strategy. (2018)
  • Author(s): Shimada S, Noguchi Y, Suzuki Y, Iwai S, Furuichi K, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第9回JSH国際シンポジウム（京都）
  • Int'l Joint Research
• [Presentation] Vascular niche regulation through RUNX1 attenuating E-selectin (2018)
  • Author(s): Noguchi Y, Suzuki Y, Furuichi K, Iwai S, Shimada S, Sugiyama H, Adachi S and Kamikubo Y
  • Organizer: 第9回JSH国際シンポジウム（京都）
  • Int'l Joint Research
• [Presentation] Novel anti-leukemia therapeutic strategy through CROX (Cluster regulation of RUNX family). (2018)
  • Author(s): Furuichi K, Noguchi Y, Suzuki Y, Iwai S, Shimada S, Iwai A, Sugiyama H, Adachi S and Kamikubo Y
  • Organizer: 第9回JSH国際シンポジウム（京都）
  • Int'l Joint Research
• [Presentation] CROX（Cluster regulation of RUNX）strategy for hematological malignancies. (2018)
  • Author(s): 上久保靖彦
  • Organizer: 日本血液学会 北陸地方会 金沢
  • Invited
• [Presentation] Apoptosis induced by CROX (Cluster regulation of RUNX) in neuroblastoma cells. (2018)
  • Author(s): Iwai S, Noguchi Y, Shimada S, Suzuki Y, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Regulation of HAT-X induces apoptotic cell death through regulating hypoxia mechanism in renal cell carcinoma and osteosarcoma cells. (2018)
  • Author(s): Takasaki S, Mikami M, Furuichi K, Iwai A, Obara M, Noguchi Y, Kanatani T, Suzuki Y, Kamikubo Y and Adachi S
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Vital role of RUNX1 both in the regulation of BCR-ABL expression and in the maintenance of CML cells (2018)
  • Author(s): Shimada S, Noguchi Y, Iwai S, Suzuki Y, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] The importance of novel “CROX: Cluster regulation of RUNX” approach for ErbB2/HER2 gastric cancer. (2018)
  • Author(s): Obara M, Takasaki S, Noguchi Y, Suzuki Y, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Genetic regulation of RUNX2-cancer stem cell marker X axis in CRPC-NE cells (2018)
  • Author(s): Noguchi Y, Wariishi N, Iwai S, Shimada S, Suzuki Y, Ohyama M, Matsui Y, SugiyamaH, Adachi S and Kamikubo Y
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Combinatorial Histone Acetyltransferases(HATs) inhibition as a potential therapeutic approach for pancreatic ductal adenocarcinoma (2018)
  • Author(s): Kobayashi S, Noguchi Y, Okinaka E, Wariishi N, Iwai S, Shimada S, Suzuki Y, OyamaY, Adachi S and Kamikubo Y
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Development of novel therapeutic strategy targeting Histone acetyltransferases for colorectal cancer (2018)
  • Author(s): Okinaka E, Noguchi Y, Kobayashi S, Iwai S, Shimada S, Suzuki Y, Oyama M, Adachi S and Kamikubo Y
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Cluster regulation of RUNX induces apoptotic cell death through regulating gene X in acute promyelocytic leukemia(APL). (2018)
  • Author(s): Furuichi K, Iwai A, Mikami M, Takasaki S, Obara M, Hattori E, Tatsuta T, Noguchi Y, Suzuki Y, Sugiyama H, Adachi S and Kamikubo Y
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Suppression of malignant rhabdoid tumors through novel drug based on“Gene Switch Technology” (2018)
  • Author(s): Mikami M, Daifu T, Kanatani T, Furuichi K, Takasaki S, Iwai A, Noguchi Y, Suzuki Y, Matsui Y, Hattori E, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] CROX (Cluster regulation of RUNX) induces apoptotic cell death through regulating Factor “X” in ATRA-resistance APL cells. (2018)
  • Author(s): Furuichi K, Iwai A, Mikami M, Takasaki S, Obara M, Hattori E, Noguchi Y, SugiyamaH, Adachi S and Kamikubo Y
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Inhibition of BCR-ABL expression through CROX (Cluster regulation of RUNX) (2018)
  • Author(s): Shimada S, Maeda S, Noguchi Y, Iwai S, Suzuki Y, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Histone acetyltransferases(HATs)コンビネーション制御による膵癌新規治療戦略の構築 (2018)
  • Author(s): 小林紫乃、野口勇貴、沖中えり佳、佐々木亜沙美、武田瑞穂、割石菜月、大山舞、鈴木雄太、足立壮一、上久保靖彦
  • Organizer: 第27回日本Cell Death学会学術集会
• [Presentation] CROXによるMRT制御法 (2018)
  • Author(s): 金谷卓弥＊、三上真充＊、大封智雄＊, 高崎作歩, 古市華菜, 野口勇貴, 杉山弘, 上久保靖彦, 足立壯一
  • Organizer: 第27回日本Cell Death学会学術集会
• [Presentation] 去勢抵抗性前立腺癌（神経内分泌型）：CRPC-NEに対する新規細胞死誘導法 (2018)
  • Author(s): 割石菜月＊、野口勇貴＊、杉山弘、上久保靖彦、足立壮一
  • Organizer: 第27回日本Cell Death学会学術集会
• [Presentation] 難治性白血病におけるRUNX1を介した不死化機構の解明 (2018)
  • Author(s): 立田俊也＊、古市華菜＊、野口勇貴、高崎作歩、上久保靖彦、足立壮一
  • Organizer: 第27回日本Cell Death学会学術集会
• [Presentation] CD146 is a potential therapeutic target in hepatoblastoma (2018)
  • Author(s): Sonoda M, Umeda K, Nodomi S, Obu S, Saida S, Kato I, Hiramatsu H, Ogawa E, Okamoto S, Morita K, Kamikubo Y, Adachi S, Nakahata T, Okajima H, Umemoto S, Takita J, and Heike T.
  • Organizer: 第60回日本小児血液がん学会学術総会
• [Presentation] Suppression of malignant rhabdoid tumors through novel drug based on “Gene Switch Technology” (2018)
  • Author(s): Miami M, Daifu T, Kanatani T, Furuichi K, Takasaki S, Iwai A, Umeda K, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第60回日本小児血液がん学会学術総会
• [Presentation] Inhibition of neuroblastoma through targeting the RUNX1-TRIM24/BCL11A-p53 axis (2018)
  • Author(s): Noguchi Y¶, Nakatani A¶, Iwai S, Suzuki Y, Shimada S, Mikami M, Umeda K, Sugiyama H, Adachi S and Kamikubo Y
  • Organizer: 第60回日本小児血液がん学会学術総会
• [Presentation] Analysis of the functional role of CBFB in leukemogenesis. (2018)
  • Author(s): Noura M, Morita K, Matsuo H, Sugiyama H, Kamikubo Y and Adachi S
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] UNX1と血液悪性疾患 (2018)
  • Author(s): 上久保靖彦
  • Organizer: JACLS総会
  • Invited
• [Remarks] 癌創薬イノベーション研究室
  • URL: http://www.med.kyoto-u.ac.jp/organization-staff/research/human_health/mt0303/
• [Remarks] 株式会社ReguGene
  • URL: https://www.regugene.co.jp/
• [Patent(Industrial Property Rights)] ＲＵＮＸ結合配列を標的とする医薬組成物およびＲＵＮＸ阻害剤 (2018)
  • Inventor(s): 杉山弘・上久保靖彦
  • Industrial Property Rights Holder: 杉山弘・上久保靖彦
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-101788
  • Filing Date: 2018
  • Overseas