Developing novel therapeutics for Translocation Renal Cell Carcinoma by sequence specific DNA alkylation

• Project/Area Number: 18K19619
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Baba Masaya 熊本大学, 国際先端医学研究機構, 准教授 (10347304)
• Co-Investigator(Kenkyū-buntansha): 杉山 弘 京都大学, 理学研究科, 教授 (50183843) ; 上久保 靖彦 京都大学, 医学研究科, 特定教授 (60548527)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 転座腎細胞癌 / 融合転写因子 / TFE3 / 抗がん剤 / 創薬 / コンセンサス配列 / 転座型腎細胞癌

Outline of Final Research Achievements

Chromosomal translocation derived fusion TFE3 drives genome wide aberrant transcription and causes Translocation Renal Cell Carcinoma (tRCC). In this research project, our goal was to develop a novel anti-cancer drug, which blocked fusion TFE3 target genes’ transcription by alkylating DNA containing fusion TFE3 recognition motifs. We evaluated the candidate drugs by measuring the inhibitory effect on fusion TFE3 target genes’ expression and selected the most promising candidate drug. The tRCC cell lines, which were treated with this candidate drug, demonstrated G2/M arrest followed by senescence and growth inhibition in a dose dependent manner.

Academic Significance and Societal Importance of the Research Achievements

転写因子を標的とした創薬はこれまで困難を極めて来た。本研究では、がんの原因となる異常な融合TFE3転写因子自体では無く、融合TFE3が結合する塩基配列を標的とするというこれまでに無い戦略をとり、薬剤の開発に挑んだ。その結果融合TFE3の転写標的遺伝子の発現を抑え、融合TFE3を発現している腎細胞がんの増殖を用量依存的に抑制する有望な薬剤候補分子を得ることができた。今後、異常な転写をゲノムワイドにブロックする画期的ながん治療薬開発への展開が期待される。

Research Products

• [Int'l Joint Research] National Cancer Institute, NIH/University of Washington(米国)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] National Cancer Institute, NIH(米国)
• [Int'l Joint Research] Cancer Science Institute of Singapore(シンガポール)
• [Journal Article] A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity (2020)
  • Author(s): Mitsuhiro Endoh, Masaya Baba, Tamie Endoh, Akiyoshi Hirayama, Ayako Nakamura-Ishizu, Terumasa Umemoto, Michihiro Hashimoto, Kunio Nagashima, Tomoyoshi Soga, Martin Lang , Laura S Schmidt , W Marston Linehan, Toshio Suda
  • Journal Title: Cell Reports Volume: 30 Issue: 6 Pages: 1823-1834
  • DOI: 10.1016/j.celrep.2020.01.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FLCN Alteration Drives Metabolic Reprogramming Towards Nucleotide Synthesis and Cyst Formation in Salivary Gland (2020)
  • Author(s): Isono Y, Furuya M, Kuwahara T, Sano D, Suzuki K, Jikuya R, Mitome T, Otake S, Kawahara T, Ito Y, Muraoka K, Nakaigawa N, Kimura Y, Baba M, Nagahama K, Takahata H, Saito I, Schmidt LS, Linehan WM, Kodama T, Yao M, Oridate N, Hasumi H.
  • Journal Title: Biochem Biophys Res Commun Volume: 522 Issue: 4 Pages: 931-938
  • DOI: 10.1016/j.bbrc.2019.11.184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity. (2019)
  • Author(s): Horiguchi H, Kadomatsu T, Kurahashi R, Hara C, Miyata K, Baba M, Osumi H, Terada K, Araki K, Takai T, Kamba T, Linehan WM, Moroishi T, Oike Y.
  • Journal Title: Genes Dev Volume: 33 Issue: 23-24 Pages: 1641-1656
  • DOI: 10.1101/gad.329417.119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3. (2019)
  • Author(s): Ramirez JA, Iwata T, Park H, Tsang M, Kang J, Cui K, Kwong W, James RG, Baba M, Schmidt LS, Iritani BM.
  • Journal Title: J Immunol. Volume: 203 Issue: 11 Pages: 2899-2908
  • DOI: 10.4049/jimmunol.1900395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. (2019)
  • Author(s): Baba M, Furuya M, Motoshima T, Lang M, Funasaki S, Ma W, Sun HW, Hasumi H, Huang Y, Kato I, Kadomatsu T, Satou Y, Morris N, Karim BO, Ileva L, Kalen JD, Wilan Krisna LA, Hasumi Y, Sugiyama A, Kurahashi R, Nishimoto K, Oyama M, Nagashima Y, Kuroda N, Araki K, Eto M, Yao M, Kamba T, Suda T, Oike Y, Schmidt LS, Linehan WM
  • Journal Title: Molecular Cancer Research Volume: 印刷中 Issue: 8 Pages: 1613-1626
  • DOI: 10.1158/1541-7786.mcr-18-1235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MiR-204-5p: a novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma. (2019)
  • Author(s): Kurahashi R, Kadomatsu T, Baba M, Hara C, Itoh H, Miyata K, Endo M, Morinaga J, Terada K, Araki K, Eto M, Schmidt LS, Kamba T, Linehan WM, Oike Y.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 6 Pages: 1897-1908
  • DOI: 10.1111/cas.14026
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RBM 10 ‐ TFE 3 Renal Cell Carcinoma Characterized by Paracentric Inversion with Consistent Closely Split Signals in Break‐apart Fluorescence in situ Hybridization: Study of Ten Cases and a Literature Review (2019)
  • Author(s): Kato Ikuma、Furuya Mitsuko、Baba Masaya、Kameda Yoichi、Yasuda Masanori、Nishimoto Koshiro、Oyama Masafumi、Yamasaki Toshinari、Ogawa Osamu、Niino Hitoshi、Nakaigawa Noboru、Yano Yuta、Sakamoto Kazumasa、Urata Yoji、Mikami Kazuya、Yamasaki Shigetaka、Tanaka Reiko、Takagi Toshio、Kondo Tsunenori、Nagashima Yoji
  • Journal Title: Histopathology Volume: 印刷中 Issue: 2 Pages: 254-265
  • DOI: 10.1111/his.13866
  • Peer Reviewed / Open Access
• [Journal Article] Editorial Comment to Annexin A1 expression is correlated with malignant potential of renal cell carcinoma. (2019)
  • Author(s): Baba M.
  • Journal Title: International Journal of Urology Volume: 26 Issue: 2 Pages: 291-291
  • DOI: 10.1111/iju.13899
  • Peer Reviewed / Open Access
• [Journal Article] Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation (2018)
  • Author(s): 3.Baba M, Endoh M, Ma W, Toyama H, Hirayama A, Nishikawa K, Takubo K, Hano H, Hasumi H, Umemoto T, Hashimoto M, Irie N, Esumi C, Kataoka M, Nakagata N, Soga T, Yao M, Kamba T, Minami T, Ishii M, and Suda T.
  • Journal Title: Journal of Bone and Mineral Research Volume: 33 Issue: 10 Pages: 1785-1798
  • DOI: 10.1002/jbmr.3477
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes (2018)
  • Author(s): Hasumi Hisashi、Furuya Mitsuko、Tatsuno Kenji、Aburatani Hiroyuki、Linehan W Marston、Yao Masahiro, et al.
  • Journal Title: Human Molecular Genetics Volume: 印刷中 Issue: 15 Pages: 2712-2724
  • DOI: 10.1093/hmg/ddy181
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Splice-site mutation causing partial retention of intron in the FLCN gene in Birt- Hogg-Dube syndrome: a case report (2018)
  • Author(s): Furuya M, Kobayashi H, Baba M, Ito T, Tanaka R, Nakatani Y
  • Journal Title: BMC Medical Genomics Volume: 42 Issue: 1 Pages: 42-42
  • DOI: 10.1186/s12920-018-0359-5
  • Peer Reviewed / Open Access
• [Presentation] TFE3再構成腎細胞癌32例の臨床病理学的解析(Clinicopathological Analyses of 32 Cases of TFE3-rearranged Renal Cell Carcinomas) (2019)
  • Author(s): 古屋 充子, 馬場 理也, 加藤 生真, 矢尾 正祐, 近藤 恒徳, 長嶋 洋治
  • Organizer: 日本癌学会総会
• [Presentation] Xp11転座型腎細胞癌と診断された7例の免疫染色によるPD-L1及びPD-L2の発現解析 (2019)
  • Author(s): 上園 英太, 馬場 理也, 菰原 義弘, 黒田 直人, 元島 崇信, 神波 大己
  • Organizer: 腎癌研究会
• [Presentation] 腕内逆位(paracentric inversion)によって融合するRBM10-TFE3腎細胞癌10例の病態解析 (2019)
  • Author(s): 古屋 充子, 馬場 理也, 加藤 生真, 安田 政実, 西本 紘嗣郎, 小山 政史, 山崎 俊成, 小川 修, 中井川 昇, 蓮見 壽史, 坂本 和優, 三神 一哉, 高木 敏男, 近藤 恒徳, 矢尾 正祐, 長嶋 洋治
  • Organizer: 腎癌研究会
• [Presentation] Xp11.2転座腎細胞癌モデルマウスの解析による新規治療標的分子の同定 (2019)
  • Author(s): 馬場 理也, 元島 崇信, 馬 文娟, 蓮見 壽史, 佐藤 賢文, 古屋 充子, 長嶋 洋治, 矢尾 正祐, 尾池 雄一, Schmidt Laura S, Linehan W. Marston, 神波 大己
  • Organizer: 日本泌尿器科学会総会
• [Presentation] Metabolic regulation by TFE3 in cell proliferation and differentiation (2019)
  • Author(s): Masaya Baba
  • Organizer: The 2nd KU-KAIST Joint Symposium
  • Int'l Joint Research
• [Presentation] Molecular Characteristics of Renal Cell Carcinomas in Patients with Birt-Hogg-Dube Syndrome (2018)
  • Author(s): Mitsuko Furuya, Hasumi Hisashi, Ikuma Kato, Masaya Baba, Yoji Nagashima, Yasuhiro Iribe, Yukio Nakatani, Masahiro Yao
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Genetic, epidemiologic and clinicopathologic studies of Japanese patients with Birt-Hogg-Dube syndrome, 2018 update (2018)
  • Author(s): Yasuhiro Iribe, Masahiro Yao, Yoji Nagashima, Masaya Baba, Yukio Nakatani, Mitsuko Furuya
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Studies to uncover the molecular mechanism for cancer development in Xp11. 2 translocation renal cell carcinoma (2018)
  • Author(s): Masaya Baba, Wenjaun Ma, Takanobu Motoshima, Yorifumi Satou, Hisashi Hasumi, Tsuyoshi Kadomatsu, Mitsuko Furuya, Yoji Nagashima, Masahiro Yao, Masatoshi Eto, W Marston Linehan, Yuichi Oike, Tomomi Kamba
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] translocation renal cell carcinoma (2018)
  • Author(s): Ryoma Kurahashi, Tsuyoshi Kadomatsu, Masaya Baba, Chiaki Hara, Motoyoshi Endo, Yuichi Oike, Tomomi Kamba
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Clinicopathological Analyses of 17 Cases of Xp11Translocation Renal Cell Carcinomas (2018)
  • Author(s): Mitsuko Furuya, Masaya Baba, Ikuma Kato, Tsunenori Kondo, Yoji Nagashima, Takao Kamai, Toshinari Yamasaki, Osamu Ogawa, Koushiro Nishimoto, Masafumi Koyama, Tomomi Kamba, Takanobu Motoshima, Masatoshi Eto
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Regulation of hypoxia response pathway by chimeric TFE3s in Xp11. 2 translocation renal cell carcinoma (2018)
  • Author(s): Wenjuan Ma, Takanobu Motoshima, Yorifumi Satou, Hisashi Hasumi, Tsuyoshi Kadomatsu, Ryoma Kurahashi, Mitsuko Furuya, Masahiro Yao, Laura S Schmidt, W Marston Linehan, Yuichi Oike, Tomomi Kamba, Masaya Baba
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Characterization of chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma (2018)
  • Author(s): Takanobu Motoshima, Yorifumi Satou, Paola Miyazato, Hisashi Hasumi, Ying Huang, Tsuyoshi Kadomatsu, Masahiro Yao, Yoji Nagashima, Mitsuko Furuya, Yuchi Oike, Laura S Schmidt, Tomomi Kamba, W Marston Linehan, Masaya Baba
  • Organizer: American Urological Association's 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] Genetic regulation of RUNX2 induce apoptotic cell death through regulating the expression of SOX2 in CRPC-NE cells (2018)
  • Author(s): Yuki Noguchi, Natsuki Wariishi, Shiina Iwai, Gengo Kashiwazaki, Junichi Taniguchi, Toshikazu Bando, Masaya Baba, Souichi Adachi, Hiroshi Sugiyama, Yasuhiko Kamikubo
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of mutations in chromatin remodeling genes (2018)
  • Author(s): Ryosuke Jikuya, Mitsuko Furuya, Masaya Baba, Hiroyuki Aburatani, Adam R Metwalli, Laura S Schmidt, W Marston Linehan, Masahiro Yao, Hisashi Hasumi
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Xp11.2転座型腎細胞癌で認めるキメラTFE3転写因子の機能解析 (2018)
  • Author(s): 馬場理也、元島崇信、馬 文娟、蓮見壽史、黄 榮、佐藤賢文、宮里パオラ、長嶋洋治、古屋充子、矢尾正祐、神波大己
  • Organizer: 第106回日本泌尿器科学会総会
• [Remarks] International Research Center for Medical Sciences
  • URL: http://ircms.kumamoto-u.ac.jp/