Nuclear receptors: possible therapeutic targets in combination with HDAC inhibitors for cutaneous T-cell lymphoma

• Project/Area Number: 16K10166
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Kagoshima University
• Principal Investigator: Fujii Kazuyasu 鹿児島大学, 医歯学域附属病院, 講師 (70452571)
• Co-Investigator(Kenkyū-buntansha): 近藤 格 国立研究開発法人国立がん研究センター, 研究所, 分野長 (30284061)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: HDAC阻害剤 / チロシンキナーゼ / 核内受容体 / 皮膚T細胞リンパ腫 / キナーゼ活性 / レチノイド / 核内受容体作動薬

Outline of Final Research Achievements

Current therapeutic options for advanced cutaneous T-cell lymphoma (CTCL) are inefficient and there are unmet needs for the novel efficient treatment. The histone deacetylase inhibitors (HDACi) are emerging therapeutic agents for CTCL, while their effects as monotherapy for patients with CTCL are limited. In this study, we focused on nuclear receptors as the targets of combination therapy with HDACi, because HDACi change chromatin structure and may modify the function of the nuclear receptor response elements. We performed the exhaustive protein kinase assay using HDACi and the screening assay using some nuclear receptor agonist with HDACi, and found that HDACi affected some nuclear receptor tyrosine kinase activities; a vitamin D receptor agonist and progesterone receptor agonist and antagonist enhanced HDACi-induced anti-proliferative effects. In conclusion, nuclear receptors are possible therapeutic targets of combination therapy with HDACi for CTCL.

Academic Significance and Societal Importance of the Research Achievements

進行期皮膚T細胞リンパ腫の治療はいずれも短期的な効果しか期待できない。ヒストン脱アセチル化酵素阻害剤は皮膚T細胞リンパ腫などの新規治療薬で、これまでの治療薬と異なるメカニズムで抗腫瘍効果を示すため治療戦略の中心となりうるが、単剤での効果は限られている。本研究で核内受容体作動薬やチロシンキナーゼ阻害剤にHDAC阻害剤の抗腫瘍効果を増強する作用があることが明らかになったことで、将来的な新規治療法の開発につながる可能性がある。

Research Products

• [Journal Article] Vulvitis granulomatosa in a patient with Crohn's disease. (2019)
  • Author(s): Katsue H, Fujii K, Nishibaba R, Higashi Y, Kanekura T.
  • Journal Title: Dermatologica Sinica. Volume: -
  • Peer Reviewed
• [Journal Article] New Therapies and Immunological Findings in Cutaneous T-Cell Lymphoma (2018)
  • Author(s): Fujii Kazuyasu
  • Journal Title: Frontiers in Oncology Volume: 8 Pages: 198-198
  • DOI: 10.3389/fonc.2018.00198
  • Peer Reviewed / Open Access
• [Journal Article] HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors. (2018)
  • Author(s): Fujii K, Suzuki N, Jimura N, Idogawa M, Kondo T, Iwatsuki K, Kanekura T.
  • Journal Title: J Dermatol Sci Volume: 90 Issue: 1 Pages: 82-89
  • DOI: 10.1016/j.jdermsci.2018.01.002
  • Peer Reviewed
• [Journal Article] Ethosuximide-induced Stevens-Johnson syndrome: Beneficial effect of early intervention with high-dose corticosteroid therapy (2018)
  • Author(s): Tachibana Kota、Hamada Toshihisa、Tsuchiya Hiroki、Shibata Takashi、Fujii Kazuyasu、Kobayashi Katsuhiro、Iwatsuki Keiji
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 5 Pages: 592-595
  • DOI: 10.1111/1346-8138.14253
  • Peer Reviewed
• [Journal Article] Comparison of oxidative stress on DNA, protein and lipids in patients with actinic keratosis, Bowen's disease and squamous cell carcinoma (2018)
  • Author(s): Yoshifuku Asuka、Fujii Kazuyasu、Kanekura Takuro
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 11 Pages: 1319-1323
  • DOI: 10.1111/1346-8138.14631
  • Peer Reviewed
• [Journal Article] Hypohidrotic ectodermal dysplasia with strabismus (2018)
  • Author(s): Okubo Aoi、Fujii Kazuyasu、Arimura Akiko、Katsue Hiromi、Higashi Yuko、Shimomura Yutaka、Kanekura Takuro
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 7
  • DOI: 10.1111/1346-8138.14252
  • Peer Reviewed
• [Journal Article] Idiopathic thrombocytopenic purpura in a patient with IgG4-related disease (2018)
  • Author(s): Jimura N.、Fujii K.、Higashi Y.、Kanekura T.
  • Journal Title: Clinical and Experimental Dermatology Volume: 43 Issue: 8 Pages: 941-943
  • DOI: 10.1111/ced.13688
  • Peer Reviewed
• [Journal Article] S?zary syndrome in an anti-human T-cell lymphotropic virus type 1 seropositive carrier (2018)
  • Author(s): Baba Naoko、Fujii Kazuyasu、Nomoto Yusuke、Jimura Nozomi、Higashi Yuko、Takami Satoko、Masamoto Izumi、Yonekura Kentaro、Mera Kentaro、Kanekura Takuro
  • Journal Title: The Journal of Dermatology Volume: 46 Issue: 1
  • DOI: 10.1111/1346-8138.14522
  • Peer Reviewed
• [Journal Article] A case of bullous pemphigoid associated with lichen sclerosus et atrophicus (2018)
  • Author(s): Yoshifuku Asuka、Okubo Aoi、Jimura Nozomi、Fujii Kazuyasu、Higashi Yuko、Kanekura Takuro
  • Journal Title: Indian Journal of Dermatology Volume: 63 Issue: 5 Pages: 427-427
  • DOI: 10.4103/ijd.ijd_127_18
  • Peer Reviewed / Open Access
• [Journal Article] Secondary skin involvement by systemic de novo CD5-positive diffuse large B-cell lymphoma. (2018)
  • Author(s): Baba N, Fujii K, Ibusuki A, Higashi Y, Kawai K, Kanekura T.
  • Journal Title: J. Dermatol. Volume: 45 Issue: 1
  • DOI: 10.1111/1346-8138.14082
  • Peer Reviewed
• [Journal Article] Spontaneous regression of a primary cutaneous diffuse large B-cell lymphoma, leg type. (2017)
  • Author(s): Jimura N, Fujii K, Baba A, Higashi Y, Kanekura T.
  • Journal Title: J Dermatol Volume: - Issue: 5 Pages: 608-609
  • DOI: 10.1111/1346-8138.13496
  • Peer Reviewed
• [Journal Article] Lymphomatoid granulomatosis initially presenting as ulcerated subcutaneous and muscle lesions without pulmonary involvement (2017)
  • Author(s): Higashi Y, Yoshioka T, Kawai K, Fujii K, Yoshimitsu M, Kusuyama J, Shima K, Tanimoto A, Kanekura T.
  • Journal Title: Journal of Dermatology Volume: 44 Issue: 5 Pages: 107-108
  • DOI: 10.1111/1346-8138.13712
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pyodermatitis vegetans with antibodies to bullous pemphigoid antigen 180. (2017)
  • Author(s): Kawahira H, Higashi Y, Matsuoka A, Fujii K, Ishii N, Hashimoto T, Kanekura T.
  • Journal Title: J Dermatol Volume: - Issue: 12 Pages: 1417-1418
  • DOI: 10.1111/1346-8138.13703
  • Peer Reviewed
• [Journal Article] Kimura's disease in the oral cavity: A rare manifestation of immunoglobulin G4-related disease. (2017)
  • Author(s): Okubo A, Fujii K, Kondo T, Semba I, Higashi Y, Kanekura T.
  • Journal Title: J. Dermatol. Volume: 44 Issue: 12
  • DOI: 10.1111/1346-8138.14021
  • Peer Reviewed
• [Journal Article] Infiltration of PD-1-positive cells in combination with tumor site PD-L1 expression is a positive prognostic factor in cutaneous angiosarcoma. (2017)
  • Author(s): Honda Y, Otsuka A, Ono S, Yamamoto Y, Seidel JA, Morita S, Hirata M, Kataoka TR, Takenouchi T, Fujii K, Kanekura T, Okubo Y, Takahashi K, Yanagi T, Hoshina D, Hata H, Abe R, Fujimura T, Funakoshi T, Yoshino K, Masuzawa M, Amoh Y, Tanaka R, Fujisawa Y, Honda T, Kabashima K.
  • Journal Title: Oncoimmunology. Volume: 6 Issue: 1 Pages: e1253657-e1253657
  • DOI: 10.1080/2162402x.2016.1253657
  • Peer Reviewed / Open Access
• [Journal Article] Romidepsin and azacitidine synergize in their epigenetic modulatory effects to induce apoptosis in CTCL. (2016)
  • Author(s): Rozati S, Cheng PF, Widmer DS, Fujii K, Levesque MP, Dummer R.
  • Journal Title: Clin Cancer Res Volume: 22 Issue: 8 Pages: 2020-2031
  • DOI: 10.1158/1078-0432.ccr-15-1435
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Psoriasis with verrucous appearance. (2016)
  • Author(s): Baba A, Fujii K, Arimura A, Tada K, Higashi Y, Matsushita S, Kanekura T.
  • Journal Title: Int J Dermatol Volume: 55 Issue: 7
  • DOI: 10.1111/ijd.13243
  • Peer Reviewed
• [Journal Article] Long-lasting Localized Pemphigus Vulgaris without Detectable Serum Autoantibodies Against Desmoglein 3 and Desmoglein 1. (2016)
  • Author(s): Yoshifuku A, Fujii K, Kawahira H, Katsue H, Baba A, Higashi Y, Aoyama Y, Kanekura T.
  • Journal Title: Indian J Dermatol Volume: 61 Issue: 4 Pages: 427-429
  • DOI: 10.4103/0019-5154.185712
  • Peer Reviewed
• [Presentation] Spontaneous regression of primary cutaneous diffuse large B-cell lymphoma, leg type, with multiple lesions. (2018)
  • Author(s): K. Fujii, N. Jimura, A. Okubo, M. Sakanoue, Y. Uchida, Y. Higashi, H. Kawabata, T. Kanekura.
  • Organizer: EORTC CLTF Meeting St.Gallen 2018.
  • Int'l Joint Research
• [Presentation] HDAC阻害剤の併用療法のターゲットとしてのHSP72の可能性 (2018)
  • Author(s): 藤井 一恭、地村 望、近藤 格、金蔵拓郎
  • Organizer: 第29回南九州腫瘍研究会
• [Presentation] 敗血疹により皮膚病変が誘発された急性型成人T細胞白血病/リンパ腫 (2018)
  • Author(s): 藤井一恭、内田洋平、有村亜希子、東裕子、有馬直佑、吉満誠、石塚賢治、金蔵拓郎
  • Organizer: 第5回日本HTLV-1学会
• [Presentation] Omenn症候群の1例 (2018)
  • Author(s): 藤井一恭、指宿敦子、西川拓朗、河野嘉文、金蔵拓郎
  • Organizer: 第275回日本皮膚科学会岡山地方会
• [Presentation] 生検で多くの病変が消退した多発性皮膚原発びまん性大細胞型B細胞リンパ腫 (2018)
  • Author(s): 藤井一恭、大久保 葵、有村亜希子、坂ノ上正直、内田洋平、東 裕子、川畑 久、金蔵拓郎
  • Organizer: 第273回日本皮膚科学会岡山地方会 藤本亘教授、岩月啓氏教授合同退任記念地方会 第85回総会
• [Presentation] Src is a possible therapeutic pathway in combination with HDAC inhibitors for CTCL. (2017)
  • Author(s): Fujii K, Jimura N, Qiao Z, Oyama R, Kito F, Kondo T, Kanekura T.
  • Organizer: EORTC CLTF MEETING LONDON 2017
  • Int'l Joint Research
• [Presentation] 皮膚病変を有するATLの治療 (2017)
  • Author(s): 藤井一恭
  • Organizer: 第33回日本皮膚悪性腫瘍学会学術大会
  • Invited
• [Presentation] 高濃度グルコース局所塗布によるClaudin-1およびFilaggrinの発現誘導：皮膚成人T細胞白血病との鑑別を要したセザリー症候群 (2017)
  • Author(s): 地村 望、藤井一恭、馬場直子、野元裕輔、松岡温子、有村亜希子、東 裕子、高味聡子、政元いずみ、米良健太郎、金蔵拓郎
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] Src pathway is a possible therapeutic target, in combination with HDACi, for CTCL. (2017)
  • Author(s): Jimura N, Fujii K, Kyou S, Oyama R, Kondo T, Kanekura T.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] CTCLにおいてSrc経路はHDAC阻害薬との併用ターゲットとなり得る (2017)
  • Author(s): 地村 望、藤井一恭、喬 志偉、紀藤房子、小山恵理子、近藤 格、金蔵拓郎
  • Organizer: 南九州腫瘍研究会第28回学術集会
• [Presentation] 皮下結節を呈したInterstitial type granuloma annulareの1例 (2017)
  • Author(s): 地村 望、藤井一恭、米良健太郎、東 裕子、金蔵拓郎
  • Organizer: 第69回日本皮膚科学会西部支部学術大会
• [Presentation] 皮膚T細胞リンパ腫においてSrc経路はHDAC阻害薬との併用ターゲットになる得る (2017)
  • Author(s): 藤井一恭、地村 望、喬 志偉、小山理恵子、紀藤房子、近藤 格、金蔵拓郎
  • Organizer: 第68回日本電気泳動学会総会
• [Presentation] Src pathway as a potential therapeutic target in combination with histone deacetylase inhibitors for cutaneous T-cell lymphoma. (2017)
  • Author(s): Fujii K, Jimura N, Kyou S, Oyama R, Kitou F, Kondo T, Kanekura T
  • Organizer: 日本研究皮膚科学会第42回年次学術大会・総会
• [Presentation] Long lasting localized pemphigus vulgaris without detectable anti-desmoglein antibodies, subsequent to systemic form. (2016)
  • Author(s): K. Fujii, A.Yoshifuku, H. Kawahira, H. Katsue, A. Baba, Y. Higashi, Y. Aoyama, T. Kanekura.
  • Organizer: 4th Eastern Asia Dermatology Congress
  • Place of Presentation: 東京ベイ舞浜ホテル クラブリゾート（千葉県浦安市）
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] 皮膚 T 細胞リンパ腫と HDAC 阻害剤 (2016)
  • Author(s): 藤井一恭
  • Organizer: 第80回日本皮膚科学会東部支部学術大会
  • Place of Presentation: アクトシティ浜松（静岡県浜松市）
  • Year and Date: 2016-10-29
• [Presentation] Proteomic analysis identified heat shock protein 72 as a possible target of combination therapy with histone deacetylase inhibitor. (2016)
  • Author(s): K Fujii, T Kondo, T Kanekura.
  • Organizer: 15th Human Proteome Organization World Congress
  • Place of Presentation: 台北市（台湾）
  • Year and Date: 2016-09-18
• [Presentation] 2D-DIGEを用いたヒストン脱アセチリ化酸素阻害剤の併用療法のターゲットの同定 (2016)
  • Author(s): 藤井一恭
  • Organizer: 第67回日本電気泳動学会総会
  • Place of Presentation: 釧路市観光国際交流センター（北海道釧路市）
  • Year and Date: 2016-08-26
• [Book] 皮膚リンパ腫アトラス 改訂・改題第3版 (2017)
  • Author(s): 藤井一恭
  • Total Pages: 244
  • Publisher: 文光堂
  • ISBN: 9784830634659
• [Book] Cutaneous Lymphomas. In: Immunology of the Skin: Basic and Clinical Sciences in Skin Immune Responses. (2016)
  • Author(s): Simone M. Goldinger, Emmanuella Guenova, Fujii K, Mirjana Urosevic-Maiwald.
  • Total Pages: 501
  • Publisher: Springer