がん創薬部

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研究テーマ

がん創薬部は、有効な新規がん治療薬の開発を目指して、免疫療法や遺伝子治療などの先端的がん治療に関する基礎的・検証的研究を行うために創設されました。その目的を達成するために、病院の各部門と密接な協力関係を構築し、様々な形で共同研究を進めるとともに、それらの活動を通して次世代を担う専門的人材を育成してゆきます。プロジェクトの概要は下記のとおりです。

1.がん患者における免疫動態の解析とその知見の臨床への還元
がん免疫療法は、いろいろなタイプのがんでその効果が検証されており、悪性黒色腫、肺がん、胃がんなどでは、すでに承認薬となっているものがあります。しかし、これらの治療を、どのような患者に、併用薬も含めどのような方法で使用するべきなのか、不明な点がまだ多く残されています。そこで当研究部では、がん患者さんの治療前・中・後の免疫動態を詳細に検討することにより、より効果的な治療法の開発に貢献することを目標として研究を進めてゆきます。

2.新規治療法の臨床開発
基礎研究のレベルでは、有望なさまざまながん治療法が考案され検討されています。本研究部では、特に免疫調節（チェックポイント）にかかわる分子の制御による治療法と、腫瘍溶解性ウイルス療法に重点を置き、これらの治療法が一日でも早く実用化され有効な新規治療法となるように、臨床に近い部分に焦点を当てて検討を進めてゆきます。
 
主な研究業績

• Kimura T, Akazawa T, Mizote Y, Nakamura H, Sakaue M, Maniwa T, Shintani Y, Honma K, Tahara H, Okami J. Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma. Int J Clin Oncol. 2024 Jun;29(6):771-779.
• Mizote Y, Inoue T, Akazawa T, Kunimasa K, Tamiya M, Kumamoto Y, Tsuda A, Yoshida S, Tatsumi K, Ekawa T, Honma K, Nishino K, Tahara H. Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG-E8. Cancer Sci. 2024 Apr;115(4):1114-1128.
• Tatsumi K, Wada H, Hasegawa S, Asukai K, Nagata S, Ekawa T, Akazawa T, Mizote Y, Okumura S, Okamura R, Ohue M, Obama K, Tahara H. Prediction for oxaliplatin-induced liver injury using patient-derived liver organoids. Cancer Med. 2024 Feb;13(3):e7042.
• Watanabe S, Takagi A, Yuba E, Kojima C, Dei N, Matsumoto A, Tanikawa J, Kawamura T, De Silva NH, Izawa T, Akazawa T, Kanegi R, Hatoya S, Inaba T, Sugiura K. In vivo transfection of cytokine genes into tumor cells using a synthetic vehicle promotes antitumor immune responses in a visceral tumor model. FASEB J. 2023 Nov;37(11):e23228.
• Kukita Y, Kunimasa K, Akazawa T, Mizote Y, Tahara H. A Method for Extending Target Regions of Genomic Profiling by Combining a Custom Probe Pool with a Commercial Targeted Panel. J Appl Lab Med. 2023 Nov 2;8(6):1065-1073.
• Harada Y, Mizote Y, Suzuki T, Hirayama A, Ikeda S, Nishida M, Hiratsuka T, Ueda A, Imagawa Y, Maeda K, Ohkawa Y, Murai J, Freeze HH, Miyoshi E, Higashiyama S, Udono H, Dohmae N, Tahara H, Taniguchi N. Metabolic clogging of mannose triggers dNTP loss and genomic instability in human cancer cells. Elife. 2023 Jul 18;12:e83870.
• Oya K, Nakamura Y, Watanabe R, Tanaka R, Ichimura Y, Kubota N, Matsumura Y, Tahara H, Okiyama N, Fujimoto M, Nomura T, Fujisawa Y. Eribulin mesylate exerts antitumor effects via CD103. Oncoimmunology. 2023 May 27;12(1):2218782.
• Tatsuguchi T, Uruno T, Sugiura Y, Sakata D, Izumi Y, Sakurai T, Hattori Y, Oki E, Kubota N, Nishimoto K, Oyama M, Kunimura K, Ohki T, Bamba T, Tahara H, Sakamoto M, Nakamura M, Suematsu M, Fukui Y. Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells. Int Immunol. 2022 Apr 20;34(5):277-289.
• Watanabe S, Yuba E, Akazawa T, Wijewardana V, Kakihara Y, Azuma A, Hagimori K, Kanegi R, Hatoya S, Inoue N, Inaba T, Sugiura K. Potent adjuvant effect elicited for tumor immunotherapy by a liposome conjugated pH-sensitive polymer and dendritic cell-targeting Toll-like-receptor ligand. Vaccine. 2022 Mar 1;40(10):1448-1457.
• Ucche S, Yokoyama S, Mojic M, Oki K, Ohshima C, Tsuihiji H, Takasaki I, Tahara H, Hayakawa Y. GSTA4 governs melanoma immune resistance and metastasis. Mol Cancer Res. 2022 Sep 27:MCR-22-0369.
• Ikezawa K, Ekawa T, Hasegawa S, Kai Y, Takada R, Yamai T, Fukutake N, Ogawa H, Akazawa T, Mizote Y, Tatsumi K, Nagata S, Asukai K, Takahashi H, Ohkawa K, Tahara H. Establishment of organoids using residual samples from saline flushes during endoscopic ultrasound-guided fine-needle aspiration in patients with pancreatic cancer. Endosc Int Open. 2022 Jan 11;10(1):E82-E87.
• Kunimasa K, Okami J, Takenaka S, Honma K, Kukita Y, Nagata S, Kawamura T, Inoue T, Tamiya M, Kuhara H, Nishino K, Tahara H, Kumagai T. Conversion Surgery for Advanced Thoracic SMARCA4-Deficient Undifferentiated Tumor With Atezolizumab in Combination With Bevacizumab, Paclitaxel, and Carboplatin Treatment: A Case Report. JTO Clin Res Rep. 2021 Oct 6;2(11):100235.
• Mojic M, Shitaoka K, Ohshima C, Ucche S, Lyu F, Hamana H, Tahara H, Kishi H, Hayakawa Y. NKG2D defines tumor-reacting effector CD8+ T cells within tumor microenvironment. Cancer Sci. 2021 Sep;112(9):3484-3490.
• Kawachi H, Kunimasa K, Kukita Y, Nakamura H, Honma K, Kawamura T, Inoue T, Tamiya M, Kuhara H, Nishino K, Mizote Y, Akazawa T, Tahara H, Kumagai T. Atezolizumab with bevacizumab, paclitaxel and carboplatin was effective for patients with SMARCA4-deficient thoracic sarcoma. Immunotherapy. 2021 Jul;13(10):799-806.
• Harada Y, Kazama S, Morikawa T, Sonoda H, Ishi H, Emoto S, Murono K, Kaneko M, Sasaki K, Shuno Y, Nishikawa T, Tanaka T, Kawai K, Hata K, Nozawa H, Ushiku T, Tahara H, Ishihara S. Clinical significance of CD8+ and FoxP3+ tumor-infiltrating lymphocytes and MFG-E8 expression in lower rectal cancer with preoperative chemoradiotherapy. Mol Clin Oncol. 2021 May;14(5):87.
• Fujimoto M, Kamiyama M, Fuse K, Ryuno H, Odawara T, Furukawa N, Yoshimatsu Y, Watabe T, Prchal-Murphy M, Sexl V, Tahara H, Hayakawa Y, Sato T, Takeda K, Naguro I, Ichijo H. ASK1 suppresses NK cell-mediated intravascular tumor cell clearance in lung metastasis. Cancer Sci. 2021 Apr;112(4):1633-1643.
• Ikeda H, Uchida H, Okubo Y, Shibata T, Sasaki Y, Suzuki T, Hamada-Uematsu M, Hamasaki R, Okuda K, Yamaguchi M, Kojima M, Tanaka M, Hamada H, Tahara H. Antibody Screening System Using a Herpes Simplex Virus (HSV)-Based Probe To Identify a Novel Target for Receptor-Retargeted Oncolytic HSVs. J Virol. 2021 Apr 12;95(9):e01766-20.
• Shiga M, Miyazaki J, Tanuma K, Nagumo Y, Yoshino T, Kandori S, Negoro H, Kojima T, Tanaka R, Okiyama N, Fujisawa Y, Watanabe M, Yamasaki S, Kiyohara H, Watanabe M, Sato TA, Tahara H, Nishiyama H, Yano I. The liposome of trehalose dimycolate extracted from M. bovis BCG induces antitumor immunity via the activation of dendritic cells and CD8+ T cells. Cancer Immunol Immunother. 2021 Sep;70(9):2529-2543.
• Miyazato K, Tahara H, Hayakawa Y. Antimetastatic effects of　thalidomide by inducing the functional maturation of peripheral natural killer cells. Cancer Science 111:2770-2778, 2020
• Yamazaki N, Kiyohara Y, Uhara H, Iizuka H, Uehara J, Otsuka F, Fujisawa Y, Takenouchi T, Isei T, Iwatsuki K, Uchi H, Ihn H, Minami H, Tahara H. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase II study for advanced melanoma. Cancer Science 108:1022-1031, 2017.
• Okubo Y, Uchida H, Wakata A, Suzuki T, Shibata T, Ikeda H, Yamaguchi M, Cohen JB, Glorioso JC, Tagaya M, Hamada H, and Tahara H. Syncytial Mutations Do not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus. J Virol. 2016 Nov 28; 90(24):11096-11105.
• Ma Z, Li W, Yoshiya S, Xu Y, Hata M, Eldaravish Y, Markova T, Yamanishi K, Yamanishi H, Tahara H, Tanaka Y, and Okamura H. Augmentation of immune checkpoint blockade therapy with IL-18. Clin Cancer Res. 2016 22(12):2969-80.
• Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, Yagita H, Takaoka A, Tahara H. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A. 108:12425-30. 2011
• Jinushi M, Sato M, Kanamoto A, Itoh A, Nagai S, Koyasu S, Dranoff G, and Tahara H. Milk Fat Globule EGF-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms. J Exp. Med. 206:1317-1326, 2009
• Wada S, Tsunoda T, Baba T, Primus FJ, Kuwano H, Shibuya M, Tahara H. Rationale for anti-angiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2 (VEGFR2). Cancer Research, 65: 4939-4946, 2005.
• Tani K, Azuma M, Nakazaki Y, Oyaizu N, Hase H, Ohata J, Takahashi K, OiwaMonna M, Hanazawa K, Wakumoto Y, Kawai K, Noguchi M, Soda Y, Kunisaki R, Watari K, Takahashi S, Machida U, Satoh N, Tojo A, Maekawa T, Eriguchi M, Tomikawa S, Tahara H, Inoue Y, Yoshikawa H, Yamada Y, Iwamoto A, Hamada H, Yamashita N, Okumura K, Kakizoe T, Akaza H, Fujime M, Clift S, Ando D, Mulligan R, Asano S. Phase I study of autologous tumor vaccines transduced with the GM-CSF gene in four patients with stage IV renal cell cancer in Japan: clinical and immunological findings. Mol Ther. 10:799-816, 2004.