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Featured researches published by Hidenori Fujita.


Molecular Cancer Therapeutics | 2013

The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile.

Hidenori Fujita; Kazutaka Miyadera; Masanori Kato; Yayoi Fujioka; Hiroaki Ochiiwa; Jinhong Huang; Kimihiro Ito; Yoshimi Aoyagi; Toru Takenaka; Takamasa Suzuki; Satoko Ito; Akihiro Hashimoto; Takashi Suefuji; Kosuke Egami; Hideki Kazuno; Yoshimitsu Suda; Kazuto Nishio; Kazuhiko Yonekura

VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI50 > 10 μmol/L) in VEGFR signal- or MET signal-independent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer–bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685–96. ©2013 AACR.


Molecular Cancer Therapeutics | 2013

Abstract A270: TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities.

Hiroaki Ochiiwa; Hidenori Fujita; Kimihiro Itoh; Hiroshi Sootome; Akihiro Hashimoto; Yayoi Fujioka; Yoko Nakatsuru; Nobuyuki Oda; Kazuhiko Yonekura; Hiroshi Hirai; Teruhiro Utsugi

Background: FGFs (fibroblast growth factors) and their receptors (FGFRs) play crucial roles in regulation of cell proliferation, survival, migration and differentiation. The FGFRs are comprised of four subtypes (FGFR1∼4) and their gene abnormalities such as gene amplification, translocation and mutations have been reported in multiple cancers including breast, bladder, lung, gastric, endometrial and multiple myeloma. We have identified a highly potent and selective irreversible FGFR inhibitor, TAS-1201) which inhibits all 4 subtypes of FGFR. In this report, we present the in vitro efficacy of this compound in tumor cells harboring the various FGFR gene abnormalities. In addition, we present the antitumor efficacy and pharmacodynamic (PD) activity of in vivo xenograft models. Materials and Methods: For a growth inhibition assay, various tumor cells with FGFR gene abnormalities were treated with TAS-120 for 3 days, and living cells were determined by using CellTiter-Glo™ which measures cellular ATP. Cellular phosphorylation of FGFR and its inhibition by TAS-120 were assayed using ELISA (R&D Systems) or western blotting method. For analysis of in vivo antitumor efficacy, various tumor cell lines were subcutaneously implanted into the side flank of nude mice. Dosing of compound was started when transplanted tumor size reached > ∼ 200 mm3 and tumor size was measured with digital calipers for the entire treatment period. To confirm target engagement by TAS-120 in human tumor xenograft models, we determined FGFR phosphorylation in tumor as a pharmacodynamic marker. FGFR phoshorylation in tumor was determined by ELISA or western blotting. Results: In a cell proliferation assay, TAS-120 selectively inhibited growth of human cancer cell lines with FGFR gene abnormalities. Growth of cell lines without FGFR abnormalities were not inhibited by TAS-120 treatment. TAS-120 inhibited cellular phosphorylation of FGFR as well as intercellular signaling pathways downstream of FGFR in these cells. In addition, TAS-120 inhibited tumor growth in human tumor xenograft mouse models and FGFR phosphorylation in tumor in a dose-dependent manner. Conclusion: TAS-120 is a highly potent irreversible FGFR inhibitor. It selectively inhibited growth of human cancer cell lines selectively, in a FGFR gene abnormality-dependent manner. In addition, TAS-120 demonstrated tumor growth inhibition in mice xenograft models. PD assays suggested this compound inhibits FGFR activity in human tumor xenograft models. 1) 24th EORTC-NCI-AACR Symposium (2012) abstract #380 & #383 Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A270. Citation Format: Hiroaki Ochiiwa, Hidenori Fujita, Kimihiro Itoh, Hiroshi Sootome, Akihiro Hashimoto, Yayoi Fujioka, Yoko Nakatsuru, Nobuyuki Oda, Kazuhiko Yonekura, Hiroshi Hirai, Teruhiro Utsugi. TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A270.


Journal of Biological Chemistry | 2016

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer.

Kenta Watanabe; Michiko Hirata; Tsukasa Tominari; Chiho Matsumoto; Hidenori Fujita; Kazuhiko Yonekura; Gillian Murphy; Hideaki Nagase; Chisato Miyaura; Masaki Inada

The tyrosine kinase inhibitor TAS-115 that blocks VEGF receptor and hepatocyte growth factor receptor MET signaling exhibits antitumor properties in xenografts of human gastric carcinoma. In this study, we have evaluated the efficacy of TAS-115 in preventing prostate cancer metastasis to the bone and bone destruction using the PC3 cell line. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction and subsequent tumor growths were detected. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation by suppressing osteoclastic bone resorption. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption when co-cultured with calvarial bone, but TAS-115 effectively suppressed the PC3-induced bone destruction. We found that macrophage colony-stimulating factor-dependent macrophage differentiation and subsequent receptor activator of NF-κB ligand-induced osteoclast formation were largely suppressed by adding TAS-115. The phosphorylation of the macrophage colony-stimulating factor receptor FMS and osteoclast related kinases such as ERK and Akt were also suppressed by the presence of TAS-115. Gene expression profiling showed that FMS expression was only seen in macrophage and in the osteoclast cell lineage. Our study indicates that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is critical for bone destruction induced by tumor cells and that targeting of MET/VEGF receptor/FMS activity makes it a promising therapeutic candidate for the treatment of prostate cancer patients with bone metastasis.


Molecular Cancer Therapeutics | 2013

Abstract A271: TAS-120, an irreversible FGFR inhibitor, was effective in tumors harboring FGFR mutations, refractory or resistant to ATP competitive inhibitors .

Hiroshi Sootome; Yayoi Fujioka; Akihiro Miura; Hidenori Fujita; Hiroshi Hirai; Teruhiro Utsugi

Background: Targeting protein kinases with irreversible small molecule inhibitors is moving to the forefront in cancer therapy. Irreversible kinase inhibitors may achieve superior potency, selectivity and longer duration of action compared to conventional reversible inhibitors, and may provide an effective approach to overcome drug resistance caused by mutations within drug binding sites1). TAS-120, a highly potent and selective irreversible FGFR inhibitor shows activity against tumors harboring FGFR gene abnormalities2). In this study, we aim at getting evidence to support the concept as “overcomer of acquired resistance” and to confirm the advantage of TAS-120 over ATP competitive inhibitor “A”. Materials and Methods: N550H and E566G mutations in the FGFR2 hinge region were reported to cause resistance to dovitinib3). The K660M within the FGFR2 activation loop is an activating mutation reported in cervical cancer. V565 was made into V565I as a model of gatekeeper mutant. These mutants were transduced to HEK293T cells and the effect of TAS-120 was determined by phospho-FGFR2 ELISA. To isolate resistant cell clones, OCUM-2MD3 cells (FGFR2 amplified human gastric cancer cell line) were treated with either TAS-120 or ATP competitive FGFR inhibitor “compound A” at increasing concentrations for several months. Following clonal selection, the kinase domain of FGFR2 in resistant clones was sequenced. Results: Inhibitory potencies of tested ATP competitive inhibitors against four FGFR2 mutants were reduced compared to that against wild type. In contrast, TAS-120 retained inhibitory potency to all mutations with the similar potency as when compared to wild type. The appearance or frequency of acquired resistance clones to TAS-120 was quite lower compared with what was observed with ATP competitive inhibitor “A”. Resistant clones to inhibitor “A” possessed a single mutation in the activation loop at a frequency of more than 60%. TAS-120 strongly inhibited the cell growth of these resistant clones carrying an FGFR2 mutation with similar potency as seen in wild type. Conclusion: TAS-120 was effective to tumors harboring FGFR mutations, which were resistant to ATP competitive FGFR inhibitors. TAS-120 is expected to be effective in tumors refractory or resistant to ATP competitive FGFR inhibitors due to a mutation in FGFR kinase domain. In addition, appearance of drug-resistance compared to ATP competitive inhibitors may also be lower. These potential advantages of TAS-120 over ATP competitive FGFR inhibitors provide a strong rationale to accelerate the development of TAS-120 for the treatment of advanced cancers which are addicted to FGFR pathway. 1) Nat Rev Drug Discov. 2011;10: 307-17, 2) 24th EORTC-NCI-AACR Symposium (2012) abstract #380 & #383, 3) Proceedings of the 102nd Annual Meeting of the AACR (2011) abstract #4733 Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A271. Citation Format: Hiroshi Sootome, Yayoi Fujioka, Akihiro Miura, Hidenori Fujita, Hiroshi Hirai, Teruhiro Utsugi. TAS-120, an irreversible FGFR inhibitor, was effective in tumors harboring FGFR mutations, refractory or resistant to ATP competitive inhibitors . [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A271.


PLOS ONE | 2016

High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells

Hidenori Fujita; Akira Gomori; Yayoi Fujioka; Yuki Kataoka; Kenji F. Tanaka; Akihiro Hashimoto; Takamasa Suzuki; Kenjiro Ito; Tomonori Haruma; Hiromi Yamamoto-Yokoi; Naomoto Harada; Motomu Sakuragi; Nobuyuki Oda; Kenichi Matsuo; Masaki Inada; Kazuhiko Yonekura

Approximately 25–40% of patients with lung cancer show bone metastasis. Bone modifying agents reduce skeletal-related events (SREs), but they do not significantly improve overall survival. Therefore, novel therapeutic approaches are urgently required. In this study, we investigated the anti-tumor effect of TAS-115, a VEGFRs and HGF receptor (MET)-targeted kinase inhibitor, in a tumor-induced bone disease model. A549-Luc-BM1 cells, an osteo-tropic clone of luciferase-transfected A549 human lung adenocarcinoma cells (A549-Luc), produced aggressive bone destruction associated with tumor progression after intra-tibial (IT) implantation into mice. TAS-115 significantly reduced IT tumor growth and bone destruction. Histopathological analysis showed a decrease in tumor vessels after TAS-115 treatment, which might be mediated through VEGFRs inhibition. Furthermore, the number of osteoclasts surrounding the tumor was decreased after TAS-115 treatment. In vitro studies demonstrated that TAS-115 inhibited HGF-, VEGF-, and macrophage-colony stimulating factor (M-CSF)-induced signaling pathways in osteoclasts. Moreover, TAS-115 inhibited Feline McDonough Sarcoma oncogene (FMS) kinase, as well as M-CSF and receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Thus, VEGFRs/MET/FMS-triple inhibition in osteoclasts might contribute to the potent efficacy of TAS-115. The fact that concomitant dosing of sunitinib (VEGFRs/FMS inhibition) with crizotinib (MET inhibition) exerted comparable inhibitory efficacy for bone destruction to TAS-115 also supports this notion. In conclusion, TAS-115 inhibited tumor growth via VEGFR-kinase blockade, and also suppressed bone destruction possibly through VEGFRs/MET/FMS-kinase inhibition, which resulted in potent efficacy of TAS-115 in an A549-Luc-BM1 bone disease model. Thus, TAS-115 shows promise as a novel therapy for lung cancer patients with bone metastasis.


Cancer Research | 2018

Abstract 2121: MET/VEGFR/FMS signaling contributes prostate cancer-induced osteoclast differentiation and bone resorption

Kenta Watanabe; Michiko Hirata; Tsukasa Tomomi; Chiho Matsumoto; Hidenori Fujita; Yukari Yamada; Kenichi Matsuo; Kazuhiko Yonekura; Chisato Miyaura; Masaki Inada

Blockage of both vascular endothelial growth factor (VEGF) receptor and hepatocyte growth factor (HGF) receptor MET signaling pathways has been reported to suppress tumor growth and angiogenesis synergistically, suggesting the possibility that the dual inhibition of VEGFR and MET signals may have potential effects on the prevention of tumor growth. Recently, we developed a novel VEGFR/MET-targeted tyrosine kinase inhibitor, TAS-115, and showed its antitumor properties in xenografts of human gastric carcinoma (Mol Cancer Ther 2013). Although bone metastases frequently occur in prostate cancer patients, the role of VEGF receptor and MET in cancer-induced bone resorption is not known. Patients with advanced prostate cancer show sclerotic bone metastases, which cause chronic pain and pathologic fractures; however, the invasion of prostate cancer cells into bone tissues first induces bone destruction by increased osteoclast-mediated bone resorption. In this study, we used TAS-115, which inhibits both MET and VEGFR, and examined its effects on human prostate cancer cell line (PC3)-induced bone resorption by directly injecting PC3 cells into the proximal medulla of tibiae in nude mouse in vivo, and by the co-culturing of calvarial bone with PC3 cells in vitro. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction was detected with subsequent tumor growth. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption effectively suppressed by the treatment of TAS-115. In the culture of the bone marrow cells, M-CSF dependent macrophage differentiation and following RANKL-induced osteoclast formation were suppressed by adding TAS-115. FMS-related receptor kinases such as ERK and Akt were also suppressed by the presence of TAS-115. FMS expression was only detected in macrophage and in osteoclast cell lineage. These results indicated that administration of TAS-115 restored bone destruction induced by PC3, mainly by inhibiting the FMS-dependent and RANKL-induced differentiation of preosteoclasts into mature osteoclasts. The additional inhibition of the tyrosine kinase FMS by TAS-115 has profound effects on prostate cancer-driven osteoclastogenesis, and its proliferation extends the capability of this agent to act as a powerful antidote to the devastating effects of metastatic spread to bone. Citation Format: Kenta Watanabe, Michiko Hirata, Tsukasa Tomomi, Chiho Matsumoto, Hidenori Fujita, Yukari Yamada, Kenichi Matsuo, Kazuhiko Yonekura, Chisato Miyaura, Masaki Inada. MET/VEGFR/FMS signaling contributes prostate cancer-induced osteoclast differentiation and bone resorption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2121.


Cancer Research | 2016

Abstract 2141: TAS-115, a novel and highly potent VEGFR/MET inhibitor, shows prominent antitumor efficacy by restoring HGF-mediated hypoxia-resistant phenotype in clear cell sarcoma

Hidenori Fujita; Yukari Yamada; Miki Terasaka; Yayoi Fujioka; Naomoto Harada; Akihiro Hashimoto; Kazutaka Miyadera; Kenichi Matsuo; Kazuhiko Yonekura

Hepatocyte growth factor (HGF) / HGF receptor (MET) signaling is considered to be involved in chemoresistance to cancer treatment. Notably, many reports have described reduced sensitivity to vascular endothelial growth factor receptor (VEGFR)-targeted inhibitors in patients with high serum HGF levels compared to those with low serum levels. This study investigated whether HGF directly influenced sensitivity to VEGFR-targeted inhibitors in human clear cell sarcoma (CCS) xenograft models using human HGF knock-in (hHGF KI) mice, and evaluated the potency of TAS-115. MET signaling pathway in SU-CCS-1, a human CCS cell line, were analyzed using Western blotting analysis. To study the effects of hypoxia in SU-CCS-1 cells, culture plates were placed in airtight jars under anaerobic conditions and cell viability was assessed by ATP-based assay. In the in vivo study, SU-CCS-1 cells were subcutaneously implanted into hHGF KI mice, and compounds were orally administered once daily for 14 consecutive days. Tumor vessel density (TVD) was determined by immunohistochemistry using anti-CD31 antibody. SU-CCS-1 cells expressed MET, and exogenous HGF phosphorylated MET and its downstream factors in SU-CCS-1 cells. Exogenous HGF also significantly enhanced SU-CCS-1 cell proliferation. TAS-115 inhibited HGF-induced MET phosphorylation and SU-CCS-1 cell proliferation in a dose-dependent manner at concentrations higher than 10 nM. In contrast, pazopanib, a VEGFR-targeted multi-kinase inhibitor, could not block HGF-induced phenotypes in SU-CCS-1 cells, even at 1 μM. To evaluate the effects of HGF on the antitumor activities of TAS-115 and pazopanib against SU-CCS-1 cells, these agents were administered in hHGF KI and wild-type (WT) mice bearing subcutaneous SU-CCS-1 tumors. TAS-115 completely suppressed tumor growth and reduced TVD in SU-CCS-1 tumor tissue in both models at a dose of 200 mg/kg/d. In contrast, pazopanib suppressed tumor growth at a dose of 100 mg/kg/d in WT mice but not in hHGF KI mice. However, pazopanib significantly reduced TVD in SU-CCS-1 tumor tissue in both models. HGF is therefore suggested to impact SU-CCS-1 cells rather than mouse endothelial cells. We considered that HGF modulated cell proliferation or survival in SU-CCS-1 cells under hypoxia. Actually, hypoxic conditions induced apoptosis in SU-CCS-1 cells, and endogenous HGF dose-dependently attenuated hypoxia-related apoptosis. TAS-115 clearly restored HGF-mediated cytoprotection under hypoxia but pazopanib did not. These results suggest that effects of VEGFR-targeted inhibitors are attenuated by HGF-mediated hypoxia resistance, and simultaneous inhibitors of the MET and VEGFR axes, such as TAS-115, are more effective in sarcoma patients with high serum HGF than inhibition of the VEGFR axis alone. Citation Format: Hidenori Fujita, Yukari Yamada, Miki Terasaka, Yayoi Fujioka, Naomoto Harada, Akihiro Hashimoto, Kazutaka Miyadera, Kenichi Matsuo, Kazuhiko Yonekura. TAS-115, a novel and highly potent VEGFR/MET inhibitor, shows prominent antitumor efficacy by restoring HGF-mediated hypoxia-resistant phenotype in clear cell sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2141.


Cancer Research | 2016

Abstract 3777: TAS4464, a novel and highly potent NEDD8 activating enzyme (NAE) inhibitor, causes apoptosis of sarcomas via cell cycle dysregulation

Hidenori Fujita; Yayoi Fujioka; Keiji Ishida; Chihoko Yoshimura; Akihiro Hashimoto; Shingo Tsuji; Takashi Mizutani; Shuichi Okubo; Kenichi Matsuo; Teruhiro Utsugi; Yoshikazu Iwasawa

Background Soft-tissue sarcomas (STSs) are heterogeneous tumors that comprise approximately 1% of adult cancers. Patients with advanced STS have a poor prognosis because few chemotherapy options are available. NAE catalyzes the first step in the NEDD8 conjugation (neddylation) pathway. Because it activates cullin-RING ligase complexes (CRLs) and thus is essential in cancer cell homeostasis, NAE is a promising target for cancer therapy. Here, we investigated the potency of the NAE inhibitor TAS4464 for various STS cell lines. Material and methods Cytotoxicity was evaluated through ATP-Based assay. The effects of TAS4464 on NEDD8 conjugation and CRL substrates were evaluated by Western analysis. Cell cycle progression was analyzed by using flow cytometry. Small interfering RNAs (siRNAs) were lipofected into a clear cell sarcoma (CCS) line (SU-CCS-1). The antitumor activity of intravenous TAS4464 was evaluated in xenograft models of the aforementioned CCS and 2 rhadomyosarcoma (RMS) lines (SJCRH30 and RD). Results TAS4464 suppressed cell growth and induced cell death in various STS cell lines at lower concentrations than did an investigational NAE inhibitor, MLN4924, and a conventional STS treatment agent, doxorubicin (DXR). Notably, the GI 50 values of TAS4464 were less than 10 nM in the tested RMS and CCS cell lines. TAS4464 treatment led to the elimination of cullin neddylation, accumulation of CRL substrate proteins (CDT1, p27, and p21), S phase arrest, and ultimately apoptosis in these STS cell lines. Furthermore, knockdown of CRL substrate proteins by siRNAs markedly attenuated TAS4464-induced cytotoxicity in STS cells. These results suggest that TAS4464-induced cell death was triggered by cell cycle dysregulation based on accumulation of CRL substrate proteins following NAE inhibition. TAS4464 also led to a decrease in cullin neddylation and accumulation of CRL substrate proteins in RMS and CCS lines subcutaneous xenografts. Weekly administration of TAS4464 (100 mg/kg, IV) completely suppressed tumor growth in mice bearing subcutaneous RD and SJCRH30 xenografts. The effects of TAS4464 significantly exceeded that of DXR and MLN4924. Furthermore, TAS4464 induced tumor regression of ∼50% in the pazopanib, a drug approved for STS, insensitive SU-CCS-1 xenograft model. Conclusion TAS4464 prominently inhibited cell growth and induced apoptosis in RMS and CSC cells through cell cycle dysregulation and demonstrated impressive antitumor activities in STS xenograft models that respond poorly to DXR and pazopanib. Therefore, TAS4464 may become a valuable therapeutic option for patients with advanced STS. Citation Format: Hidenori Fujita, Yayoi Fujioka, Keiji Ishida, Chihoko Yoshimura, Akihiro Hashimoto, Shingo Tsuji, Takashi Mizutani, Shuichi Okubo, Kenichi Matsuo, Teruhiro Utsugi, Yoshikazu Iwasawa. TAS4464, a novel and highly potent NEDD8 activating enzyme (NAE) inhibitor, causes apoptosis of sarcomas via cell cycle dysregulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3777.


Molecular Cancer Therapeutics | 2015

Abstract A108: TAS-115, a VEGFR/MET-targeted kinase inhibitor, potently suppresses HGF-induced aggressive bone and systemic metastasis in HGF knock-in mice bearing UM-UC-3 bladder tumors

Yukari Yamada; Hidenori Fujita; Yayoi Fujioka; Naomoto Harada; Akihiro Hashimoto; Tomonori Haruma; Shingo Tsuzi; Ryouto Fujita; Kenichi Matsuo; Teruhiro Utsugi; Kazuhiko Yonekura

Background: Invasive bladder cancer frequently shows bone and systemic metastasis. Thus, development of a drug that is effective not only against the primary lesion but also the metastatic lesions is needed for therapy of bladder cancer. The expression level of hepatocyte growth factor (HGF) is high in invasive bladder cancer patients and associated with poor outcomes. Moreover, several recent clinical reports show that HGF receptor (MET) expression level was related to cancer grade, stage, tumor size, and poor prognosis in invasive bladder cancer patients. Because HGF-MET signaling has shown a species difference between humans and mice, the usual human cancer xenotransplantation models using nude mice are inadequate to evaluate the effect of agents against tumor growth and metastasis driven by hHGF-MET paracrine signaling. Thus, hHGF knock-in (hHGF KI) mice were generated, and the antitumor efficacy of TAS-115, a MET/VEGFR-targeted kinase inhibitor, was evaluated in a systemic metastasis model of bladder cancer. Material and Methods: A luciferase-transfected human bladder cancer cell line (UM-UC-3-luc) was established. Cell proliferation, invasion, and gene expression analyses were conducted in UM-UC-3-luc after HGF stimulation using Cell titer Glo, a migration assay kit, and DNA array analyses. In the in vivo metastasis model, UM-UC-3-luc cells were injected into the left ventricular cavity of hHGF KI mice. Luciferase activity was measured under deep anesthesia once a week as an index of tumor growth. TAS-115 was administered orally once daily for 4 weeks, when photons emitted from tumor-transplanted regions reached the order of 107. Results: In vitro, HGF significantly enhanced proliferation and invasion of UM-UC-3-luc cells through MET activation. Based on DNA array analyses, several tumor metastasis and invasion-related genes (MMPs, chemokines, transcription factors, and phosphatases) were changed in UM-UC-3-luc cells after HGF stimulation. TAS-115 completely inhibited HGF-driven proliferation and invasion activity in UM-UC-3-luc cells and blocked HGF-induced expression changes of tumor metastasis and invasion-related genes in in vivo xenograft models. Tumorigenicity and metastasis of UM-UC-3-luc cells showed approximately 60% increase in hHGF KI mice compared with WT mice. The major metastatic sites were lower jaw bone, adrenal gland, lymph node, and ovary. Tumor metastasis-related genes in UM-UC-3-luc cell-bearing hHGF KI mice were also changed, as in the in vitro experiments. TAS-115 suppressed >80% of systemic metastasis of UM-UC-3-luc cells in both hHGF KI and WT mice without severe body weight loss. Notably, the more aggressive metastasis of UM-UC-3-luc cells in hHGF KI mice was clearly inhibited by TAS-115 treatment. TAS-115 inhibited phosphorylation of MET and regulated tumor metastasis-related gene expression in metastasized tumor tissue. Conclusions:HGF provided a more aggressive phenotype related to tumor progression to UM-UC-3-luc cells in this in vivo models. TAS-115, a VEGFR/MET-targeted kinase inhibitor, significantly suppressed tumor progression and systemic metastasis in UM-UC-3-luc cell-bearing hHGF KI mice. TAS-115 appears to be a novel therapeutic strategy for patients with advanced bladder cancer. Citation Format: Yukari Yamada, Hidenori Fujita, Yayoi Fujioka, Naomoto Harada, Akihiro Hashimoto, Tomonori Haruma, Shingo Tsuzi, Ryouto Fujita, Kenichi Matsuo, Teruhiro Utsugi, Kazuhiko Yonekura. TAS-115, a VEGFR/MET-targeted kinase inhibitor, potently suppresses HGF-induced aggressive bone and systemic metastasis in HGF knock-in mice bearing UM-UC-3 bladder tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A108.


Molecular Cancer Therapeutics | 2013

Abstract A272: Intermittent treatment with TAS-120, an irreversible FGFR inhibitor, is effective in tumors harboring a FGFR gene abnormality.

Yoko Nakatsuru; Hiroaki Ochiiwa; Hiroshi Sootome; Hidenori Fujita; Akihiro Hashimoto; Yoshihiro Shibata; Masato Chiba; Yayoi Fujioka; Kazuhiro Yonekura; Hiroshi Hirai; Teruhiro Utsugi

Background: FGFs (fibroblast growth factors) and their receptors (FGFRs) play crucial roles in regulation of cell proliferation, survival, migration and differentiation. Deregulation of FGFR expression has been reported in multiple cancers, including breast, bladder, lung, gastric, endometrial and multiple myeloma. FGFRs are overactivated by several mechanisms such as gene amplification, translocation and mutations. FGFR gene alterations are reported in a variety of cancers. We have identified a highly potent, irreversible and selective FGFR inhibitor, TAS-120 (1). In this report, we investigated FGFR turnover in human cancer cell lines. Moreover, we present the antitumor efficacy and pharmacodynamic (PD) activity of TAS-120 in xenograft tumor models to determine the optimal dosing schedule. Materials and Methods: For in vitro turnover experiments, cell lines were treated with Brefeldin A which suppresses de novo protein synthesis. The cellular level of FGFR was determined by ELISA. For in animal efficacy studies, FGFR2 gene amplified human tumor cell lines were subcutaneously transplanted into the side flank of nude mice or rats. Dosing of compound was started when transplanted tumor size reached > ∼ 200 mm3. For antitumor efficacy, tumor size was measured with digital calipers. To determine the optimal dosing schedule of TAS-120 in a human tumor xenograft model, we orally administered TAS-120 by daily, every other day and other intermittent dosing schedule. The time course of phospho-FGFR inhibition in tumor after single dosing of TAS-120 was also examined as a pharmacodynamic marker. Results: FGFR turnover was investigated in 2 human cancer cell lines, OCUM-2M (gastric cancer cell line with FGFR2 amplification) and OPM-2 (multiple myeloma cell line with FGFR3 gene translocation). When cells were treated with Brefeldin A, cellular FGFR levels were reduced to < 20% at 4 and 6 hr respectively. FGFR turnover in these cells is rapid as most FGFR protein was replaced within 4 or 6 hr. In animal studies, we determined the PD/efficacy correlation. The time course of phosphor-FGFR inhibition in tumor at efficacious doses suggests that continuous inhibition of the target is not necessary to maintain efficacy. Additional studies in OCUM-2MD3 and SNU-16 models demonstrated that TAS-120 is efficacious even with intermittent dosing schedules of every other day or twice/week schedule. Conclusion: TAS-120 is a highly potent, selective, irreversible FGFR inhibitor, which demonstrated strong tumor growth inhibition across continuous and intermittent dosing schedules in mice and rat xenograft models. 1) 24th EORTC-NCI-AACR Symposium (2012) abstract #380 & #383 Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A272. Citation Format: Yoko Nakatsuru, Hiroaki Ochiiwa, Hiroshi Sootome, Hidenori Fujita, Akihiro Hashimoto, Yoshihiro Shibata, Masato Chiba, Yayoi Fujioka, Kazuhiro Yonekura, Hiroshi Hirai, Teruhiro Utsugi. Intermittent treatment with TAS-120, an irreversible FGFR inhibitor, is effective in tumors harboring a FGFR gene abnormality. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A272.

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Teruhiro Utsugi

University of Texas MD Anderson Cancer Center

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Masaki Inada

Tokyo University of Agriculture and Technology

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