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Yamamoto N.,Shizuoka Cancer Center | Muraakmi H.,Shizuoka Cancer Center | Nishina T.,National Shikoku Cancer Center | Hirashima T.,Osaka Prefectural Medical Center for Respiratory and Allergic Diseases | And 8 more authors.
Annals of Oncology | Year: 2013

Background: Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). Patients and methods: Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. Results: Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC0-12 compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. Conclusion: Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source


Kitamura Y.,Shizuoka Cancer Center Research Institute
Japan Journal of Nursing Science | Year: 2010

Aim: In order to support patients' decision-making regarding cancer treatments, it is important to clarify which criteria that cancer patients use to set priorities in their treatment choices. Using the analytic hierarchy process (AHP), a mathematical decision-making method, this article investigates the criteria and the priorities of patients with gynecological cancer. Methods: In the AHP, multiple and hierarchical criteria in the decision-making process were organized by a repeated pairwise judgment of the participants so as to serialize the alternatives along with the rational order of the priorities. For the alternatives "to receive treatment" and "to not receive treatment," the following five criteria were set: "anxiety about relapse and metastasis", "distress about side-effects", "advice of family", "advice of medical staff", and "economic burden". The participants determined a pairwise priority scale, as well as a priority scale between the alternatives for every criterion. The logical consistency of their answers was checked by a consistency index (CI). The participants were 31 patients with ovarian or endometrial cancer who were being followed up after undergoing surgery and adjuvant chemotherapy. Results: Of the participants who answered the questionnaire, 17 satisfied the logical consistency. Of the five criteria for the treatment choices, "anxiety about relapse and metastasis" and "advice of medical staff" were found to be the important factors for treatment choice; however, the weight attached to the priority criteria differed much among the patients. Conclusion: The AHP made it possible to support patients' decision-making in order to clarify their priority criteria and to quantitatively present their decision-making process. © 2010 The Author. Journal compilation © 2010 Japan Academy of Nursing Science. Source


Serizawa M.,Shizuoka Cancer Center Research Institute | Takahashi T.,Shizuoka Cancer Center Hospital | Yamamoto N.,Shizuoka Cancer Center Hospital | Koh Y.,Shizuoka Cancer Center Research Institute
Journal of Thoracic Oncology | Year: 2013

INTRODUCTION: Despite an initial dramatic response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, the majority of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations develop acquired resistance. Therefore, there is an urgent need to elucidate the unknown mechanisms and biological behaviors of EGFR TKI-resistant lung tumors. We investigated the motility of EGFR TKI-resistant cells, as these characteristics are relevant to cancer metastasis. METHODS: Erlotinib-resistant PC-9ER cells were generated from PC-9 NSCLC cells, which harbor an EGFR-activating mutation, and used in this study. We investigated the involvement of the transforming growth factor beta (TGF-β) pathway in cell motility, and tested the effects of erlotinib and TGF-β type I receptor (RI) inhibition on cell motility. RESULTS: PC-9ER cells displayed enhanced motility resulting from autocrine activation of the TGF-β pathway. Increased TGF-β2 secretion resulting from TGF-β2 up-regulation at the transcriptional level was suggested to be responsible for the phosphorylation of Smad2 and the subsequently elevated transcriptional regulatory activity in PC-9ER cells. The motility of PC-9ER cells was suppressed by treatment with either the TGF-βRI inhibitor LY364947 or erlotinib, and greater suppression was observed when used in combination. LY364947 or erlotinib exerted no growth-inhibitory effects, suggesting that motility and growth are driven by different signaling pathways in PC-9ER cells. CONCLUSIONS: Our results imply that blockade of the TGF-β signaling pathway combined with continuous EGFR TKI treatment will be beneficial in preventing metastasis in patients with EGFR TKI-resistant NSCLC without the EGFR T790M resistance mutation. Copyright © 2013 by the International Association for the Study of Lung Cancer. Source


Kaira K.,Shizuoka Cancer Center | Serizawa M.,Shizuoka Cancer Center Research Institute | Koh Y.,Shizuoka Cancer Center Research Institute | Takahashi T.,Shizuoka Cancer Center | And 7 more authors.
Lung Cancer | Year: 2014

Background: The aim of this study is to investigate the underlying biologic mechanisms of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) uptake on positron emission tomography (PET) in non-small cell lung cancer (NSCLC). Methods: One-hundred forty patients with NSCLC who underwent 18F-FDG PET were included in the study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), GLUT3, hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessels (CD34), epidermal growth factor receptor (EGFR), and molecules relevant to PI3K/Akt/mTOR signaling pathway (PTEN, p-Akt, p-mTOR and p-S6). We also conducted in vitro studies of 18F-FDG uptake and mTOR inhibition in NSCLC cells. Results: High 18F-FDG uptake was significantly associated with poor prognosis in NSCLC patients. 18F-FDG uptake was significantly correlated with GLUT1, hexokinase I, HIF-1α, VEGF, CD34, p-Akt, p-mTOR and EGFR. PTEN expression showed inverse correlation with 18F-FDG uptake. In in vitro study, 18F-FDG uptake was markedly decreased by the inhibition of GLUT1 and GLUT1 upregulation by the induction of HIF-1α increased the 18F-FDG uptake. Inhibition of both mTOR complex1 (mTORC1) and mTORC2 suppressed cell growth, but activity of mTORC1 regulated the 18F-FDG uptake. NCI-H1650 cells with PTEN loss showed the highest 18F-FDG uptake and the least sensitivity to mTOR inhibitors. Conclusion: The amount of 18F-FDG accumulation is associated with molecules relevant to glucose metabolism, hypoxia, angiogenesis and mTOR signaling pathway. Especially, PTEN status may affect not only 18F-FDG uptake but also effect of mTOR inhibitors on the growth of NSCLC. © 2013 Elsevier Ireland Ltd. Source


Serizawa M.,Shizuoka Cancer Center Research Institute | Takahashi T.,Shizuoka Cancer Center Hospital | Yamamoto N.,Shizuoka Cancer Center Hospital | Yamamoto N.,Wakayama Medical University | Koh Y.,Shizuoka Cancer Center Research Institute
Anticancer Research | Year: 2013

Background/Aim: Mechanisms of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are not fully-understood. In this study we aimed to elucidate remaining unknown mechanisms using erlotinib-resistant NSCLC cells. Materials and Methods: We performed array comparative genomic hybridization (aCGH) to identify genomic aberrations associated with EGFR-TKI resistance in erlotinib-resistant PC-9ER cells. Real-time polymerase chain reaction (PCR) and immunoblot analyses were performed to confirm the results of aCGH. Results: Among the five regions with copy number gain detected in PC-9ER cells, we focused on 22q11.2-q12.1 including v-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL), the overexpression of which seemed to be associated with EGFR-TKI resistance. Blockade of downstream phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT) signaling using NVP-BEZ235 suppressed the proliferation of PC-9ER cells, implying the involvement of acquired CRKL amplification in EGFR-TKI resistance. Conclusion: Acquired CRKL amplification was identified as contributing to EGFR-TKI resistance; this cell line model can be utilized to study this resistance mechanism. Source

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