ＦＧＦ３遺伝子増幅による肝細胞癌ソラフェニブ治療の効果予測

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24240122
• Research Institution: Kinki University
• Principal Investigator: 西尾 和人 近畿大学, 医学部, 教授 (10208134)
• Co-Investigator(Kenkyū-buntansha): 工藤 正俊 近畿大学, 医学部, 教授 (10298953)
• Project Period (FY): 2012-10-31 – 2015-03-31
• Keywords: 肝細胞がん / ソラフェニブ / バイオマーカー / TGF-α / PECAM1 / NRG1

Outline of Annual Research Achievements

本年度は、FGF3/FGF4を含む領域のコピー数アッセイを実施し、ソラフェニブ著効例のアーカイブサンプルを用いて標準法である蛍光 in situ ハイブリダイゼーション法との比較により、コピー数アッセイ法のカットオフ値検討を行った。その他のソラフェニブ効果予測因子の探索として、多施設共同研究での肝細胞がんのソラフェニブ著効例の組織検体を対象に、次世代シーケンサーを用いたソラフェニブ著効例の遺伝子変異解析およびコピー数変動を実施した。その結果、新たな予測因子として、FGF19を見出した。また、ソラフェニブの有効性予測のためのバイオマーカー試験として、多施設共同研究による46例のソラフェニブ治療前の肝針生検腫瘍組織検体を用いて、ソラフェニブ効果予測因子の探索研究を行った。DNA シーケンスにより、βカテニン遺伝子、TP53遺伝子での遺伝子変異が既報と同等の頻度で検出された。他に複数のがん遺伝子での遺伝子変異が検出され、変異検出頻度の解析を行った結果、がん抑制遺伝子を除いた遺伝子変異の頻度は、ソラフェニブ奏功例と不応例との間に有意な差異を認めた。この結果から肝細胞がんにおいて、oncogene mutationの少ない腫瘍において、ソラフェニブが効果を示す可能性が示された。RNAシーケンスの結果からは、不応例において、ヒトトランスフォーミング成長因子α（TGF-α）および血小板内皮細胞接着分子（PECAM1）の発現が有意に低値であることが示された。また、耐性関連因子であるNeuregulin 1遺伝子が腫瘍部で低値な群では、無増悪生存期間を有意に延長することが示された。本研究の結果、新たなソラフェニブの効果を予測するマーカーとして、腫瘍部のがん遺伝子の変異頻度およびTGF-α, PECAM1, Neuregulin 1遺伝子発現を見出した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal. (2015)
  • Author(s): Togashi Y, Hayashi H, Okamoto K, Fumita S, Terashima M, de Velasco MA, Sakai K, Fujita Y, Tomida S, Nakagawa K, Nishio K.
  • Journal Title: Lung Cancer Volume: 88(1) Pages: 16-23
  • DOI: http://dx.doi.org/10.1016/j.lungcan.2015.01.027
  • Peer Reviewed
• [Journal Article] Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. (2015)
  • Author(s): Togashi Y, Kogita A, Sakamoto H, Hayashi H, Terashima M, de Velasco MA, Sakai K, Fujita Y, Tomida S, Kitano M, Okuno K, Kudo M, Nishio K.
  • Journal Title: Cancer Lett Volume: 356(2PtB) Pages: 819-27
  • DOI: http://dx.doi.org/10.1016/j.canlet.2014.10.037
  • Peer Reviewed
• [Journal Article] Inter- and intra-tumor profiling of multi-regional colon cancer and metastasis. (2015)
  • Author(s): Kogita A, Yoshioka Y, Sakai K, Togashi Y, Sogabe S, Nakai T, Okuno K, Nishio K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 458(1) Pages: 52-6
  • DOI: http://dx.doi.org/10.1016/j.bbrc.2015.01.064
  • Peer Reviewed
• [Journal Article] Performance of a novel KRAS mutation assay for formalin-fixed paraffin embedded tissues of colorectal cancer. (2015)
  • Author(s): Sakai K, Yoneshige A, Ito A, Ueda Y, Kondo S, Nobumasa H, Fujita Y, Togashi Y, Terashima M, De Velasco MA, Tomida S, Nishio K.
  • Journal Title: Springerplus Volume: 4 Pages: 7
  • DOI: http://www.springerplus.com/content/4/1/7
  • Peer Reviewed
• [Journal Article] Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer. (2015)
  • Author(s): Kogita A, Togashi Y, Hayashi H, Banno E, Terashima M, De Velasco MA, Sakai K, Fujita Y, Tomida S, Takeyama Y, Okuno K, Nakagawa K, Nishio K.
  • Journal Title: Int J Cancer Volume: 46(3) Pages: 1025-30
  • Peer Reviewed
• [Journal Article] Transcriptional CCND1 expression as a predictor of poor response to neoadjuvant chemotherapy with trastuzumab in HER2-positive/ER-positive breast cancer. (2015)
  • Author(s): Tanioka M, Sakai K, Sudo T, Sakuma T, Kajimoto K, Hirokaga K, Takao S, Negoro S, Minami H, Nakagawa K, Nishio K.
  • Journal Title: Breast Cancer Res Treat Volume: 147(3) Pages: 513-25
  • DOI: 10.1007/s10549-014-3121-5
  • Peer Reviewed
• [Journal Article] Inhibition of β-catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small cell lung cancer with a T790M mutation. (2015)
  • Author(s): Togashi Y, Hayashi H, Terashima M, de Velasco MA, Sakai K, Fujita Y, Tomida S, Nakagawa K, Nishio K.
  • Journal Title: J Thorac Oncol Volume: 10(1) Pages: 93-101
  • Peer Reviewed
• [Journal Article] Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition. (2015)
  • Author(s): Kogita A, Togashi Y, Hayashi H, Sogabe S, Terashima M, Velasco MA, Sakai K, Fujita Y, Tomida S, Takeyama Y, Okuno K, Nakagawa K, Nishio K.
  • Journal Title: Int J Oncol Volume: 45(4) Pages: 1430-6
  • DOI: 10.3892/ijo.2014.2574
  • Peer Reviewed
• [Journal Article] Multiple regulatory mechanisms of hepatocyte growth factor expression in malignant cells with a short poly(dA) sequence in the HGF gene promoter. (2015)
  • Author(s): Sakai K, Takeda M, Okamoto I, Nagakawa K, Nishio K.
  • Journal Title: Oncology Letter Volume: 9(1) Pages: 405-10
  • DOI: 10.3892/ol.2014.2702
  • Peer Reviewed
• [Journal Article] Multiplex genomic profiling of non–small cell lung cancers from the LETS phase III trial of first-line S-1/carboplatin versus paclitaxel/carboplatin: results of a West Japan Oncology Group study (2014)
  • Author(s): Okamoto I, Sakai K, Morita S, Yoshioka H, Kaneda H, Takeda K, Hirashima T, Kogure Y, Kimura T, Takahashi T, Atagi S, Seto T, Sawa T, Yamamoto M, Satouchi M, Okuno M, Nagase S, Takayama K, Tomii K, Maeda T, Oizumi S, Fujii S, Akashi Y, Nishino K, Ebi N, Nakagawa K, Nakanishi Y, Nishio K.
  • Journal Title: Oncotarget Volume: 5(8) Pages: 2293-304
  • Peer Reviewed
• [Journal Article] MEK inhibitor for gastric cancer with MEK1 gene mutations. (2014)
  • Author(s): Sogabe S, Togashi Y, Kato H, Kogita A, Mizukami T, Sakamoto Y, Banno E, Terashima M, Hayashi H, Develasco MA, Sakai K, Fujita Y, Tomida S, Yasuda T, Takeyama Y, Okuno K, Nishio K.
  • Journal Title: Mol Cancer Ther Volume: 13(12) Pages: 3098-106
  • DOI: 10.1158/1535-7163.MCT-14-0429
  • Peer Reviewed
• [Journal Article] Chemoradiation provides a physiological selective pressure that increases the expansion of aberrant TP53 tumor variants in residual rectal cancerous regions. (2014)
  • Author(s): Sakai K, Kazama S, Nagai Y, Muruno K, Tanaka T, Ishihara S, Sunami E, Tomida S, Nishio K, Watanabe T.
  • Journal Title: Oncotarget Volume: 5(20) Pages: 9641-9
  • Peer Reviewed
• [Journal Article] Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines. (2014)
  • Author(s): Terashima M, Sakai K, Togashi Y, Hayashi H, De Velasco MA, Tsurutani J, Nishio K.
  • Journal Title: Springerplus Volume: 3 Pages: 417
  • DOI: 10.1186/2193-1801-3-417
  • Peer Reviewed
• [Journal Article] Targeting MET Amplification as a New Oncogenic Driver. (2014)
  • Author(s): Kawakami H, Okamoto I, Okamoto W, Tanizaki J, Nakagawa K, Nishio K.
  • Journal Title: Cancers(Basel) Volume: 6(3) Pages: 1540-52
  • DOI: 10.3390/cancers6031540
  • Peer Reviewed
• [Journal Article] KIAA1199 interacts with glycogen phosphorylase kinase b-subunit (PHKB) to promote glycogen breakdown and cancer cell survival. (2014)
  • Author(s): Terashima M, Fujita Y, Togashi Y, Sakai K, Velasco MA, Tomida S, Nishio K.
  • Journal Title: Oncotarget Volume: 5(16) Pages: 7040-50
  • Peer Reviewed
• [Journal Article] Clinical utility of erlotinib for the treatment of non-small-cell lung cancer in Japanese patients: current evidence. (2014)
  • Author(s): Togashi Y, Hayashi H,Nakagawa, K, Nishio K.
  • Journal Title: Drug Des Devel Ther. Volume: 8 Pages: 1037-46
  • DOI: http://dx.doi.org/10.2147/DDDT.S50358
  • Peer Reviewed
• [Journal Article] Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production. (2014)
  • Author(s): Togashi Y, Arao T, Kato H, Matsumoto K, Terashima M, Hayashi H, de Velasco MA, Fujita Y, Kimura H, Yasuda T, Shiozaki H, Nishio K.
  • Journal Title: Oncotarget Volume: 5(10) Pages: 2962-73
  • Peer Reviewed
• [Journal Article] Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma. (2014)
  • Author(s): Hayashi H, Arao T, Matsumoto K, Kimura H, Togashi Y, Hirashima Y, Horita Y, Iwasa S, Okita NT, Honma Y, Takashima A, Kato K, Hamaguchi T, Shimada Y, Nakagawa K, Nishio K, Yamada Y.
  • Journal Title: Oncotarget Volume: 5(9) Pages: 2588-95
  • Peer Reviewed
• [Journal Article] Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer. (2014)
  • Author(s): Togashi Y, Sakamoto H, Hayashi H, Terashima M, de Velasco MA, Fujita Y, Kodera Y, Sakai K, Tomida S, Kitano M, Ito A, Kudo M, Nishio K.M, Ito A, Kudo M, Nishio K.
  • Journal Title: Molecular Cancer Volume: 13 Pages: 126
  • DOI: 10.1186/1476-4598-13-126
  • Peer Reviewed
• [Journal Article] Melanoma transition is frequently accompanied by a loss of cytoglobin expression in melanocytes: a novel expression site of cytoglobin. (2014)
  • Author(s): Fujita Y, Koinuma S, Develasco MA, Bolz J, Togashi Y, Terashima M, Hayashi H, Matsuo T, Nishio K.
  • Journal Title: PLOS ONE Volume: 9(4) Pages: e94772
  • DOI: 10.1371/journal.pone.0094772
  • Peer Reviewed
• [Journal Article] Analytical performance of the cobas EGFR mutation assay for Japanese non-small-cell lung cancer. (2014)
  • Author(s): Kimura H, Ohira T, Uchida O, Matsubayashi J, Shimizu S, Nagao T, Ikeda N, Nishio K.
  • Journal Title: Lung Cancer Volume: 83(3) Pages: 329-33
  • DOI: http://dx.doi.org/10.1016/j.lungcan.2013.12.012
  • Peer Reviewed
• [Presentation] New insights for sequencing data in lung cancer. (2014)
  • Author(s): Nishio K.
  • Organizer: The ESMO 2014 Congress
  • Place of Presentation: Madorid
  • Year and Date: 2014-09-26 – 2014-09-30
  • Invited
• [Presentation] Serum biomarker analysis of WJOG4107: A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage Ii-IIIA non-small cell lung cancer (NSCLC). (2014)
  • Author(s): Mitsudomi T, Iwamoto Y, Tomida S, Sakai K, Yamanaka T, Tada H, Yoshioka H, Uchino K, Yoshino I, Sugawara S, Mitsuoka S, Takahashi T, Ohta M, Seto T, Atagi S, Okada M, Saka H, Nakagawa K, Nakanishi Y, Nishio K.
  • Organizer: American Society of Clinical Oncology Annual Meeting 2014
  • Place of Presentation: Chicago
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] Transcriptional expression of Bcl-2 as predictive of response to neoadjuvant chemotherapy with trastuzumab in HER2-positive ER-positive breast cancer patients. (2014)
  • Author(s): Tanioka M, Sakai K, Sudo T, Sakuma T, Hirokaga K, Takao S, Minami H, Negoro S, Nakagawa K, Nishio K.
  • Organizer: American Society of Clinical Oncology Annual Meeting 2014
  • Place of Presentation: Chicago
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] Early phase trials in the future-Basic resaercher's perspective. (2014)
  • Author(s): Nishio K.
  • Organizer: 3rd Japan Taiwan Oncoloy PhaseI Trial Conference (JTOPIC)
  • Place of Presentation: Taipei
  • Year and Date: 2014-04-19
  • Invited
• [Presentation] Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer. (2014)
  • Author(s): Togashi Y, Sakamoto H, Hayashi H, Terashima M, Velasco MA, Fujita Y, Kodera Y, Sakai K, Tomida S, Kitano M, Kudo M, Nishio K.
  • Organizer: American Association for Cancer Research 104th Annual Meeting 2014
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary cancer. (2014)
  • Author(s): Fujita Y, Kurahashi I, Kurata T, Koh Y, Sakai K, Nakagawa K, Nishio K.
  • Organizer: American Association for Cancer Research 104th Annual Meeting 2014
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Noninvasive analysis of acquired resistance to EGFR-TKI. (2014)
  • Author(s): Kimura H, Nishio M, Daito T, Nishio K.
  • Organizer: American Association for Cancer Research 104th Annual Meeting 2014
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Patent(Industrial Property Rights)] Use of Eribulin and S-1as combination therapy for the treatment of cancer (2014)
  • Inventor(s): Kazuto Nishio
  • Industrial Property Rights Holder: エーザイ
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 62/016,241
  • Filing Date: 2014-06-24
  • Overseas