Novel molecular targeted therapy for peritoneal dissemination of gastric cancer

• Project/Area Number: 18591463
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: FUJIWARA Yoshiyuki Osaka University, Graduate School of Medicine, Assistant Professor (40314330)
• Co-Investigator(Kenkyū-buntansha): DOKI Yuichiro Osaka Univetsty, Graduate School of Medicine, Associate Professor (20291445) ; YASUDA Takushi Kinki University, Faculty of Medicine, Associate Professor (10324782) ; TAKIGUCHI Syuji Osaka University, Graduate School of Medicine, Assistant Professor (00301268)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: gastric cancer / peritonitis carcinomatosa / molecular targeted therapy / ets-1 / parthenolide / NFkappaB

Research Abstract

Novel molecular targeted therapy for peritoneal dissemination of gastric cancer was examined in this study.
1, The purpose of this study was to evaluate the efficacy of double-stranded decoy oligonucleotides targeting ets-1-binding cis elements for the suppression of ets-1 in treatment of a peritoneal dissemination model of gastric cancer. We have demonstrated that intra-peritoneal injection of ets-1 decoy inhibited the peritoneal dissemination of gastric cancer through suppression of tumor angiogenesis in a nude mice model. These results indicate that the decoy strategy for ets-1 can offer a promising therapy for patients with incurable peritoneal dissemination of gastric cancers.
2, The transcription factor nuclear factor-kB (NF-kB) plays important roles in tumor invasion, metastasis, and chemoresistance. Aberrant NF-kB expression correlates with aggressive tumor behavior and poor prognosis in patients with various malignancies. This study evaluated the sesquiterpene lactone parthenolide, an inhibitor of NF-kB, in the treatment of gastric cancer. Parthenolide significantly inhibited cell growth in three gastric cancer cell lines. It downregulated the phosphorylation of NF-kB, and acted synergistically with chemotherapeutic drugs, paclitaxel and cisplatin. In the peritoneal dissemination model, parthenolide as a single agent significantly suppressed the formation of disseminated nodules, and enhanced chemosensitivity to paclitaxel when used in combination. Furthermore, the combined parthenolide and paclitaxel therapy significantly prolonged survival. Parthenolide, a selective NF-□B inhibitor, seems to enhance the chemosensitivity of paclitaxel and cisplatin in the incurable peritoneal dissemination of gastric cancers.

Research Products

• [Journal Article] Gene therapy using ets-1 transcription factor decoy for peritoneal dissemination of gastric cancer. (2007)
  • Author(s): Taniguchi H, Fujiwara Y
  • Journal Title: International Journal of Cancer 121 Pages: 1609-1617
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Genetic detection of free cancer cells in the peritoneal cavity of the patient with gastric cancer: present status and future perspectives. (2007)
  • Author(s): Fujiwara Y
  • Journal Title: Gastric Cancer 10 Pages: 197-204
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gene therapy using ets-1 transcription factor decoy for peritoneal dissemination of gastric cancer (2007)
  • Author(s): Taniguchi, H., Fujiwara, Y
  • Journal Title: International Journal of Cancer 121 Pages: 1609-1617
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic detection of free cancer cells in the peritoneal cavity of the patient with gastric cancer : present status and future perspectives (2007)
  • Author(s): Fujiwara, Y
  • Journal Title: Gastric Cancer 10 Pages: 197-204
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer. (2006)
  • Author(s): Urano N., Fujiwara Y., Doki Y., Kim S. J., Miyoshi Y., Noguchi S., Miyata H., Takiguchi S., Yasuda T., Yano M., Monden M.
  • Journal Title: Int J Oncol 28(2) Pages: 375-381
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of hepatoma-derived growth factor is correlated with lymph nodemetastasis and prognosis of gastric carcinoma. (2006)
  • Author(s): Yamamoto S., Tomita Y., Hoshida Y., Takiguchi S., Fujiwara Y., Yasuda T., Doki Y., Yoshida K., Aozasa K., Nakamura H., Monden M.
  • Journal Title: Clin Cancer Res 12(1) Pages: 117-122
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma. (2006)
  • Author(s): Urano N., Fujiwara Y., Doki Y., Tsujie M., Yamamoto H., Miyata H., Takiguchi S., Yasuda T., Yano M., Monden M.
  • Journal Title: Gastric Cancer 9(1) Pages: 44-49
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A prospective trial for avoiding cervical lymph node dissection for thoracic esophageal cancers, based on infra-operative genetic diagosis of micrometastasis in recurrent laryngeal nerve chain nodes. (2006)
  • Author(s): Miyata H., Yano M., Doki Y., Yasuda T., Yoshioka S., Sugita Y., Takiguchi S., Fujiwara Y., Monden M.
  • Journal Title: J Surg Oncol 93 Pages: 477-484
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prediction of peritoneal metastasis in advanced gastric cancer by gene expression profiling of the primary site. (2006)
  • Author(s): Motoori M., Takemasa I., Doki Y., Saito S., Miyata H., Takiguchi S., Fujiwara Y., Yasuda T., Yano M., Kurokawa Y., Komori T., Yamasaki M., Ueno N., Oba S., Ishii S., Monden M., Kato K.
  • Journal Title: Eur J Cancer 42 Pages: 1897-1903
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer (2006)
  • Author(s): Urano, N., Fujiwara, Y., Doki, Y., Kim, S.J., Miyoshi, Y., Noguchi, S., Miyata, H., Takiguchi, S., Yasuda, T., Yano, M., Monden, M
  • Journal Title: Int J Oncol 28(2) Pages: 375-381
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of hepatoma-derived growth factor is correlated with lymph node metastasis and prognosis of gastric carcinoma (2006)
  • Author(s): Yamamoto, S., Tomita, Y., Hoshida, Y., Takiguchi, S., Fujiwara, Y., Yasuda, T., Doki Y., Yoshida, K., Aozasa, K., Nakamura, H., Monden, M
  • Journal Title: Clin Cancer Res 12(1) Pages: 117-122
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma (2006)
  • Author(s): Urano, N., Fujiwara, Y., Doki, Y., Tsujie, M., Yamamoto, H., Miyata, H., Takiguchi, S., Yasuda, T., Yano, M., Monden, M
  • Journal Title: Gastric Cancer 9(1) Pages: 44-49
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A prospective trial for avoiding cervical lymph node dissection for thoracic esophageal cancers, based on intra-operative genetic diagnosis of micrometastasis in recurrent laryngeal nerve chain nodes (2006)
  • Author(s): Miyata, H., Yano, M., Doki, Y., Yasuda, T., Yoshioka, S., Sugita, Y., Takiguchi, S., Fujiwara, Y., Monden, M
  • Journal Title: J Surg Oncol 932 Pages: 477-484
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prediction of peritoneal metastasis in advanced gastric cancer by gene expression profiling of the primary site (2006)
  • Author(s): Motoori, M., Takemasa, I., Doki, Y., Saito, S., Miyata, H., Takiguchi, S., Fujiwara, Y., Yasuda, T., Yano, M., Kurokawa, Y., Komori, T., Yamasaki, M., Ueno, N., Oba, S., Ishii, S., Monden, M., Kato, K
  • Journal Title: Eur J Cancer 42 Pages: 1897-1903
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer. (2006)
  • Author(s): Urano N., Fujiwara Y., Doki Y., Kim S.J., Miyoshi Y., Noguchi S., Miyata H., Takiguchi S., Yasuda T., Yano M., Monden M.
  • Journal Title: Int J Oncol 28(2) Pages: 375-381
• [Journal Article] Expression of hepatoma-derived growth factor is correlated with lymph node metastasis and prognosis of gastric carcinoma. (2006)
  • Author(s): Yamamoto S., Tomita Y., Hoshida Y., Takiguchi S., Fujiwara Y., Yasuda T., Doki Y., Yoshida K., Aozasa K., Nakamura H., Monden M.
  • Journal Title: Clin Cancer Res 12(1) Pages: 117-122
• [Journal Article] A prospective trial for avoiding cervical lymph node dissection for thoracic esophageal cancers, based on intra-operative genetic diagnosis of micrometastasis in recurrent laryngeal nerve chain nodes. (2006)
  • Author(s): Miyata H., Yano M., Doki Y., Yasuda T., Yoshioka S., Sugita Y., Takiguchi S., Fujiwara Y., Monden M.
  • Journal Title: J Surg Oncol 93 Pages: 477-484
• [Presentation] Parthenolide, a selective NF-kB inhibitor, suppreses tumor growth and enhances response to chemotherapy in gastric cancer (2007)
  • Author(s): Fujiwara Y
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Parthenolide, a selective NF-kB inhibitor, suppreses tumor growth and enhances response to chemotherapy in gastric cancer (2007)
  • Author(s): Fujiwara, Y
  • Organizer: Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Description: 「研究成果報告書概要(欧文)」より