Dae-Eun Kim

Prognostic significance of a systemic inflammatory response in patients receiving first-line palliative chemotherapy for recurred or metastatic gastric cancer.

BackgroundThere is increasing evidence that the presence of an ongoing systemic inflammatory response is associated with poor prognosis in patients with advanced cancers. We evaluated the relationships between clinical status, laboratory factors and progression free survival (PFS), and overall survival (OS) in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy.MethodsWe reviewed 402 patients with advanced gastric adenocarcinoma who received first-line palliative chemotherapy from June 2004 and December 2009. Various chemotherapy regimens were used. Eastern Cooperative Oncology Group performance status (ECOG PS), C-reactive protein (CRP), albumin, Glasgow prognostic score (GPS), and clinical factors were recorded immediately prior to first-line chemotherapy. Patients with both an elevated CRP (>1.0 mg/dL) and hypoalbuminemia (<3.5 mg/dL) were assigned a GPS of 2. Patients in whom only one of these biochemical abnormalities was present were assigned a GPS of 1, and patients with a normal CRP and albumin were assigned a score of 0. To evaluate the factors that affected PFS and OS, univariate and multivariate analyses were performed.ResultsAccording to multivariate analysis, the factors independently associated with PFS were ECOG PS (HR 1.37, 95% CI 1.02-1.84, P = 0.035), bone metastasis (HR 1.74, 95% CI 1.14-2.65, P = 0.009), and CRP elevation (HR 1.64, 95% CI 1.28-2.09, P = 0.001). The factors independently associated with OS were ECOG PS (HR 1.33, 95% CI 1.01-1.76, P = 0.037), bone metastasis (HR 1.61, 95% CI 1.08-2.39, P = 0.017), and GPS ≥ 1 (HR 1.76, 95% CI 1.41-2.19, P = 0.001).ConclusionsThe results of this study showed that the presence of a systemic inflammatory response as evidenced by the CRP, GPS was significantly associated with shorter PFS and OS in patients with recurrent or metastatic gastric cancer receiving first-line palliative chemotherapy. Bone metastasis and GPS were very useful indicator for survival in patients with recurrent or metastatic gastric cancer receiving palliative chemotherapy.

Docetaxel-loaded thermoresponsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal metastasis of gastric cancer.

We evaluated the potential of a thermoresponsive hydrogel consisting of conjugated linoleic acid-coupled Pluronic F-127 (Plu-CLA) as a controlled release, intraperitoneal delivery system for docetaxel with the aim of treating peritoneal dissemination of gastric cancer. Previously, we established a peritoneal metastasis model that involves the injection of BALB/c mice with TMK1 human gastric cancer cells. One week after the TMK1 cells were injected, the mice were injected intraperitoneally with docetaxel alone or docetaxel-loaded Plu-CLA. Tumor progression and response to therapy were monitored by micro-positron emission tomography. The total number of peritoneal tumors and the ascites volume were also measured. Compared with docetaxel alone, the combination of docetaxel and Plu-CLA (docetaxel-Plu-CLA) significantly and synergistically reduced tumor cell survival. Docetaxel-Plu-CLA showed excellent anti-tumor activity, inducing apoptosis more potently than docetaxel alone. Docetaxel-Plu-CLA also significantly reduced the number of peritoneal metastatic nodules and increased survival in the peritoneal gastric cancer xenograft model. Our results show that intraperitoneal administration of docetaxel-Plu-CLA synergistically inhibits peritoneal metastasis and prolongs survival in a peritoneal gastric cancer model. Therefore, Plu-CLA is a potential intraperitoneal-route carrier for hydrophobic docetaxel for the effective treatment of peritoneal metastatic gastric cancer.

Blockade of VEGFR-1 and VEGFR-2 Enhances Paclitaxel Sensitivity in Gastric Cancer Cells

Purpose Hypoxia-inducible factor-1α (HIF-1α) increases transcription of the vascular endothelial growth factor (VEGF) gene. Inhibition of VEGF abolishes VEGF mediated induction of HIF-1α. Recent reports suggested that HIF-1α also mediated the induction of class III β-tubulin (TUBB3) in hypoxia. TUBB3 confers resistance to taxanes. Inhibition of VEGF may decrease the expression of HIF-1α and TUBB3. This study was undertaken to investigate the roles of vascular endothelial growth factor receptor (VEGFR) in gastric cancer cell behavior and to identify methods to overcome paclitaxel resistance in vitro. Materials and Methods The protein expression levels of HIF-1α and TUBB3 were measured in human gastric cancer cell lines (AGS) under normoxic and hypoxic conditions. The relationship between TUBB3 and paclitaxel resistance was assessed with small interfering TUBB3 RNA. AGS cells were treated with anti-VEGFR-1, anti-VEGFR-2, placental growth factor (PlGF), bevacizuamb, and paclitaxel. Results Hypoxia induced paclitaxel resistance was decreased by knockdown of TUBB3. Induction of HIF-1α and TUBB3 in AGS is VEGFR-1 mediated and PlGF dependent. Hypoxia-dependent upregulation of HIF-1α and TUBB3 was reduced in response to paclitaxel treatment. Expressions of HIF-1α and TUBB3 were most decreased when AGS cells were treated with a combination of paclitaxel and anti-VEGFR-1. AGS cell cytotoxicity was most increased in response to paclitaxel, anti-VEGFR-1, and anti-VEGFR-2. Conclusion We suggest that blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in TUBB3-expressing gastric cancer cells.

Dendritic cell-based immunotherapy for colon cancer using an HLA-A*0201-restricted cytotoxic T-lymphocyte epitope from tumor-associated antigen 90K

Tumor-associated antigen 90K is implicated in cell–cell and cell-extracellular matrix adhesion through its interaction with galectin-3 and integrin-β1 and is highly expressed in malignant tissues, making it a novel target for the development of new immunotherapies. We investigated a potential immunotherapy treatment for colon cancer using 90K-specific cytotoxic T lymphocytes induced by autologous dendritic cells and pulsed with 90K peptides. We selected three peptides (90K351, 90K5 and 90K523) that bind to HLA-A*0201 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Dendritic cells pulsed with 90K peptides resulted in the efficient generation of mature dendritic cells and exhibited enhanced T-cell stimulation and polarization of naive T cells toward Th1. Dendritic cells pulsed with 90K peptides generated potent cytotoxic T-lymphocytes that lysed T2 cells loaded with each 90K peptide, and 90K+/HLA-A2+ colon cancer cell lines, including HCT116 and SW480, in a dose-dependent and HLA-A*0201-restricted manner. No killing was observed in 90K+/HLA-A2− DLD1 or 90K−/HLA-A2− K562 cells. Therefore, we believe that cytotoxic T-lymphocytes stimulated by 90K peptide-pulsed dendritic cells naturally recognize the 90K peptide presented by colon cancer cells in the context of HLA-A2, and kill 90K-positive tumor cells. Dendritic cells pulsed with 90K peptides led to the induction of granzyme B and perforin positive CD8+ T cells against HCT116 and SW480 cells, but not DLD1 cells. In conclusion, 90K-specific cytotoxic T lymphocytes, generated by stimulating T cells with 90K peptide-pulsed dendritic cells, could be useful effector cells for the immunotherapy treatment of colon cancer.

Intravenous KITENIN shRNA Injection Suppresses Hepatic Metastasis and Recurrence of Colon Cancer in an Orthotopic Mouse Model

KITENIN (KAI1 C-terminal interacting tetraspanin) promotes invasion and metastasis in mouse colon cancer models. In the present study, we evaluated the effects of KITENIN knockdown by intravenous administration of short hairpin RNAs (shRNAs) in an orthotopic mouse colon cancer model, simulating a primary or adjuvant treatment setting. We established orthotopic models for colon cancer using BALB/c mice and firefly luciferase-expressing CT-26 (CT26/Fluc) cells. Tumor progression and response to therapy were monitored by bioluminescence imaging (BLI). In the primary therapy model, treatment with KITENIN shRNA substantially delayed tumor growth (P = 0.028) and reduced the incidence of hepatic metastasis (P = 0.046). In the adjuvant therapy model, KITENIN shRNA significantly reduced the extent of tumor recurrence (P = 0.044). Mice treated with KITENIN shRNA showed a better survival tendency than the control mice (P = 0.074). Our results suggest that shRNA targeting KITENIN has the potential to be an effective tool for the treatment of colon cancer in both adjuvant and metastatic setting.

Abstract 4344: Intraperitoneal administration of docetaxel loaded in thermo-responsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal dissemination of gastric cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Thermo-responsive hydrogel consisting of conjugated linoleic acid-coupled Pluronic F127 (Plu-CLA) is an optimized drug delivery system with anti-cancer activity for controlled release of the hydrophobic drug, docetaxel. In this study, we evaluated the effect of Plu-CLA as a potential new intraperitoneal docetaxel delivery system for peritoneal dissemination of gastric cancer. We have established a peritoneal metastasis models using BALB/c mice by injection with TMK-1 human gastric cancer cells. Mice were injected intraperitoneally with docetaxel alone and docetaxel loaded Plu-CLA at 1 week after TMK1 cells were injected. Tumor progression and response to therapy were monitored by micro-positron emission tomography. The total number of peritoneal tumors and ascites volume were also measured. Compared to docetaxel alone, the combination of docetaxel and Plu-CLA significantly and synergistically reduced cell survival. The combination of docetaxel and Plu-CLA showed excellent anti-tumor activity inducing stronger apoptosis than docetaxel alone. The combination of docetaxel and Plu-CLA also significantly reduced number of peritoneal metastatic nodules and increased the survival in the peritoneal gastric cancer xenograft model. Our results showed that intraperitoneal administration of docetaxel combined with Plu-CLA synergistically inhibited peritoneal metastasis and prolonged the survival in peritoneal gastric cancer model. Therefore, Plu-CLA could be a potential intraperitoneal carrier for hydrophobic docetaxel for the effective treatment of peritoneal metastatic gastric cancer. Citation Format: Woo Kyun Bae, Lothar Hennighausen, Ji Hee Lee, Dae Eun Kim, Jun Eul Hwang, Hyun Jeong Shim, Sang Hee Cho, In-Kyu Park, Ik-Joo Chung. Intraperitoneal administration of docetaxel loaded in thermo-responsive conjugated linoleic acid-incorporated poloxamer hydrogel for the suppression of peritoneal dissemination of gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4344. doi:10.1158/1538-7445.AM2013-4344

Abstract 4691: Class III beta tubulin is a strong predictive marker for taxane-based first-line palliative chemotherapy in recurrent or metastatic gastric cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Backgrounds. Class III β tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in advanced gastric cancer is not clearly defined yet. We analyzed the significance of TUBB3 expression along with ERCC1 in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy. Methods. We reviewed 146 patients with advanced gastric adenocarcinoma who received taxane based first-line palliative chemotherapy between 2004 and 2010 at Chonnam National University Hwasun hospital. Immunohistochemical stain of TUBB3 and ERCC1 was done in paraffin-embedded tumor tissue. We evaluated response to chemotherapy, progression-free survival (PFS), and overall survival (OS). Results. A total of 146 patients with advanced gastric cancer received docetaxel and cisplatin (n=15), or paclitaxel and cisplatin (n=131). The median PFS was significantly shorter for patients with TUBB3 high expression than patients with TUBB3 low expression (3.63 versus 6.67 months, p=0.001). OS was not associated with TUBB3 expression status (12.9 versus 13.1 months, p=0.769). In multivariate analysis, only TUBB3 was related to shorter PFS (HR 2.74, 95% CI 1.91-3.91, p=0.001). Patients with ERCC1 high expression showed lower response rate than patients with ERCC1 low expression (24% versus 63.2%, p=0.001), however ERCC1 showed no clinical influence on PFS and OS. Conclusions. TUBB3 is a strong predictive marker in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy. Clinical impact of ERCC1 is not evident in this setting. Citation Format: Jun-Eul Hwang, Dae-Eun Kim, Hyun-Jeong Shim, Woo-Kyun Bae, In-Jae Oh, Sang-Hee Cho, Ik-Joo Chung. Class III beta tubulin is a strong predictive marker for taxane-based first-line palliative chemotherapy in recurrent or metastatic gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4691. doi:10.1158/1538-7445.AM2013-4691