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33 "Yung-Jue Bang"
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Original Articles
Gastrointestinal cancer
A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer
Keun-Wook Lee, Sae-Won Han, Tae Won Kim, Joong Bae Ahn, Ji Yeon Baek, Sang Hee Cho, Howard Lee, Jin Won Kim, Ji-Won Kim, Tae-You Kim, Yong Sang Hong, Seung-Hoon Beom, Yongjun Cha, Yoonjung Choi, Seonhui Kim, Yung-Jue Bang
Cancer Res Treat. 2024;56(2):590-601.   Published online December 7, 2023
DOI: https://doi.org/10.4143/crt.2023.1117
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a).
Materials and Methods
Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study.
Results
RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0).
Conclusion
GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Citations

Citations to this article as recorded by  
  • Drug combinations of camptothecin derivatives promote the antitumor properties
    Zhen Liu, Yajie Yuan, Ning Wang, Peng Yu, Yuou Teng
    European Journal of Medicinal Chemistry.2024; 279: 116872.     CrossRef
  • 3,539 View
  • 138 Download
  • 1 Web of Science
  • 1 Crossref
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Gastrointestinal Cancer
Phase II Trial of Postoperative Adjuvant Gemcitabine and Cisplatin Chemotherapy Followed by Chemoradiotherapy with Gemcitabine in Patients with Resected Pancreatic Cancer
Kyung-Hun Lee, Eui Kyu Chie, Seock-Ah Im, Jee Hyun Kim, Jihyun Kwon, Sae-Won Han, Do-Youn Oh, Jin-Young Jang, Jae-Sung Kim, Tae-You Kim, Yung-Jue Bang, Sun Whe Kim, Sung W. Ha
Cancer Res Treat. 2021;53(4):1096-1103.   Published online December 30, 2020
DOI: https://doi.org/10.4143/crt.2020.928
AbstractAbstract PDFPubReaderePub
Purpose
Despite curative resection, the 5-year survival for patients with resectable pancreatic cancer is less than 20%. Recurrence occurs both locally and at distant sites and effective multimodality adjuvant treatment is needed.
Materials and Methods
Patients with curatively resected stage IB-IIB pancreatic adenocarcinoma were eligible. Treatment consisted of chemotherapy with gemcitabine 1,000 mg/m2 on days 1 and 8 and cisplatin 60 mg/m2 on day 1 every 3 weeks for two cycles, followed by chemoradiotherapy (50.4 Gy/28 fx) with weekly gemcitabine (300 mg/m2/wk), and then gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks for four cycles. The primary endpoint was 1-year disease-free survival rate. The secondary endpoints were disease-free survival, overall survival, and safety.
Results
Seventy-four patients were enrolled. One-year disease-free survival rate was 57.9%. Median disease-free and overall survival were 15.0 months (95% confidence interval [CI], 11.6 to 18.4) and 33.0 months (95% CI, 21.8 to 44.2), respectively. At the median follow-up of 32 months, 57 patients (77.0%) had recurrence including 11 patients whose recurrence was during the adjuvant treatment. Most of the recurrences were systemic (52 patients). Stage at the time of diagnosis (70.0% in IIA, 51.2% in IIB, p=0.006) were significantly related with 1-year disease-free survival rate. Toxicities were generally tolerable, with 53 events of grade 3 or 4 hematologic toxicity and four patients with febrile neutropenia.
Conclusion
Adjuvant gemcitabine and cisplatin chemotherapy followed by chemoradiotherapy with gemcitabine and maintenance gemcitabine showed efficacy and good tolerability in curatively resected pancreatic cancer.

Citations

Citations to this article as recorded by  
  • NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis
    Xiao-Dong Huang, Yong-Wei Chen, Lv Tian, Li Du, Xiao-Chen Cheng, Yu-Xin Lu, Dong-Dong Lin, Feng-Jun Xiao
    Journal of Cancer Research and Clinical Oncology.2024;[Epub]     CrossRef
  • Efficacy of Cisplatin-Containing Chemotherapy Regimens in Patients of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis
    Obaid Ur Rehman, Eeshal Fatima, Zain Ali Nadeem, Arish Azeem, Jatin Motwani, Habiba Imran, Hadia Mehboob, Alishba Khan, Omer Usman
    Journal of Gastrointestinal Cancer.2024; 55(2): 559.     CrossRef
  • OTUB1/NDUFS2 axis promotes pancreatic tumorigenesis through protecting against mitochondrial cell death
    Xiao-Dong Huang, Li Du, Xiao-Chen Cheng, Yu-Xin Lu, Qiao-Wei Liu, Yi-Wu Wang, Ya-Jin Liao, Dong-Dong Lin, Feng-Jun Xiao
    Cell Death Discovery.2024;[Epub]     CrossRef
  • Impact of obesity on pathological complete remission in early stage breast cancer patients after neoadjuvant chemotherapy: a retrospective study from a German University breast center
    Johannes Felix Englisch, Alexander Englisch, Dominik Dannehl, Kenneth Eissler, Christian Martin Tegeler, Sabine Matovina, Léa Louise Volmer, Diethelm Wallwiener, Sara Y. Brucker, Andreas Hartkopf, Tobias Engler
    Archives of Gynecology and Obstetrics.2024; 311(2): 437.     CrossRef
  • A Photothermal Therapy Study Based on Electrospinning Nanofibers Blended and Coated with Polydopamine Nanoparticles
    Chunhong Sui, Yijia Luo, Xiao Xiao, Jiaxue Liu, Xiaotong Shao, Yingxue Xue, Cheng Wang, Wenliang Li
    ChemistrySelect.2023;[Epub]     CrossRef
  • Ivermectin and gemcitabine combination treatment induces apoptosis of pancreatic cancer cells via mitochondrial dysfunction
    Da Eun Lee, Hyeon Woong Kang, So Yi Kim, Myeong Jin Kim, Jae Woong Jeong, Woosol Chris Hong, Sungsoon Fang, Hyung Sun Kim, Yun Sun Lee, Hyo Jung Kim, Joon Seong Park
    Frontiers in Pharmacology.2022;[Epub]     CrossRef
  • CircLMTK2 Silencing Attenuates Gemcitabine Resistance in Pancreatic Cancer by Sponging miR-485-5p and to Target PAK1
    Yeting Lu, Shuping Zhou, Gong Cheng, Yi Ruan, Yuan Tian, Kaiji Lv, Shuo Han, Xinhua Zhou, Xiangya Ding
    Journal of Oncology.2022; 2022: 1.     CrossRef
  • Effects of Radiotherapy and Chemotherapy on Postoperative Prognosis of Patients Undergoing Radical Surgery for Pancreatic Cancer—Based on SEER Database Analysis
    媛媛 苏
    Advances in Clinical Medicine.2022; 12(10): 9540.     CrossRef
  • Zebrafish Patient-Derived Xenografts Identify Chemo-Response in Pancreatic Ductal Adenocarcinoma Patients
    Alice Usai, Gregorio Di Franco, Margherita Piccardi, Perla Cateni, Luca Emanuele Pollina, Caterina Vivaldi, Enrico Vasile, Niccola Funel, Matteo Palmeri, Luciana Dente, Alfredo Falcone, Dimitri Giunchi, Alessandro Massolo, Vittoria Raffa, Luca Morelli
    Cancers.2021; 13(16): 4131.     CrossRef
  • Hypoxia-Induced ZWINT Mediates Pancreatic Cancer Proliferation by Interacting With p53/p21
    Peng Chen, Zhiwei He, Jie Wang, Jian Xu, Xueyi Jiang, Yankun Chen, Xinyuan Liu, Jianxin Jiang
    Frontiers in Cell and Developmental Biology.2021;[Epub]     CrossRef
  • 6,939 View
  • 153 Download
  • 10 Crossref
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Gastrointestinal cancer
Adjuvant Chemotherapy in Microsatellite Instability–High Gastric Cancer
Jin Won Kim, Sung-Yup Cho, Jeesoo Chae, Ji-Won Kim, Tae-Yong Kim, Keun-Wook Lee, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im
Cancer Res Treat. 2020;52(4):1178-1187.   Published online June 11, 2020
DOI: https://doi.org/10.4143/crt.2020.313
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Microsatellite instability (MSI) status may affect the efficacy of adjuvant chemotherapy in gastric cancer. In this study, the clinical characteristics of MSI-high (MSI-H) gastric cancer and the predictive value of MSI-H for adjuvant chemotherapy in large cohorts of gastric cancer patients were evaluated. Material and Methods This study consisted of two cohorts. Cohort 1 included gastric cancer patients who received curative resection with pathologic stage IB-IIIC. Cohort 2 included patients with MSI-H gastric cancer who received curative resection with pathologic stage II/III. MSI was examined using two mononucleotide markers and three dinucleotide markers.
Results
Of 359 patients (cohort 1), 41 patients (11.4%) had MSI-H. MSI-H tumors were more frequently identified in older patients (p < 0.001), other histology than poorly cohesive, signet ring cell type (p=0.005), intestinal type (p=0.028), lower third tumor location (p=0.005), and absent perineural invasion (p=0.027). MSI-H status has a tendency of better disease-free survival (DFS) and overall survival (OS) in multivariable analyses (hazard ratio [HR], 0.4; p=0.059 and HR, 0.4; p=0.063, respectively). In the analysis of 162 MSI-H patients (cohort 2), adjuvant chemotherapy showed a significant benefit with respect to longer DFS and OS (p=0.047 and p=0.043, respectively). In multivariable analysis, adjuvant chemotherapy improved DFS (HR, 0.4; p=0.040).
Conclusion
MSI-H gastric cancer had distinct clinicopathologic findings. Even in MSI-H gastric cancer of retrospective cohort, adjuvant chemotherapy could show a survival benefit, which was in contrast to previous prospective studies and should be investigated in a further prospective trial.

Citations

Citations to this article as recorded by  
  • Management of Microsatellite Instability High (MSI-H) Gastroesophageal Adenocarcinoma
    Katherine I. Zhou, Brent A. Hanks, John H. Strickler
    Journal of Gastrointestinal Cancer.2024; 55(2): 483.     CrossRef
  • The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023
    Feng‐Hua Wang, Xiao‐Tian Zhang, Lei Tang, Qi Wu, Mu‐Yan Cai, Yuan‐Fang Li, Xiu‐Juan Qu, Hong Qiu, Yu‐Jing Zhang, Jie‐Er Ying, Jun Zhang, Ling‐Yu Sun, Rong‐Bo Lin, Chang Wang, Hao Liu, Miao‐Zhen Qiu, Wen‐Long Guan, Sheng‐Xiang Rao, Jia‐Fu Ji, Yan Xin, Wei‐
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    Huakai Tian, Zitao Liu, Zuo Zhang, Lipeng Zhang, Zhen Zong, Jiang Liu, Houqun Ying, Hui Li
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    Frontiers in Immunology.2022;[Epub]     CrossRef
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    Satya Das, Taymeyah Al-Toubah, Jonathan Strosberg
    Cancers.2021; 13(19): 4872.     CrossRef
  • 10,593 View
  • 259 Download
  • 20 Web of Science
  • 5 Crossref
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Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer
Ah-Rong Nam, Mei-Hua Jin, Ju-Hee Bang, Kyoung-Seok Oh, Hye-Rim Seo, Do-Youn Oh, Yung-Jue Bang
Cancer Res Treat. 2020;52(3):945-956.   Published online April 17, 2020
DOI: https://doi.org/10.4143/crt.2020.080
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC.
Materials and Methods
In this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models.
Results
AZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy.
Conclusion
Taken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

Citations

Citations to this article as recorded by  
  • Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma
    Philipp Heumann, Andreas Albert, Karsten Gülow, Denis Tümen, Martina Müller, Arne Kandulski
    Cancers.2024; 16(9): 1690.     CrossRef
  • Inhibition of the ATR-DNAPKcs-RB axis drives G1/S-phase transition and sensitizes triple-negative breast cancer (TNBC) to DNA holliday junctions
    Yue-miao Hu, Xue-cun Liu, Lei Hu, Zhi-wen Dong, Hong-ying Yao, Ying-jie Wang, Wen-jing Zhao, Yu-ke Xiang, Yi Liu, Hong-bo Wang, Qi-kun Yin
    Biochemical Pharmacology.2024; 225: 116310.     CrossRef
  • Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer cells
    Yoshihito Morimoto, Kimihiko Takada, Ami Nakano, Osamu Takeuchi, Kazuhiro Watanabe, Masayoshi Hirohara, Yutaka Masuda
    Cancer Chemotherapy and Pharmacology.2024; 94(6): 763.     CrossRef
  • Immunomodulatory effects of trastuzumab deruxtecan through the cGAS-STING pathway in gastric cancer cells
    Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Su In Lee, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
    Cell Communication and Signaling.2024;[Epub]     CrossRef
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  • Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma
    Giulia Anichini, Chiara Raggi, Mirella Pastore, Laura Carrassa, Luisa Maresca, Enrica Crivaro, Tiziano Lottini, Lea Duwe, Jesper B. Andersen, Lorenzo Tofani, Luca Di Tommaso, Jesus M. Banales, Annarosa Arcangeli, Fabio Marra, Barbara Stecca
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  • Enrichment of Wee1/CDC2 and NF-κB Signaling Pathway Constituents Mutually Contributes to CDDP Resistance in Human Osteosarcoma
    Zhengbo Hu, Lugen Li, Wenxing Lan, Xiao Wei, Xiangyuan Wen, Penghuan Wu, Xianliao Zhang, Xinhua Xi, Yufa Li, Liqi Wu, Wenhu Li, Xiaohong Liao
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    Takuya Suzuki, Takahisa Hirokawa, Anri Maeda, Shinnosuke Harata, Kaori Watanabe, Takeshi Yanagita, Hajime Ushigome, Nozomi Nakai, Yuzo Maeda, Kazuyoshi Shiga, Ryo Ogawa, Akira Mitsui, Masahiro Kimura, Yoichi Matsuo, Hiroki Takahashi, Shuji Takiguchi
    Oncology Reports.2022;[Epub]     CrossRef
  • Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer
    Hye-Rim Seo, Ah-Rong Nam, Ju-Hee Bang, Kyoung-Seok Oh, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
    Cancer Research and Treatment.2022; 54(2): 541.     CrossRef
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    Cancers.2021; 13(15): 3790.     CrossRef
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    Jacqueline Nathansen, Felix Meyer, Luise Müller, Marc Schmitz, Kerstin Borgmann, Anna Dubrovska
    Cancers.2021; 13(19): 4818.     CrossRef
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    Giulia Anichini, Laura Carrassa, Barbara Stecca, Fabio Marra, Chiara Raggi
    Cancers.2021; 13(19): 4774.     CrossRef
  • Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers
    Chiao-En Wu, Yi-Ru Pan, Chun-Nan Yeh, John Lunec
    Biomolecules.2020; 10(11): 1474.     CrossRef
  • 9,409 View
  • 268 Download
  • 18 Web of Science
  • 17 Crossref
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Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer
Mei Hua Jin, Ah-Rong Nam, Ji Eun Park, Ju-Hee Bang, Yung-Jue Bang, Do-Youn Oh
Cancer Res Treat. 2020;52(1):149-166.   Published online June 25, 2019
DOI: https://doi.org/10.4143/crt.2019.183
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors.
Materials and Methods
We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1–mouse model for in vivo experiments to confirm our findings.
Results
In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3β serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion.
Conclusion
Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken toget

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    OncoImmunology.2022;[Epub]     CrossRef
  • Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor–resistant cancer
    Nitasha Gupta, Tzu-Ting Huang, Sachi Horibata, Jung-Min Lee
    Pharmacological Research.2022; 178: 106162.     CrossRef
  • DNA damage response inhibition‐based combination therapies in cancer treatment: Recent advances and future directions
    Tianen Chen, Suparat Tongpeng, Ziyi Lu, Win Topatana, Sarun Juengpanich, Shijie Li, Jiahao Hu, Jiasheng Cao, Cheeshin Lee, Yitong Tian, Mingyu Chen, Xiujun Cai
    Aging and Cancer.2022; 3(1): 44.     CrossRef
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    Mahmoud Mohammad Yaseen, Nizar Mohammad Abuharfeil, Homa Darmani
    Clinical and Translational Oncology.2022; 24(8): 1478.     CrossRef
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    Giulia Petroni, Aitziber Buqué, Lisa M. Coussens, Lorenzo Galluzzi
    Nature Reviews Drug Discovery.2022; 21(6): 440.     CrossRef
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    Mahmoud Mohammad Yaseen, Nizar Mohammad Abuharfeil, Homa Darmani
    Cancer Immunology, Immunotherapy.2022; 71(10): 2325.     CrossRef
  • Targeting protein kinases benefits cancer immunotherapy
    Zhengkun Zhang, Lang Bu, Junhang Luo, Jianping Guo
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2022; 1877(4): 188738.     CrossRef
  • CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment
    Tong Zhang, Haixiang Yu, Xiangpeng Dai, Xiaoling Zhang
    Frontiers in Immunology.2022;[Epub]     CrossRef
  • The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy
    Congqi Shi, Kaiyu Qin, Anqi Lin, Aimin Jiang, Quan Cheng, Zaoqu Liu, Jian Zhang, Peng Luo
    Journal of Experimental & Clinical Cancer Research.2022;[Epub]     CrossRef
  • CMTM6 as a candidate risk gene for cervical cancer: Comprehensive bioinformatics study
    Xiaoting Huang, Wei Liu, Chunshan Liu, Jijie Hu, Baiyao Wang, Anbang Ren, Xiaona Huang, Yawei Yuan, Jinquan Liu, Mingyi Li
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    Cancer Genetics.2021; 252-253: 6.     CrossRef
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  • WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers
    Mei-Hua Jin, Ah-Rong Nam, Ju-Hee Bang, Kyoung-Seok Oh, Hye-Rim Seo, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
    Gastric Cancer.2021; 24(5): 1003.     CrossRef
  • ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer
    Ah-Rong Nam, Jeesun Yoon, Mei-Hua Jin, Ju-Hee Bang, Kyoung-Seok Oh, Hye-Rim Seo, Jae-Min Kim, Tae-Yong Kim, Do-Youn Oh
    Cancer Letters.2021; 516: 38.     CrossRef
  • Development of Immunotherapy Combination Strategies in Cancer
    Timothy A. Yap, Eileen E. Parkes, Weiyi Peng, Justin T. Moyers, Michael A. Curran, Hussein A. Tawbi
    Cancer Discovery.2021; 11(6): 1368.     CrossRef
  • Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities
    Aditi Jain, Vikas Bhardwaj
    World Journal of Gastroenterology.2021; 27(39): 6527.     CrossRef
  • A steroidal saponin isolated from Allium chinense simultaneously induces apoptosis and autophagy by modulating the PI3K/Akt/mTOR signaling pathway in human gastric adenocarcinoma
    Jingwen Xu, Mingmei Zhang, Xiaoying Lin, Yihai Wang, Xiangjiu He
    Steroids.2020; : 108672.     CrossRef
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Therapeutic Targeting of the DNA Damage Response Using an ATR Inhibitor in Biliary Tract Cancer
Ah-Rong Nam, Mei Hua Jin, Ji Eun Park, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang
Cancer Res Treat. 2019;51(3):1167-1179.   Published online December 3, 2018
DOI: https://doi.org/10.4143/crt.2018.526
AbstractAbstract PDFPubReaderePub
Purpose
The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor.
Materials and Methods
A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings.
Results
Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug.
Conclusion
In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.

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    Wenjun Wang, Yu Liu, Dong Chen, Jiajia Pang, Chunyu Lai, Mingbao Gu, Meilun Zhai, Qian Yu, Yang Wang, Xuanwen Bao, Yangyang Li, Xiaomeng Dai, Dong Chen, Peng Zhao, Jinghong Xu, Rui Lei
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    Hye-Rim Seo, Ah-Rong Nam, Ju-Hee Bang, Kyoung-Seok Oh, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
    Cancer Research and Treatment.2022; 54(2): 541.     CrossRef
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    Longxiang Huang, Qin Ye, Chunlin Lan, Xiaohui Wang, Yihua Zhu
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    Longxiang Huang, Zhenni Wei, Xiaohui Wang, Chunlin Lan, Yihua Zhu, Qin Ye
    Biochemical Pharmacology.2022; 206: 115340.     CrossRef
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    Jin Hur, Mithun Ghosh, Tae Heon Kim, Nahee Park, Kamal Pandey, Young Bin Cho, Sa Deok Hong, Nar Bahadur Katuwal, Minsil Kang, Hee Jung An, Yong Wha Moon
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  • ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer
    Ah-Rong Nam, Jeesun Yoon, Mei-Hua Jin, Ju-Hee Bang, Kyoung-Seok Oh, Hye-Rim Seo, Jae-Min Kim, Tae-Yong Kim, Do-Youn Oh
    Cancer Letters.2021; 516: 38.     CrossRef
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  • Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer
    Ah-Rong Nam, Mei-Hua Jin, Ju-Hee Bang, Kyoung-Seok Oh, Hye-Rim Seo, Do-Youn Oh, Yung-Jue Bang
    Cancer Research and Treatment.2020; 52(3): 945.     CrossRef
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Dynamics of Soluble Programmed Death-Ligand 1 (sPDL1) during Chemotherapy and Its Prognostic Implications in Cancer Patients: Biomarker Development in Immuno-oncology
Hyerim Ha, Ju-Hee Bang, Ah-Rong Nam, Ji-Eun Park, Mei Hua Jin, Yung-Jue Bang, Do-Youn Oh
Cancer Res Treat. 2019;51(2):832-840.   Published online October 5, 2018
DOI: https://doi.org/10.4143/crt.2018.311
AbstractAbstract PDFPubReaderePub
Purpose
The soluble programmed death-ligand 1 (sPDL1) has immunosuppressive activity and is a candidate biomarker for immuno-oncology drug development. In this study, we measured sPDL1 at pre- and post-chemotherapy and at disease progression to uncover the dynamics of sPDL1 during treatment in biliary tract cancer (BTC) patients.
Materials and Methods
From 90 BTC patients (training cohort, 53; validation cohort, 37) who were candidates for palliative first-line chemotherapy, blood was collected at pre- and post-chemotherapy (at the time of best response) and at disease progression. The sPDL1 levels were measured using an enzyme-linked immunosorbent assay. Responses to chemotherapy, overall survival (OS), and other prognostic factors including the neutrophil-lymphocyte ratio (NLR) were analyzed.
Results
The OS of all patients was 11.5 months (confidence interval [CI], 9.7 to 16.2). The best response was complete response in seven (7.8%), partial response in 20 (22.2%), stable disease in 52 (57.8%), and disease progression (PD) in 11 patients (12.2%). Patients with high pre-chemotherapy sPDL1 (≥ 1.30 ng/mL) showed worse OS than patients with low prechemotherapy sPDL1 (9.1 months vs. 12.5 months, p=0.003). In multivariate analyses, high pre-chemotherapy sPDL1 (hazard ratio [HR], 1.96; 95% CI, 1.2 to 3.9; p=0.011) and high pre-chemotherapy NLR (HR, 1.82; 95% CI, 1.1 to 3.0; p=0.020) were independent poor prognostic factors for OS. At the time of PD, sPDL1 was increased significantly compared with pre-chemotherapy sPDL1 (1.59 ng/mL vs. 0.72 ng/mL, p=0.003).
Conclusion
The sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlate with disease burden and have prognostic value.

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    Yangyang Ding, Cheng Sun, Linhui Hu, Shudao Xiong, Zhimin Zhai
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    Woochan Park, Ju-Hee Bang, Ah-Rong Nam, Mei Hua Jin, Hyerim Seo, Jae-Min Kim, Kyoung Seok Oh, Tae-Yong Kim, Do-Youn Oh
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    Shujun Liu, Yadi Zhu, Chenxi Zhang, Xiangrui Meng, Bo Sun, Guojun Zhang, Yubo Fan, Xixiong Kang
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    Hyunkyung Park, Ju‐Hee Bang, Ah‐Rong Nam, Ji Eun Park, Mei Hua Jin, Yung‐Jue Bang, Do‐Youn Oh
    Cancer Medicine.2020; 9(1): 43.     CrossRef
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Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer
Ah-Rong Nam, Ji-Won Kim, Ji Eun Park, Ju-Hee Bang, Mei Hua Jin, Do-Youn Oh, Yung-Jue Bang
Cancer Res Treat. 2019;51(3):886-900.   Published online October 1, 2018
DOI: https://doi.org/10.4143/crt.2018.375
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied.
Materials and Methods
We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC.
Results
Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and p27 expression.
Conclusion
Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations.

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  • COP9 signalosome complex is a prognostic biomarker and corresponds with immune infiltration in hepatocellular carcinoma
    Jiahui Liu, Dexing Han, Junfeng Xuan, Jinye Xie, Weijia Wang, Quan Zhou, Kang Chen
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    Liping Wang, Xiaojiao Zeng, Gui Yang, Guohong Liu, Yunbao Pan
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    Chunjue Yuan, Dong Wang, Guohong Liu, Yunbao Pan
    International Journal of Clinical Oncology.2021; 26(7): 1159.     CrossRef
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  • 225 Download
  • 6 Web of Science
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Pan-Pim Kinase Inhibitor AZD1208 Suppresses Tumor Growth and Synergistically Interacts with Akt Inhibition in Gastric Cancer Cells
Miso Lee, Kyung-Hun Lee, Ahrum Min, Jeongeun Kim, Seongyeong Kim, Hyemin Jang, Jee Min Lim, So Hyeon Kim, Dong-Hyeon Ha, Won Jae Jeong, Koung Jin Suh, Yae-Won Yang, Tae Yong Kim, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im
Cancer Res Treat. 2019;51(2):451-463.   Published online June 6, 2018
DOI: https://doi.org/10.4143/crt.2017.341
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells.
Materials and Methods
The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis.
Results
AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines.
Conclusion
Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.

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    Maiara Bernardes Marques, Michael González-Durruthy, Bruna Félix da Silva Nornberg, Bruno Rodrigues Oliveira, Daniela Volcan Almeida, Ana Paula de Souza Votto, Luis Fernando Marins
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Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
Tae Min Kim, Keun-Wook Lee, Do-Youn Oh, Jong-Seok Lee, Seock-Ah Im, Dong-Wan Kim, Sae-Won Han, Yu Jung Kim, Tae-You Kim, Jee Hyun Kim, Hyesun Han, Woo Ho Kim, Yung-Jue Bang
Cancer Res Treat. 2018;50(3):835-842.   Published online August 29, 2017
DOI: https://doi.org/10.4143/crt.2017.303
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors.
Materials and Methods
Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort.
Results
A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Doselimiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer).
Conclusion
Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

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TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study
Yung-Jue Bang, Toshimi Takano, Chia-Chi Lin, Adedigbo Fasanmade, Huyuan Yang, Hadi Danaee, Takayuki Asato, Thea Kalebic, Hui Wang, Toshihiko Doi
Cancer Res Treat. 2018;50(2):398-404.   Published online May 10, 2017
DOI: https://doi.org/10.4143/crt.2017.074
AbstractAbstract PDFPubReaderePub
Purpose
This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC).
Materials and Methods
Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264.
Results
Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response.
Conclusion
TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose.

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Korean Cancer Patients’ Awareness of Clinical Trials, Perceptions on the Benefit and Willingness to Participate
Yoojoo Lim, Jee Min Lim, Won Jae Jeong, Kyung-Hun Lee, Bhumsuk Keam, Tae-Yong Kim, Tae Min Kim, Sae-Won Han, Do Youn Oh, Dong-Wan Kim, Tae-You Kim, Dae Seog Heo, Yung-Jue Bang, Seock-Ah Im
Cancer Res Treat. 2017;49(4):1033-1043.   Published online April 7, 2017
DOI: https://doi.org/10.4143/crt.2016.413
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to assess current levels of awareness of clinical trials (CTs), perceptions regarding their benefits and willingness to participate to CTs among Korean cancer patients.
Materials and Methods
From December 2012 to August 2015, we distributed questionnaires to cancer patients receiving systemic anti-cancer therapy at Seoul National University Hospital, Seoul, Korea.
Results
A total of 397 out of 520 requested patients (76.3%) responded to the survey. Among the 397 patients, 62.5% were female and the median age was 52 years. Overall, 97.4% (387/397) answered that they have at least heard of CTs. When asked about their level of awareness, 23.8% (92/387) answered that they could more than roughly explain about CTs. The average visual analogue scale score of CT benefit in all patients was 6.43 (standard deviation, 2.20). Patients who were only familiar with the term without detailed knowledge of the contents had the least expectation of benefit from CTs (p=0.015). When asked about their willingness to participate in CTs, 56.7% (225/397) answered positively. Patients with higher levels of awareness of CTs showed higher willingness to participate (p < 0.001). Heavily treated patients and patients with previous experience regarding CTs also showed a higher willingness to participate (p < 0.001). The perceived benefit of CTs was higher in the group willing to participate (p=0.026).
Conclusion
The patient’s level of awareness regarding CTs was positively related to the positive perception and willingness to participate. Although the general awareness of CTs was high, a relatively large proportion of patients did not have accurate knowledge; therefore, proper and accurate patient education is necessary.

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S-1–Induced Lacrimal Drainage Obstruction and Its Association with Ingredients/Metabolites of S-1 in Tears and Plasma: A Prospective Multi-institutional Study
Namju Kim, Jin Won Kim, Je-Hyun Baek, Jin-Soo Kim, Ho-Kyung Choung, Tae-Yong Kim, Kyung-Hun Lee, Yung-Jue Bang, Sang In Khwarg, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Jae-Yong Chung, Soyeon Ahn, Keun-Wook Lee
Cancer Res Treat. 2018;50(1):30-39.   Published online February 27, 2017
DOI: https://doi.org/10.4143/crt.2016.569
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This prospective study was conducted to determine the incidence of lacrimal drainage obstruction (LDO) during S-1 chemotherapy and evaluate the association between the development of LDO and the concentrations of ingredients/metabolites of S-1 in tears and plasma.
Materials and Methods
A total of 145 patients with gastric cancer who received adjuvant S-1 therapy were enrolled. Ophthalmologic examinations were performed regularly during S-1 chemotherapy. Concentrations of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and 5-fluorouracil at steady-state trough level were measured in both tears and plasma.
Results
Fifty-three patients (37%) developed LDO. The median time to the onset of LDO was 10.9 weeks, and LDO developed most frequently in the nasolacrimal duct. Univariable analyses revealed that an older age (≥ 70 years), creatinine clearance rate (Ccr) < 80 mL/min, 5-fluorouracil concentration in plasma ≥ 22.3 ng/mL (median), CDHP concentration in plasma ≥ 42.0 ng/mL (median), and tegafur concentration in tears ≥ 479.2 ng/mL (median) were related to increased development of LDO. Multivariable analysis indicated that a high plasma 5-fluorouracil concentration was predictive of increased development of LDO (hazard ratio, 2.02; p=0.040), along with older age and decreased Ccr. Patients with LDO also developed S-1–related non-hematologic toxicity more frequently than those without LDO (p=0.016).
Conclusion
LDO is a frequent adverse event during S-1 chemotherapy. An older age, decreased Ccr, and high plasma 5-fluorouracil concentration were found to be independent risk factors for LDO. The high incidence of LDO warrants regular ophthalmologic examination and early intervention in patients receiving S-1 therapy.

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  • Ocular complication induced by anticancer drug S-1: association with drug concentrations in tears
    Masakazu Yamada, Tomoyuki Kamao, Atsushi Shiraishi, Jo Sakai, Yuichi Ohashi, Masashi Mimura, Yoshitsugu Inoue, Kazuyoshi Ohtomo, Tai-ichiro Chikama, Chika Miyazaki, Yuka Hosotani
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    Shubin Li, Xuebin Peng, MinJie Wang, Wenqian Wang, Yuye Liu, Qian Yang, Makoto Ozawa
    Transboundary and Emerging Diseases.2024;[Epub]     CrossRef
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    Vasily D. Yartsev, Eugenia L. Atkova
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    Camilla Duarte Silva, Fabricio Lopes da Fonseca, Juliana Mika Kato, Suzana Matayoshi
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    Hisataka Ominato, Michihisa Kono, Hidekiyo Yamaki, Takumi Kumai, Miki Takahara, Akihiro Katada, Tatsuya Hayashi
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    Hirofumi Yasui, Takeshi Kawakami, Hiroya Kashiwagi, Keita Mori, Katsuhiro Omae, Jun Kasai, Kunihiro Yoshisue, Masahiro Kawahira, Takahiro Tsushima, Nozomu Machida, Akira Fukutomi, Ken Yamaguchi
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CA19-9 or CEA Decline after the First Cycle of Treatment Predicts Survival in Advanced Biliary Tract Cancer Patients Treated with S-1 and Cisplatin Chemotherapy
Dae-Won Lee, Seock-Ah Im, Yu Jung Kim, Yaewon Yang, Jiyoung Rhee, Im Il Na, Kyung-Hun Lee, Tae-Yong Kim, Sae-Won Han, In Sil Choi, Do-Youn Oh, Jee Hyun Kim, Tae-You Kim, Yung-Jue Bang
Cancer Res Treat. 2017;49(3):807-815.   Published online January 18, 2017
DOI: https://doi.org/10.4143/crt.2016.326
AbstractAbstract PDFPubReaderePub
Purpose
While tumor markers (carbohydrate antigen 19-9 [CA 19-9] and carcinoembryonic antigen [CEA]) can aid in the diagnosis of biliary tract cancer, their prognostic role has not been clearly elucidated. Therefore, this study was conducted to evaluate the prognostic role of tumor markers and tumor marker change in patients with advanced biliary tract cancer.
Materials and Methods
Patients with pathologically proven metastatic or relapsed biliary tract cancer who were treated in a phase II trial of first-line S-1 and cisplatin chemotherapy were enrolled. Serum tumor markers were measured at baseline and after the first cycle of chemotherapy.
Results
Among a total of 104 patients, 80 (77%) had elevated baseline tumor markers (69 with CA 19-9 elevation and 40 with CEA). A decline ≥ 30% of the elevated tumor marker level after the first cycle of chemotherapy conferred an improved time to progression (TTP), overall survival (OS), and better chemotherapy response. Multivariate analysis revealed tumor marker decline as an independent positive prognostic factor of TTP (adjusted hazard ratio [HR], 0.44; p=0.003) and OS (adjusted HR, 0.37; p < 0.001). Subgroup analysis revealed similar results in each group of patients with CA 19-9 elevation and CEA elevation. In addition, elevated baseline CEA was associated with poor survival in both univariate and multivariate analysis.
Conclusion
Tumor marker decline was associated with improved survival in biliary tract cancer. Measuring tumor marker after the first cycle of chemotherapy can be used as an early assessment of treatment outcome.

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Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis
Seongyeong Kim, Ahrum Min, Kyung-Hun Lee, Yaewon Yang, Tae-Yong Kim, Jee Min Lim, So Jung Park, Hyun-Jin Nam, Jung Eun Kim, Sang-Hyun Song, Sae-Won Han, Do-Youn Oh, Jee Hyun Kim, Tae-You Kim, David Hangauer, Johnson Yiu-Nam Lau, Kyongok Im, Dong Soon Lee, Yung-Jue Bang, Seock-Ah Im
Cancer Res Treat. 2017;49(3):643-655.   Published online October 6, 2016
DOI: https://doi.org/10.4143/crt.2016.168
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo.
Materials and Methods
The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects.
Results
KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho- Src and proliferative-signaling molecules were down-regulated in KX-01–sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01– induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01–sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model.
Conclusion
KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.

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Real-World Treatment Patterns among Patients with Advanced Gastric Cancer in South Korea
Gebra Cuyun Carter, Anna Kaltenboeck, Jasmina Ivanova, Astra M. Liepa, Alexandra San Roman, Maria Koh, Narayan Rajan, Rebecca Cheng, Howard G. Birnbaum, Jong Seok Kim, Yung-Jue Bang
Cancer Res Treat. 2017;49(3):578-587.   Published online September 12, 2016
DOI: https://doi.org/10.4143/crt.2016.001
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to understand patient treatment patterns, outcomes, and healthcare resource use in cases of metastatic and/orlocally recurrent, unresectable gastric cancer (MGC) in South Korea.
Materials and Methods
Thirty physicians reviewed charts of eligible patients to collect de-identified data. Patients must have received platinum/fluoropyrimidine first-line therapy followed by second-line therapy or best supportive care, had no other primary cancer, and not participated in a clinical trial following MGC diagnosis. Data were summarized using descriptive statistics. Kaplan-Meier analysis was used to describe survival.
Results
Of 198 patients, 73.7% were male, 78.3% were diagnosed with MGC after age 55 (mean, 61.3 years), and 47.0% were current orformer smokers. The majority of tumorswere located in the antrum/pylorus (51.5%). Metastatic sites most often occurred in the peritoneum (53.5%), lymph nodes (47.5%), and liver (38.9%). At diagnosis, the mean Charlson comorbidity indexwas 0.4 (standard deviation, 0.6). The most common comorbiditieswere chronic gastritis (22.7%) and cardiovascular disease (18.7%). Most patients (80.3%) received second-line treatment. Single-agent fluoropyrimidine was reported for 22.0% of patients, while 19.5% were treated with irinotecan and a fluoropyrimidine or platinum agent. The most common physician-reported symptoms during second-line treatment were nausea/vomiting (44.7%) and pain (11.3%), with antiemetics (44.7%), analgesics (36.5%), and nutritional support (11.3%) most often used as supportive care. Two-thirds of inpatient hospitalizations were for chemotherapy infusion. Outpatient hospitalization (31.6%) and visits to the oncologist (58.8%) were common among second-line patients.
Conclusion
Most patients received second-line treatment, although regimens varied. Understanding MGC patient characteristics and treatment patterns in South Korea will help address unmet needs.

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Long-Term Outcome of Distal Cholangiocarcinoma after Pancreaticoduodenectomy Followed by Adjuvant Chemoradiotherapy: A 15-Year Experience in a Single Institution
Byoung Hyuck Kim, Kyubo Kim, Eui Kyu Chie, Jeanny Kwon, Jin-Young Jang, Sun Whe Kim, Do-Youn Oh, Yung-Jue Bang
Cancer Res Treat. 2017;49(2):473-483.   Published online August 23, 2016
DOI: https://doi.org/10.4143/crt.2016.166
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study was conducted to evaluate the long-term outcome in patients undergoing pancreaticoduodenectomy (PD) followed by adjuvant chemoradiotherapy for distal cholangiocarcinoma (DCC) in a high-volume center and to identify the prognostic impact of clinicopathologic factors.
Materials and Methods
A total of 132 consecutive patients who met the inclusion criteria were retrieved from the institutional database from January 1995 to September 2009. All patients received adjuvant treatments at a median of 45 days after the surgery. Median follow-up duration was 57 months (range, 6 to 225 months) for all patients and 105 months for survivors (range, 13 to 225 months).
Results
The 5-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates were 70.7%, 55.7%, 49.4%, and 48.1%, respectively. Univariate analysis revealed poorly differentiated (P/D) tumors and lymph node (LN) metastasis were significantly associated with DMFS and OS. Additionally, preoperative carbohydrate antigen 19-9 level was significantly correlated with DFS, LRRFS, and DMFS. Upon multivariate analysis for OS, P/D tumors (p=0.015) and LN metastasis (p=0.003) were significant prognosticators that predicted inferior OS. Grade 3 or higher late gastrointestinal toxicity occurred in only one patient (0.8%).
Conclusion
Adjuvant chemoradiotherapy after PD for DCC is an effective and tolerable strategy without significant side effects. During long-term follow-up, we found that prognosis of DCC was mainly influenced by histologic differentiation and LN metastasis. For patients with these risk factors, further research should focus on improving adjuvant strategies as well as other treatment approaches.

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Splenomegaly and Its Associations with Genetic Polymorphisms and Treatment Outcome in Colorectal Cancer Patients Treated with Adjuvant FOLFOX
Mi-Jung Kim, Sae-Won Han, Dae-Won Lee, Yongjun Cha, Kyung-Hun Lee, Tae-Yong Kim, Do-Youn Oh, Se Hyung Kim, Seock-Ah Im, Yung-Jue Bang, Tae-You Kim
Cancer Res Treat. 2016;48(3):990-997.   Published online January 14, 2016
DOI: https://doi.org/10.4143/crt.2015.296
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Splenomegaly is a clinical surrogate of oxaliplatin-induced sinusoidal obstruction syndrome (SOS). We investigated development of splenomegaly and its association with treatment outcome and genetic polymorphisms following adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in colorectal cancer (CRC) patients.
Materials and Methods
Splenomegaly was determined by spleen volumetry using computed tomography images obtained before initiation of chemotherapy and after completion of adjuvant FOLFOX in CRC patients. Ten genetic polymorphisms in 4 SOS-related genes (VEGFA, MMP9, NOS3, and GSTP1) were analyzed using DNA from peripheral blood mononuclear cells.
Results
Of 124 patients included, increase in spleen size was observed in 109 (87.9%). Median change was 31% (range, –42% to 168%). Patients with splenomegaly had more severe thrombocytopenia compared to patients without splenomegaly during the chemotherapy period (p < 0.0001). The cumulative dose of oxaliplatin and the lowest platelet count during the chemotherapy period were clinical factors associated with splenomegaly. However, no significant associations were found between genetic polymorphisms and development of splenomegaly. Disease-free survival was similar regardless of the development of splenomegaly.
Conclusion
Splenomegaly was frequently observed in patients receiving adjuvant FOLFOX and resulted in more severe thrombocytopenia but did not influence treatment outcome. Examined genetic polymorphisms did not predict development of splenomegaly.

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Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study
Younak Choi, Do-Youn Oh, Kyubo Kim, Eui Kyu Chie, Tae-Yong Kim, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Sung Whan Ha, Yung-Jue Bang
Cancer Res Treat. 2016;48(3):1045-1055.   Published online October 16, 2015
DOI: https://doi.org/10.4143/crt.2015.226
AbstractAbstract PDFPubReaderePub
Purpose
The optimal treatment strategy for locally advanced pancreatic cancer (LAPC), particularly the role of concurrent chemoradiotherapy (CCRT), remains debatable. We compared the clinical outcomes of CCRT and palliative chemotherapy alone (CA) in patients with unresectable LAPC. Materials and Methods Patients with LAPC who were consecutively treated between 2003 and 2010 were included. Resectability was evaluated according to National Comprehensive Cancer Network ver. 1.2012. The clinical outcomes for each treatment group (CCRT vs. CA) were evaluated retrospectively.
Results
Sixty-three patients (58.9%) and 44 patients (41.1%) were treated with CCRT and CA, respectively. The CCRT cohort included patients who were treated with CCRT with or without chemotherapy backbone (CCRT alone, induction chemotherapy-CCRT, CCRT-maintenance chemotherapy, and induction-CCRT-maintenance chemotherapy). Median progression-free survival (PFS) and overall survival (OS) of all patients were 7.2 months and 13.1 months. PFS of the CCRT and CA groups was 9.0 months and 4.4 months, respectively (p=0.020). OS of the CCRT and CA groups was 15.4 months and 9.3 months, respectively (p=0.011). In multivariate analysis, the adjusted hazard ratio of CCRT was 0.536 (p=0.003) for OS and 0.667 (p=0.078) for PFS. Although the pattern of failure was similar in the CCRT and CA groups, the times to both local and distant failure were significantly longer in the CCRT group. Conclusion In patients with unresectable LAPC, those who underwent CCRT during their entire treatment courses had longer OS than patients treated with chemotherapy alone.

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VEGF and Ki-67 Overexpression in Predicting Poor Overall Survival in Adenoid Cystic Carcinoma
Seongyeol Park, Soo Jeong Nam, Bhumsuk Keam, Tae Min Kim, Yoon Kyung Jeon, Se-Hoon Lee, J. Hun Hah, Tack-Kyun Kwon, Dong-Wan Kim, Myung-Whun Sung, Dae Seog Heo, Yung-Jue Bang
Cancer Res Treat. 2016;48(2):518-526.   Published online July 14, 2015
DOI: https://doi.org/10.4143/crt.2015.093
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to evaluate potential prognostic factors in patients with adenoid cystic carcinoma (ACC). Materials and Methods A total of 68 patients who underwent curative surgery and had available tissue were enrolled in this study. Their medical records and pathologic slides were reviewed and immunohistochemistry for basic fibroblast growth factor, fibroblast growth factor receptor (FGFR) 2, FGFR3, c-kit, Myb proto-oncogene protein, platelet-derived growth factor receptor beta, vascular endothelial growth factor (VEGF), and Ki-67 was performed. Univariate and multivariate analysis was performed for determination of disease-free survival (DFS) and overall survival (OS).
Results
In univariate analyses, primary site of nasal cavity and paranasal sinus (p=0.022) and Ki-67 expression of more than 7% (p=0.001) were statistically significant factors for poor DFS. Regarding OS, perineural invasion (p=0.032), high expression of VEGF (p=0.033), and high expression of Ki-67 (p=0.007) were poor prognostic factors. In multivariate analyses, primary site of nasal cavity and paranasal sinus (p=0.028) and high expression of Ki-67 (p=0.004) were independent risk factors for poor DFS, and high expression of VEGF (p=0.011) and Ki-67 (p=0.011) showed independent association with poor OS. Conclusion High expression of VEGF and Ki-67 were independent poor prognostic factors for OS in ACC.

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The Impact of Diabetes Mellitus and Metformin Treatment on Survival of Patients with Advanced Pancreatic Cancer Undergoing Chemotherapy
Younak Choi, Tae-Yong Kim, Do-Youn Oh, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Yung-Jue Bang
Cancer Res Treat. 2016;48(1):171-179.   Published online March 13, 2015
DOI: https://doi.org/10.4143/crt.2014.292
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
A causal relationship between diabetes mellitus (DM) and pancreatic cancer is well established. However, in patients with advanced pancreatic cancer (APC) who receive palliative chemotherapy, the impact of DM on the prognosis of APC is unclear. Materials and Methods We retrospectively enrolled APC patients who received palliative chemotherapy between 2003 and 2010. The patients were stratified according to the status of DM, in accordance with 2010 DM criteria (American Heart Association/American Diabetes Association). DM at least 2 years’ duration prior to diagnosis of APC was defined as remote-onset DM (vs. recent-onset).
Results
Of the 349 APC patients, 183 (52.4%) had DM. Among the patients with DM, 160 patients had DM at the time of diagnosis of APC (remote-onset, 87; recent-onset, 73) and the remaining 23 patients developed DM during treatment of APC. Ultimately, 73.2% of patients (134/183) with DM received antidiabetic medication, including metformin (56 patients, 41.8%), sulfonylurea (62, 45.5%), and insulin (43, 32.1%). In multivariate analysis, cancer extent (hazard ratio [HR], 1.792; 95% confidence interval [CI], 1.313 to 2.445; p < 0.001) showed association with decreased overall survival (OS), whereas a diagnosis of DM (HR, 0.788; 95% CI, 0.615 to 1.009; p=0.059) conferred positive tendency on the OS. Metformin treatment itself conferred better OS in comparison within DM patients (HR 0.693; 95% CI, 0.492 to 0.977; p=0.036) and even in all APC patients (adjusted HR, 0.697; 95% CI, 0.491 to 1.990; p=0.044). Conclusion For APC patients receiving palliative chemotherapy, metformin treatment is associated with longer OS. Patients with DM tend to survive longer than those without DM.

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Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors
Do-Youn Oh, Se-Hoon Lee, Sae-Won Han, Mi-Jung Kim, Tae-Min Kim, Tae-You Kim, Dae Seog Heo, Miyuki Yuasa, Yasuo Yanagihara, Yung-Jue Bang
Cancer Res Treat. 2015;47(4):607-615.   Published online February 26, 2015
DOI: https://doi.org/10.4143/crt.2014.249
AbstractAbstract PDFPubReaderePub
Purpose
OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. Materials and Methods Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute–Common Terminology Criteria for Adverse Events (NCICTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively.
Results
Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression. Conclusion This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.

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Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors
Do-Youn Oh, Tae-Min Kim, Sae-Won Han, Dong-Yeop Shin, Yun Gyoo Lee, Keun-Wook Lee, Jee Hyun Kim, Tae-You Kim, In-Jin Jang, Jong-Seok Lee, Yung-Jue Bang
Cancer Res Treat. 2016;48(1):28-36.   Published online February 23, 2015
DOI: https://doi.org/10.4143/crt.2014.258
AbstractAbstract PDFPubReaderePub
Purpose
CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. Materials and Methods Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1.
Results
Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m2/day (n=3), 2 mg/m2/day (n=3), 3.3 mg/m2/day (n=3), 5 mg/m2/day (n=3), 7 mg/m2/day (n=3), 9 mg/m2/day (n=6), and 12 mg/m2/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m2/day. The MTD was determined as 12 mg/m2/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). Conclusion This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m2/day on D1 and D8 every 3 weeks.

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Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer
Do-Youn Oh, Toshihiko Doi, Kuniaki Shirao, Keun-Wook Lee, Sook Ryun Park, Ying Chen, Liqiang Yang, Olga Valota, Yung-Jue Bang
Cancer Res Treat. 2015;47(4):687-696.   Published online February 12, 2015
DOI: https://doi.org/10.4143/crt.2014.225
AbstractAbstract PDFPubReaderePub
Purpose
This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination.
Materials and Methods
Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which ≤ 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data.
Results
Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months.
Conclusion
In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

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TGF-β Suppresses COX-2 Expression by Tristetraprolin-Mediated RNA Destabilization in A549 Human Lung Cancer Cells
Soyeong Kang, Ahrum Min, Seock-Ah Im, Sang-Hyun Song, Sang Gyun Kim, Hyun-Ah Kim, Hee-Jun Kim, Do-Youn Oh, Hyun-Soon Jong, Tae-You Kim, Yung-Jue Bang
Cancer Res Treat. 2015;47(1):101-109.   Published online October 22, 2014
DOI: https://doi.org/10.4143/crt.2013.192
AbstractAbstract PDFPubReaderePub
Purpose
Overexpression of cyclooxygenase 2 (COX-2) is thought to promote survival of transformed cells. Transforming growth factor β (TGF-β) exerts anti-proliferative effects on a broad range of epithelial cells. In the current study, we investigated whether TGF-β can regulate COX-2 expression in A549 human lung adenocarcinoma cells, which are TGF-β-responsive and overexpress COX-2.
Materials and Methods
Western blotting, Northern blotting, and mRNA stability assays were performed to demonstrate that COX-2 protein and mRNA expression were suppressed by TGF-β. We also evaluated the effects of tristetraprolin (TTP) on COX-2 mRNA using RNA interference.
Results
We demonstrated that COX-2 mRNA and protein expression were both significantly suppressed by TGF-β. An actinomycin D chase experiment demonstrated that COX-2 mRNA was more rapidly degraded in the presence of TGF-β, suggesting that TGF-β–induced inhibition of COX-2 expression is achieved via decreased mRNA stability. We also found that TGF-β rapidly and transiently induced the expression of TTP, a well-known mRNA destabilizing factor, before suppression of COX-2 mRNA expression was observed. Using RNA interference, we confirmed that increased TTP levels play a pivotal role in the destabilization of COX-2 mRNA by TGF-β. Furthermore, we showed that Smad3 is essential to TTP-dependent down-regulation of COX-2 expression in response to TGF-β.
Conclusion
The results of this study show that TGF-β down-regulated COX-2 expression via mRNA destabilization mediated by Smad3/TTP in A549 cells.

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Prognostic Value of Splenic Artery Invasion in Patients Undergoing Adjuvant Chemoradiotherapy after Distal Pancreatectomy for Pancreatic Adenocarcinoma
Byoung Hyuck Kim, Kyubo Kim, Eui Kyu Chie, Jin-Young Jang, Sun Whe Kim, Sae-Won Han, Do-Youn Oh, Seock-Ah Im, Tae-You Kim, Yung-Jue Bang, Ijin Joo, Sung W. Ha
Cancer Res Treat. 2015;47(2):274-281.   Published online September 12, 2014
DOI: https://doi.org/10.4143/crt.2014.025
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to evaluate the outcome of adjuvant chemoradiotherapy (CRT) after distal pancreatectomy (DP) in patients with pancreatic adenocarcinoma, and to identify the prognostic factors for these patients.
Materials and Methods
We performed a retrospective review of 62 consecutive patients who underwent curative DP followed by adjuvant CRT between 2000 and 2011. There were 31 men and 31 women, and the median age was 64 years (range, 38 to 80 years). Adjuvant radiotherapy was delivered to the tumor bed and regional lymph nodes with a median dose of 50.4 Gy (range, 40 to 55.8 Gy). All patients received concomitant chemotherapy, and 53 patients (85.5%) also received maintenance chemotherapy. The median follow-up period was 24 months.
Results
Forty patients (64.5%) experienced relapse. Isolated locoregional recurrence developed in 5 patients (8.1%) and distant metastasis in 35 patients (56.5%), of whom 13 had both locoregional recurrence and distant metastasis. The median overall survival (OS) and disease-free survival (DFS) were 37.5 months and 15.4 months, respectively. On multivariate analysis, splenic artery (SA) invasion (p=0.0186) and resection margin (RM) involvement (p=0.0004) were identified as significant adverse prognosticators for DFS. Also, male gender (p=0.0325) and RM involvement (p=0.0007) were associated with a significantly poor OS. Grade 3 or higher hematologic and gastrointestinal toxicities occurred in 22.6% and 4.8% of patients, respectively.
Conclusion
Adjuvant CRT may improve survival after DP for pancreatic body or tail adenocarcinoma. Our results indicated that SA invasion was a significant factor predicting inferior DFS, as was RM involvement. When SA invasion is identified preoperatively, neoadjuvant treatment may be considered.

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A New Isolated Mediastinal Lymph Node or Small Pulmonary Nodule Arising during Breast Cancer Surveillance Following Curative Surgery: Clinical Factors That Differentiate Malignant from Benign Lesions
Tae-Yong Kim, Kyung-Hun Lee, Sae-Won Han, Do-Youn Oh, Seock-Ah Im, Tae-You Kim, Wonshik Han, Kyubo Kim, Eui Kyu Chie, In-Ae Park, Young Tae Kim, Dong-Young Noh, Sung Whan Ha, Yung-Jue Bang
Cancer Res Treat. 2014;46(3):280-287.   Published online July 15, 2014
DOI: https://doi.org/10.4143/crt.2014.46.3.280
AbstractAbstract PDFPubReaderePub
Purpose
A newly isolated mediastinal lymph node (LN) or a small pulmonary nodule, which appears during breast cancer surveillance, may pose a diagnostic dilemma with regard to malignancy. We conducted this study to determine which clinical factors were useful for the differentiation of malignant lesions from benign lesions under these circumstances. Materials and Methods We enrolled breast cancer patients who were presented with a new isolated mediastinal LN or small pulmonary nodule that arose during surveillance, and whose lesions were pathologically confirmed. Tissue diagnosis was made by mediastinoscopy, video-assisted thoracic surgery or thoracotomy. Results A total of 43 patients were enrolled (mediastinal LN, 13 patients; pulmonary nodule, 30 patients). Eighteen patients (41.9%) were pathologically confirmed to have a benign lesion (benign group), and 25 patients (58.1%) were confirmed to have malignant lesion (malignant group). Between the two groups, the initial tumor size (p=0.096) and N stage (p=0.749) were similar. Hormone receptor negativity was more prevalent in the malignant group (59.1% vs. 40.9%, p=0.048). The mean lesion size was larger in the malignant group than in the benign group (20.8 mm vs. 14.4 mm, p=0.024). Metastatic lesions had a significantly higher value of maximal standardized uptake (mSUV) than that of benign lesions (6.4 vs. 3.4, p=0.021). Conclusion Hormone receptor status, lesion size, and mSUV on positron emission tomography are helpful in the differentiation of malignant lesions from benign lesions in breast cancer patients who were presented with a new isolated mediastinal LN or small pulmonary nodule during surveillance.

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A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer
Hyun Jung Lee, Dae-Seog Heo, Joo-Youn Cho, Sae-Won Han, Hye-Jung Chang, Hyeon-Gyu Yi, Tae-Eun Kim, Se-Hoon Lee, Do-Youn Oh, Seock-Ah Im, In-Jin Jang, Yung-Jue Bang
Cancer Res Treat. 2014;46(3):234-242.   Published online July 15, 2014
DOI: https://doi.org/10.4143/crt.2014.46.3.234
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. Materials and Methods Patients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from 30-210 mg/m2. Results A total of twenty-four patients were enrolled. Only one patient experienced a doselimiting toxicity—a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration- time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease. Conclusion The study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m2.

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Clinical Implications of VEGF, TGF-beta1, and IL-1beta in Patients with Advanced Non-small Cell Lung Cancer
Ji-Won Kim, Youngil Koh, Dong-Wan Kim, Yong-Oon Ahn, Tae Min Kim, Sae-Won Han, Do-Youn Oh, Se-Hoon Lee, Seock-Ah Im, Tae-You Kim, Dae Seog Heo, Yung-Jue Bang
Cancer Res Treat. 2013;45(4):325-333.   Published online December 31, 2013
DOI: https://doi.org/10.4143/crt.2013.45.4.325
AbstractAbstract PDFPubReaderePub
PURPOSE
Vascular endothelial growth factor (VEGF)-A, VEGF165b, interleukin (IL)-1beta, and transforming growth factor (TGF)-beta1 are known to influence tumor angiogenesis. Clinical implications of these cytokines need to be elucidated.
MATERIALS AND METHODS
Using clinical data and baseline serum samples of 140 consecutive patients with advanced non-small cell lung cancer who received platinum-based combination chemotherapy, we investigated the association among serum cytokine levels, treatment outcomes, as well as leukocyte and platelet counts.
RESULTS
The median age of patients was 64 years (range, 26 to 86 years). The male to female ratio was 104:36. High TGF-beta1 and IL-1beta levels were associated with shorter progression-free survival, and high VEGF-A and IL-1beta levels were associated with shorter overall survival in the univariate analysis. VEGF165b was not related to the treatment outcomes. Leukocytosis and thrombocytosis were associated with shorter overall survival. The multivariate analysis demonstrated that VEGF-A, IL-1beta, and leukocytosis were significant prognostic factors (p=0.0497, p=0.047, and p<0.001, respectively). Leukocytosis was not associated with recent pneumonia (p=0.937) and correlated with VEGF-A (p<0.001) and TGF-beta1 (p=0.020) levels.
CONCLUSION
Serum VEGF-A, TGF-1beta, and IL-1beta levels, in addition to leukocyte and platelet counts, are shown to be associated with clinical outcomes. Leukocyte and platelet counts are correlated with serum VEGF-A and TGF-beta1 levels.

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Public Awareness of Gastric Cancer Risk Factors and Disease Screening in a High Risk Region: A Population-Based Study
Do-Youn Oh, Kui Son Choi, Hae-Rim Shin, Yung-Jue Bang
Cancer Res Treat. 2009;41(2):59-66.   Published online June 30, 2009
DOI: https://doi.org/10.4143/crt.2009.41.2.59
AbstractAbstract PDFPubReaderePub
Purpose

This study involved a population-based survey to provide evidence of public awareness of risk factors of gastric cancer and to investigate attitudes for the screening of gastric cancer in the South Korean population.

Materials and Methods

Using a nationwide random selection method, 2014 subjects were enrolled in the study between 5 September 2006 and 25 September 2006.

Results

In terms of the awareness of risk factors, awareness was scored as the percentage of the probability of developing gastric cancer when a subject had a particular risk factor. For the risk factors, stress ranked highest with a score of 73.5%, followed by chronic gastritis (score of 72.1%), gastric ulcer (score of 71.2%) and a previous gastrectomy history (score of 68.7%). Other factors included a diet of charred foods (score of 67.3%), alcohol use (score of 65.3%), salty diet (score of 65.1%), history of smoking (score of 64.3%) and Helicobacter pylori infection (score of 57.5%). Subjects believed that 60.4% of all gastric cancers were preventable by lifestyle modification and the subjects believed that regular screening could prevent 72.1% of all gastric cancers. However, 54% of subjects did not receive regular screening and the most common reason for not undergoing screening was a lack of symptoms.

Conclusion

Public education about the risk factors of gastric cancer and of lifestyle modifications and the importance of regular screening regardless of the presence of symptoms should be emphasized to reduce gastric cancer mortality in South Korea.

Citations

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