Cancer Research and Treatment

Original Articles

Gastrointestinal cancer

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 Res Treat. 2022;54(2):541-553. Published online August 6, 2021; DOI: https://doi.org/10.4143/crt.2021.473

Purpose
Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors in BTC.
Materials and Methods
We used 10 BTC cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments.
Results
In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug.
Conclusion
This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients.

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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
Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer
Yijun Xie, Di Xiao, Duo Li, Mei Peng, Wei Peng, Huaxin Duan, Xiaoping Yang
Frontiers in Oncology.2024;[Epub] CrossRef
Update on Combination Strategies of PARP Inhibitors
Zhuoqun Lin, Lingfang Wang, Ziyu Xing, Fenfen Wang, Xiaodong Cheng
Cancer Control.2024;[Epub] CrossRef
The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
Deqian Xie, Bowen Jiang, Shijin Wang, Qifei Wang, Guangzhen Wu
Frontiers in Cell and Developmental Biology.2023;[Epub] CrossRef
DNA Damage Response Inhibitors in Cholangiocarcinoma: Current Progress and Perspectives
Öykü Gönül Geyik, Giulia Anichini, Engin Ulukaya, Fabio Marra, Chiara Raggi
Cells.2022; 11(9): 1463. CrossRef
Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors
Ourania N. Kostopoulou, Mark Zupancic, Mariona Pont, Emma Papin, Monika Lukoseviciute, Borja Agirre Mikelarena, Stefan Holzhauser, Tina Dalianis
Viruses.2022; 14(7): 1372. CrossRef
Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited
Karin Byskata, Monika Lukoseviciute, Filippo Tuti, Mark Zupancic, Ourania N. Kostopoulou, Stefan Holzhauser, Tina Dalianis
Cancers.2022; 15(1): 93. CrossRef

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Prognostic Value of Serum Soluble Programmed Death-Ligand 1 and Dynamics During Chemotherapy in Advanced Gastric Cancer Patients: 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; Cancer Res Treat. 2021;53(1):199-206. Published online October 6, 2020; DOI: https://doi.org/10.4143/crt.2020.497

Abstract PDF Supplementary Material PubReader ePub

Purpose
The soluble form programmed death-ligand 1 (sPDL1) has immunosuppressive properties and is being studied as a candidate biomarker for immuno-oncology drug development. We measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC).
Materials and Methods
We prospectively enrolled 68 GC patients who were candidates for palliative standard first-line chemotherapy, and serially collected blood at baseline and after one cycle of chemotherapy, at the best response and after disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progressionfree survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off value of sPDL1 levels for survival analysis was found using C-statistics.
Results
The median baseline sPDL1 was 0.8 ng/mL (range, 0.06 to 6.06 ng/mL). The median OS and PFS were 14.9 months and 8.0 months, respectively. sPDL1 and NLR showed a weak positive correlation (Spearman’s rho=0.301, p=0.013). Patients with low levels of sPDL1 at diagnosis (< 1.92 ng/mL) showed a better OS and PFS than patients with a high sPDL1. The baseline sPDL1 before treatment was higher in the progressive disease group than in the stable disease and partial response groups. Patients whose sPDL1 increased after the first cycle of chemotherapy showed worse PFS and OS. Following disease progression, sPDL1 increased compared with the baseline.
Conclusion
sPDL1 at prechemotherapy confers a prognostic value for PFS and OS in GC patients under palliative first-line chemotherapy. Dynamics of sPDL1 during chemotherapy correlates with disease progression.

Citations

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Laccase-inspired bi-amino acid MOFs with high substrate affinity: Catalytic deposition induced “signal-down” electrochemical response towards PD-L1
Ruhui Hu, Suyun Zhong, Hezhen Liu, Yawen Liu, Hongxia Chen, Xiaojun Hu
Sensors and Actuators B: Chemical.2024; 399: 134773. CrossRef
Prognostic significance of soluble PD-L1 in prostate cancer
Margarita Zvirble, Zilvinas Survila, Paulius Bosas, Neringa Dobrovolskiene, Agata Mlynska, Gintaras Zaleskis, Jurgita Jursenaite, Dainius Characiejus, Vita Pasukoniene
Frontiers in Immunology.2024;[Epub] CrossRef
CRP and soluble CTLA4 are determinants of anti-PD1 resistance in gastrointestinal cancer
Kotoe Oshima
American Journal of Cancer Research.2024; 14(3): 1174. CrossRef
Soluble immune checkpoint molecules in cancer risk, outcomes prediction, and therapeutic applications
Lin Chen, Yuqing Chao, Wenjing Li, Zhixia Wu, Qinchuan Wang
Biomarker Research.2024;[Epub] CrossRef
Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study)
Hirokazu Shoji, Chie Kudo-Saito, Kengo Nagashima, Hiroshi Imazeki, Kai Tsugaru, Naoki Takahashi, Takeshi Kawakami, Yusuke Amanuma, Takeru Wakatsuki, Naohiro Okano, Yukiya Narita, Yoshiyuki Yamamoto, Rika Kizawa, Kei Muro, Kazunori Aoki, Narikazu Boku
Journal for ImmunoTherapy of Cancer.2024; 12(11): e010174. CrossRef
Prognostic value of tumor mutation burden in patients with advanced gastric cancer receiving first-line chemotherapy
Xiao-Peng Duan, Ke Liu, Xiao-Dong Jiao, Bao-Dong Qin, Bing Li, Xi He, Yan Ling, Ying Wu, Shi-Qi Chen, Yuan-Sheng Zang
Frontiers in Oncology.2023;[Epub] CrossRef
Prognostic value of soluble PD-L1 and exosomal PD-L1 in advanced gastric cancer patients receiving systemic chemotherapy
Kabsoo Shin, Joori Kim, Se Jun Park, Myung Ah Lee, Jae Myung Park, Myung-Gyu Choi, Donghoon Kang, Kyo Young Song, Han Hong Lee, Ho Seok Seo, Sung Hak Lee, Bohyun Kim, Okran Kim, Juyeon Park, Nahyeon Kang, In-Ho Kim
Scientific Reports.2023;[Epub] CrossRef
Site-specific protein biomarkers in gastric cancer: a comprehensive review of novel biomarkers and clinical applications
Takahiro Shinozuka, Mitsuro Kanda, Yasuhiro Kodera
Expert Review of Molecular Diagnostics.2023; 23(8): 701. CrossRef
The predictive role of soluble programmed death ligand 1 in digestive system cancers
Jian Ruan, Zhihong Zhao, Yuting Qian, Ruilian Xu, Guixiang Liao, Feng-Ming (Spring) Kong
Frontiers in Oncology.2023;[Epub] CrossRef
Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?
Magdolna Dank, Dorottya Mühl, Magdolna Herold, Lilla Hornyák, Attila Marcell Szasz, Zoltan Herold
Journal of Clinical Medicine.2022; 11(16): 4815. CrossRef
How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches
Michele Ghidini, Angelica Petrillo, Andrea Botticelli, Dario Trapani, Alessandro Parisi, Anna La Salvia, Elham Sajjadi, Roberto Piciotti, Nicola Fusco, Shelize Khakoo
Journal of Clinical Medicine.2021; 10(7): 1412. CrossRef

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135 Download
12 Web of Science
11 Crossref

Occludin Expression in Brain Tumors and its Relevance to Peritumoral Edema and Survival: Min-Woo Park, Choong-Hyun Kim, Jin-Hwan Cheong, Koang-Hum Bak, Jae-Min Kim, Suck-Jun Oh; Cancer Res Treat. 2006;38(3):139-143. Published online June 30, 2006; DOI: https://doi.org/10.4143/crt.2006.38.3.139

Abstract PDF PubReader ePub

Purpose

Peritumoral brain edema (PTBE) is a serious causative factor that contributes the morbidity or mortality of brain tumors. The development of PTBE is influenced by many factors, including such tight junction proteins as occludin. We evaluated the PTBE volume and survival time with respect to the occludin expression in various pathological types of brain tumors.

Materials and Methods

Fresh-frozen specimens from sixty patients who had brain tumors were obtained during surgery and the tumors were confirmed pathologically. The occludin expression was investigated by Western blot analysis. The PTBE volume was measured by using preoperative magnetic resonance (MR) imaging, and the survival time in each patient was estimated retrospectively.

Results

Occludin was detected in 41 (68.3%) of the cases with brain tumors and it was not expressed in the other 19 (31.7%) cases. Although the lowest expression was revealed in high-grade gliomas, its expression was variable according to the pathology of the brain tumors (p>0.05). The difference of PTBE volume between occludin-positive and negative brain tumors was statistically significant (2072.46±328.73 mm³ vs. 7452.42±1504.19 mm³, respectively, p=0.002). The mean survival time was longer in the occludin-positive tumor group than in the occludin-negative group (38.63±1.57 months vs. 26.16±3.83 months, respectively; p=0.016).

Conclusions

This study suggests that the occludin expression is highly correlated to the development of PTBE in brain tumors and it might be a prognostic indicator for patient survival.

Citations

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Lipid-Based Nanocarriers for Neurological Disorders: A Review of the State-of-the-Art and Therapeutic Success to Date
Bwalya Angel Witika, Madan Sai Poka, Patrick Hulisani Demana, Scott Kaba Matafwali, Siyabonga Melamane, Sandile Maswazi Malungelo Khamanga, Pedzisai Anotida Makoni
Pharmaceutics.2022; 14(4): 836. CrossRef
Blood-Brain Barrier Alterations and Edema Formation in Different Brain Mass Lesions
Peter Solar, Michal Hendrych, Martin Barak, Hana Valekova, Marketa Hermanova, Radim Jancalek
Frontiers in Cellular Neuroscience.2022;[Epub] CrossRef
Evaluation of AQP4/TRPV4 Channel Co-expression, Microvessel Density, and its Association with Peritumoral Brain Edema in Intracranial Meningiomas
Konstantinos Faropoulos, Afroditi Polia, Chrisi Tsakona, Eleanna Pitaraki, Athanasia Moutafidi, George Gatzounis, Martha Assimakopoulou
Journal of Molecular Neuroscience.2021; 71(9): 1786. CrossRef
Peripheral Blood Occludin Level as a Biomarker for Perioperative Cerebral Edema in Patients with Brain Tumors
Shuhai Shi, Jingli Cheng, Chunyang Zhang, Tao Liang, Yunxin Zhang, Yongxing Sun, Ying Zhao, Weili Li, Baoguo Wang
Disease Markers.2020; 2020: 1. CrossRef
Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer’s disease mice
De S Shang, Yi M Yang, Hu Zhang, Li Tian, Jiu S Jiang, Yan B Dong, Ke Zhang, Bo Li, Wei D Zhao, Wen G Fang, Yu H Chen
Journal of Cerebral Blood Flow & Metabolism.2016; 36(11): 1978. CrossRef
Abnormal expression of an ADAR2 alternative splicing variant in gliomas downregulates adenosine-to-inosine RNA editing
Jun Wei, Zhaohui Li, Chao Du, Bin Qi, Xingli Zhao, Liping Wang, Lirong Bi, Guan Wang, Xuan Zhang, Xiaoyun Su, Yuzhuo Pan, Yu Tian
Acta Neurochirurgica.2014; 156(6): 1135. CrossRef
Evaluation of mast cells and hypoxia inducible factor-1 expression in meningiomas of various grades in correlation with peritumoral brain edema
Joanna Reszec, Adam Hermanowicz, Robert Rutkowski, Piotr Bernaczyk, Zenon Mariak, Lech Chyczewski
Journal of Neuro-Oncology.2013; 115(1): 119. CrossRef
Involvement of PI3K and ROCK signaling pathways in migration of bone marrow-derived mesenchymal stem cells through human brain microvascular endothelial cell monolayers
Mei-Na Lin, De-Shu Shang, Wei Sun, Bo Li, Xin Xu, Wen-Gang Fang, Wei-Dong Zhao, Liu Cao, Yu-Hua Chen
Brain Research.2013; 1513: 1. CrossRef

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