39 results on '"Hui-Jen, Tsai"'
Search Results
2. Phase I Dose-Escalation Study of SCB01A, a Microtubule Inhibitor with Vascular Disrupting Activity, in Patients with Advanced Solid Tumors
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Chia-Chi Lin, Shang Yin Wu, Her Shyong Shiah, Hui Jen Tsai, Kwang Yu Chang, Chia Jui Yen, Wu Chou Su, Jang Yang Chang, Ching Chiung Wang, Li-Tzong Chen, and Nai Jung Chiang
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Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Nausea ,Antineoplastic Agents ,Microtubules ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Neoplasms ,Internal medicine ,medicine ,Humans ,Adverse effect ,Dose-Response Relationship, Drug ,biology ,business.industry ,Clinical Trial Results ,Neurotoxicity ,medicine.disease ,Tubulin Modulators ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cohort ,Toxicity ,biology.protein ,Vomiting ,Creatine kinase ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Lessons Learned SCB01A is a novel microtubule inhibitor with vascular disrupting activity. This first-in-human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity. SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity. Background SCB01A, a novel microtubule inhibitor, has vascular disrupting activity. Methods In this phase I dose-escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m2 to the maximum tolerated dose (MTD) based on dose-limiting toxicity (DLT). SCB01A-induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints. Results Treatment-related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m2 cohort; grade 3 gastric hemorrhage in the 6.5 mg/m2 cohort; grade 2 thromboembolic event in the 24 mg/m2 cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m2 cohort. The MTD was 24 mg/m2, and average half-life was ~2.5 hours. The area under the curve-dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A-induced neurotoxicity was reversible in vitro. Conclusion The MTD of SCB01A was 24 mg/m2 every 21 days; it is safe and tolerable in patients with solid tumors.
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- 2020
3. c‐Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation
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Pei-Yi Chu, Tsung Ming Chang, Wen Chun Hung, Hui Jen Tsai, Yan Shen Shan, Li-Tzong Chen, Kuo Wei Huang, Hui You Lin, and Jeffrey S. Chang
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Male ,0301 basic medicine ,Cancer Research ,Vascular Endothelial Growth Factor C ,Mice, SCID ,medicine.disease_cause ,pancreatic neuroendocrine tumor ,Neuroendocrine differentiation ,Metastasis ,Proto-Oncogene Proteins c-myc ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell, Molecular, and Stem Cell Biology ,Mice, Inbred NOD ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,PI3K/AKT/mTOR pathway ,Tube formation ,business.industry ,Endothelial Cells ,General Medicine ,medicine.disease ,Up-Regulation ,Lymphangiogenesis ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,lymphangiogenesis ,Neuroendocrine Tumors ,030104 developmental biology ,Lymphatic system ,Oncology ,Vascular endothelial growth factor C ,c‐Myc ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,mTOR ,Cancer research ,Heterografts ,Original Article ,business ,Carcinogenesis - Abstract
Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long‐term survival, whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is essential for tumor metastasis via the lymphatic system and may overhead distant metastasis. c‐Myc overexpression is involved in tumorigenesis. The role of c‐Myc in lymphangiogenesis is unclear. In this study, we evaluated the mechanism and effect of c‐Myc on lymphangiogenesis of pNET via interaction of lymphatic endothelial cells (LECs) and pNET cells. Lymph node metastasis was evaluated in pNET xenograft mice. Potential target agents to inhibit lymph node metastasis were evaluated in an animal model. We found that vascular endothelial growth factor C (VEGFC) expression and secretion was increased in pNET cell lines with c‐Myc overexpression. c‐Myc transcriptionally upregulates VEGFC expression and the secretion of pNET cells by directly binding to the E‐box of the VEGFC promoter and enhances VEGF receptor 3 phosphorylation and the tube formation of LECs. c‐Myc overexpression is associated with lymph node metastasis in pNET xenograft mice. Combinational treatment with an mTOR inhibitor and c‐Myc inhibitor or VEGFC‐neutralizing chimera protein reduced lymph node metastasis in the mice with c‐Myc overexpression. The mTOR inhibitor acts on lymphangiogenesis by reducing VEGFC expression in pNET cells and inhibiting the tube formation of LECs. In conclusion, mTOR and c‐Myc are important for lymphangiogenesis of pNET and are potential therapeutic targets for prevention and treatment of lymph node metastasis in pNET., c‐Myc promotes lymph node metastases of pancreatic neuroendocrine tumors via upregulation of vascular endothelial growth factor C (VEGFC). Combined targeting of mTOR with c‐Myc or VEGFC is a potential therapy for the treatment of pNET.
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- 2020
4. Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia
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Hui-You Lin, Yi-Hui Peng, Kuo Wei Huang, Chen-Lung Huang, Mine-Hsine Wu, Chuan Shih, Teng-Kuang Yeh, Weir-Torn Jiaang, Ching-Chuan Kuo, Tsu Hsu, Ching-Ping Chen, Ya-Ling Weng, Chiung-Tong Chen, Fang-Chun Kung, Wen-Hsing Lin, Hui Yi Shiao, Jen-Shin Song, Ling-Hui Chou, Tsung-Sheng Wu, Kuei-Jung Yen, Pei-Chen Wang, Ching-Cheng Hsueh, Yu-Chieh Su, Cheng-Tai Lu, Hui-Jen Tsai, Su-Ying Wu, Li-Tzong Chen, and Po-Chu Kuo
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Male ,Stromal cell ,Gastrointestinal Stromal Tumors ,medicine.drug_class ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Stem cell factor ,Mice, SCID ,Tyrosine-kinase inhibitor ,Receptor tyrosine kinase ,Rats, Sprague-Dawley ,Mice ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Phosphorylation ,Kinase activity ,Protein Kinase Inhibitors ,neoplasms ,Cell Proliferation ,Gastrointestinal Neoplasms ,Mice, Inbred ICR ,biology ,Chemistry ,Kinase ,Cell growth ,Myeloid leukemia ,Xenograft Model Antitumor Assays ,digestive system diseases ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,Pyrimidines ,fms-Like Tyrosine Kinase 3 ,Mutation ,biology.protein ,Cancer research ,Molecular Medicine ,Female - Abstract
Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.
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- 2019
5. The Prognostic and Predictive Role of Chromogranin A in Gastroenteropancreatic Neuroendocrine Tumors – A Single-Center Experience
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Hui-Jen Tsai, Chin-Fu Hsiao, Jeffrey S. Chang, Li-Tzong Chen, Ying-Jui Chao, Chia-Ju Yen, and Yan-Shen Shan
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Oncology ,medicine.medical_specialty ,endocrine system ,Cancer Research ,gastroenteropancreas ,chromogranin A ,Neuroendocrine tumors ,predictive factor ,Internal medicine ,Medicine ,prognostic factor ,RC254-282 ,Original Research ,Predictive marker ,biology ,business.industry ,Hazard ratio ,Chromogranin A ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Odds ratio ,medicine.disease ,Confidence interval ,Tumor progression ,biology.protein ,Biomarker (medicine) ,neuroendocrine tumors ,business - Abstract
Chromogranin A (CgA) is a non-specific biomarker excreted by neuroendocrine tumor (NET) cells. Elevation of circulating CgA level can be detected in gastroenteropancreatic (GEP)-NET patients and has been shown to correlate with tumor burden. The prognostic and predictive roles of CgA level and the change of CgA level are controversial. In this study, we retrospectively analyzed 102 grade 1/2 GEP-NET patients with available baseline or serial follow-up CgA levels from the National Cheng Kung University Hospital to evaluate the association between circulating CgA level and the tumor extent, overall survival (OS), and tumor response prediction. The baseline characteristics, baseline CgA level, and change of CgA level during follow-up and their association was analyzed. Sixty cases had baseline CgA levels available prior to any treatment and ninety-four cases had serial follow-up CgA levels available during treatment or surveillance. Baseline CgA levels were associated with stage and sex. Higher baseline CgA levels were associated with worse OS after adjusting for sex, stage, grade, primary site, and functionality (hazard ratio=13.52, 95% confidence interval (CI), 1.06-172.47, P=0.045). The cross-sectional analysis for the change of CgA level during follow-up showed that a ≥ 40% increase of CgA meant a higher probability of developing tumor progression or recurrence than those with a < 40% increase of CgA level (odds ratio=5.04, 95% CI, 1.31-19.4, P=0.019) after adjusting for sex, age, grade, stage, and functionality. Our study results suggest that CgA may be a predictive marker for tumor burden, OS, and tumor progression in GEP-NET patients.
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- 2021
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6. Insulin-like growth factor binding protein 3 promotes radiosensitivity of oral squamous cell carcinoma cells via positive feedback on NF-κB/IL-6/ROS signaling
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Ssu Han Wang, Yu Lin Chen, Jenn Ren Hsiao, Shih Sheng Jiang, Ya-Wen Chen, Fang Yu Tsai, Hui Jen Tsai, and Alan Yueh Luen Lee
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Male ,Cancer Research ,Programmed cell death ,medicine.medical_treatment ,Mice, Nude ,Apoptosis ,lcsh:RC254-282 ,NF-κB ,Flow cytometry ,Mice ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Radiosensitivity ,Radiation ,medicine.diagnostic_test ,Chemistry ,Research ,Growth factor ,NF-kappa B ,ROS ,Cell migration ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oral squamous cell carcinoma cells ,Insulin-Like Growth Factor Binding Protein 3 ,Cytokine ,Oncology ,IGFBP3 ,Carcinoma, Squamous Cell ,Cancer research ,Mouth Neoplasms ,Reactive Oxygen Species ,Signal Transduction - Abstract
Background Ectopic insulin-like growth factor binding protein 3 (IGFBP3) expression has been shown to enhance cell migration and lymph node metastasis of oral squamous cell carcinoma (OSCC) cells. However, OSCC patients with high IGFBP3 expression had improved survival compared with those with low expression. Therefore, we speculated that IGFBP3 expression may play a role in response to conventional OSCC therapies, such as radiotherapy. Methods We used in vitro and in vivo analyses to explore IGFBP3-mediated radiosensitivity. Reactive oxygen species (ROS) detection by flow cytometry was used to confirm IGFBP3-mediated ionizing radiation (IR)-induced apoptosis. Geneset enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were used to analyze the relationship between IGFBP3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. Assays involving an NF-κB inhibitor, ROS scavenger or interleukin 6 (IL-6) were used to evaluate the NF-κB/IL-6/ROS signaling in IGFBP3-mediated radiosensitivity. Results Ectopic IGFBP3 expression enhanced IR-induced cell-killing in vitro. In vivo, IGFBP3 reduced tumor growth and increased apoptotic signals of tumor tissues in immunocompromised mice treated with IR. Combined with IR, ectopic IGFBP3 expression induced mitochondria-dependent apoptosis, which was apparent through mitochondrial destruction and increased ROS production. Ectopic IGFBP3 expression enhanced NK-κB activation and downstream cytokine expression. After IR exposure, IGFBP3-induced NF-κB activation was inhibited by the ROS scavenger N-acetyl-L-cysteine (NAC). IGFBP3-mediated ROS production was reduced by the NF-κB inhibitor BMS-345541, while exogenous IL-6 rescued the NF-κB-inhibited, IGFBP3-mediated ROS production. Conclusions Our data demonstrate that IGFBP3, a potential biomarker for radiosensitivity, promotes IR-mediated OSCC cell death by increasing ROS production through NF-κB activation and cytokine production.
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- 2021
7. Phase 1 study of nanoliposomal irinotecan in combination with trifluridine/tipiracil in refractory solid tumors
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Li-Yuan Bai, Nai-Jung Chiang, Chih-Hung Hsu, Yi-Hsin Liang, Chang-Fang Chiu, Ching-Chan Lin, Kwang-Yu Chang, Shang-Hung Chen, Hui-Jen Tsai, Yu-Ping Lin, Li-Tzong Chen, and Chia-Chi Lin
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Cancer Research ,Oncology - Abstract
660 Background: Nal-IRI is irinotecan (as known as CPT-11) encapsulated in a nanoliposome drug delivery system (nanoliposomal irinotecan; nal-IRI). Nal-IRI + 5-FU/LV has been approved in patients with metastatic pancreatic cancer after gemcitabine-based therapy through the NAPOLI-1 study. TAS-102 is a combination drug of trifluridine (FTD), an antineoplastic thymidine analog, and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TAS-102 has been approved in metastatic colorectal cancer and gastric or gastroesophageal junction adenocarcinoma. Given both drugs show antitumor activity in various cancers, this study is to identify the MTD (maximum tolerated dose) and recommended phase II dose (RP2D), and to explore the preliminary efficacy of nal-IRI and TAS-102 combination in solid tumors. Methods: This multi-center phase I study consists of a classical 3 + 3 dose finding portion and an expansion portion. Eligible patients have pathologically confirmed solid malignancies with no standard treatment available. Patients will be treated with nal-IRI at dose of 60, 70, 80 mg/m2 over 90 minutes on day 1, and oral TAS-102 25, 30, 35 mg/m2 twice daily on day 1-5, every 14 days. Patients who have homozygous for the UGT1A1*28 allele ( TA7/TA7) or UGT1A1*6 allele ( A/A), or double heterozygous for both UGT1A1*28 allele ( TA6/TA7) and UGT1A1*6 allele ( G/A) will be excluded from the dose finding portion. This trial is registered with ClinicalTrials.gov, NCT 03810742. Results: From February 2019 to May 2021, a total of 43 (male/female: 27/16; median age 56, range 25-69) patients (pts) were treated, including 28 in the dose finding portion in which 3, 3, 3, 3, 7, 3 and 6 pts were at levels 1, 2A, 2B, 3, 4A, 4B and 5, respectively, and 15 pts in the expansion portion. The results here are reported from the dose finding portion. The most common cancer types were cholangiocarcinoma (N = 6), neuroendocrine tumor (N = 3), and ampulla of Vater (N = 3). DLTs were noted at one patient who had G4 sepsis and G3 diarrhea at level 4A (80/30), and two subjects who had G3 diarrhea and G3 dehydration at level 5 (80/35). The dosage of the level 4A is determined to be the MTD and it is also the RP2D for the expansion phase. Most common treatment related toxicities during the DLT observation period (the first 2 cycles) are neutropenia, thrombocytopenia, diarrhea, fatigue, and vomiting. In this dose finding portion, 4 pts had partial response and 17 pts had stable disease as the best response. Conclusions: The MTD of Nal-IRI in combination with TAS-102 every 2 weeks is 80/30 mg/m2, which is also the RP2D for expansion study. The clinical benefit was observed in pts at different dose levels. The expansion portion of the study is still ongoing and pts will be followed until disease progression or consent withdrawal. Clinical trial information: NCT03810742.
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- 2022
8. <scp>BPR</scp> 1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor
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Hui-You Lin, Jonathan A. Fletcher, Li-Tzong Chen, Weir-Torn Jiaang, Chiung-Tong Chen, Ming-Yu Yang, Chun-Chieh Wu, Ming‐Jon Lin, Neng‐Yao Shih, Hui-Jen Tsai, and Tsu-An John Hsu
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Male ,0301 basic medicine ,Cancer Research ,BPR1J373 ,gastrointestinal stromal tumor ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Aurora kinase ,Medicine ,Stromal tumor ,multitargeted kinase inhibitor ,GiST ,Sunitinib ,Myeloid leukemia ,KIT ,General Medicine ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-kit ,Oncology ,030220 oncology & carcinogenesis ,Original Article ,Female ,Signal Transduction ,medicine.drug ,Cell Survival ,Gastrointestinal Stromal Tumors ,Aurora kinase A ,03 medical and health sciences ,Cell Line, Tumor ,Regorafenib ,Animals ,Humans ,Protein Kinase Inhibitors ,neoplasms ,Cell Proliferation ,business.industry ,Cancer ,Imatinib ,Original Articles ,Cell Cycle Checkpoints ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,Drug Discovery and Delivery ,Pyrimidines ,030104 developmental biology ,chemistry ,Mutation ,Cancer research ,business - Abstract
Gastrointestinal stromal tumor (GIST) is a type of KIT-driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first-line treatment for advanced GIST, with a significant improvement in progression-free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second- and third-line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT-driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT-mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT-null COS-1 cell-based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor-grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.
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- 2018
9. The incidence and survival of pancreatic cancer by histology, including rare subtypes: a nation‐wide cancer registry‐based study from Taiwan
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Yan Shen Shan, Hui Jen Tsai, Pei-Yi Chu, Jeffrey S. Chang, Li-Tzong Chen, and Chia Rung Tsai
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,pancreatic cancer ,Taiwan ,Neuroendocrine tumors ,Adenocarcinoma ,survival ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pancreatic cancer ,Internal medicine ,Carcinoma ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Original Research ,Aged ,Aged, 80 and over ,business.industry ,Proportional hazards model ,Incidence (epidemiology) ,Incidence ,Middle Aged ,medicine.disease ,Survival Analysis ,Lymphoma ,Cancer registry ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,030220 oncology & carcinogenesis ,Female ,business ,Cancer Prevention - Abstract
Studies have indicated a significant rise in the incidence of pancreatic adenocarcinoma. However, the epidemiology of other rare histologic subtypes of pancreatic cancer is not well understood. This study analyzed the incidence and survival of pancreatic cancer in Taiwan by histologic subtype, sex, age group, and year of diagnosis. The incidence trends of pancreatic cancer in Taiwan from 2002 to 2013 were calculated using data from the Taiwan Cancer Registry. The survival of pancreatic cancer patients was assessed using the life‐table method and Cox proportional hazards analysis. The incidence of pancreatic cancer increased from 4.62 per 100,000 in 2002 to 6.04 per 100,000 in 2013 in Taiwan. The most common histologic subtype of pancreatic cancer was adenocarcinoma followed by carcinoma and neuroendocrine tumors (NETs). Adenocarcinoma and NETs showed a rapid increase in incidence, while the incidences of other subtypes did not change significantly. Patients with adenocarcinoma showed a poor survival with a 5‐year survival of 5.2%. Patients with endocrinomas, NETs, and lymphoma displayed a better survival than those with adenocarcinoma, with a 5‐year survival ranging from 41.8% to 59.1%. The survival of adenocarcinoma, lymphoma, and NETs improved after the introduction of novel therapies. Understanding the risk factors and identifying the biomarkers for the early diagnosis of pancreatic cancer are important to prevent the development and improve the survival of pancreatic cancer.
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- 2018
10. An Open‐Label, Single‐Arm, Two‐Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas
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Shih Sheng Jiang, Shih-Feng Cho, Tsang Wu Liu, Chia Hsun Hsich, Wen-Chi Chou, Yan Shen Shan, Ta Chih Liu, Yi-Ping Hung, Hui Jen Tsai, Yee Chao, Chiun Hsu, Chin-Fu Hsiao, Yi-Chang Liu, Ming Huang Chen, and Chao Hua Chiu
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Taiwan ,Phases of clinical research ,Gene mutation ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Adverse effect ,Etoposide ,Aged ,Chemotherapy ,Leukopenia ,business.industry ,Genomics ,Middle Aged ,Carcinoma, Neuroendocrine ,030104 developmental biology ,030220 oncology & carcinogenesis ,Topotecan ,DPYD ,Camptothecin ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
Background The discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC. Methods This single-arm, two-stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m2 of TLC388 intravenously on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Gene mutations were analyzed by next-generation sequencing. Results Twenty-three patients with a median age of 61 (range, 44–73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0–6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progression-free survival was 1.8 (95% confidence interval [CI], 0.4–15) months, and the median overall survival was 4.3 (95% CI, 1.7–15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH. Conclusion TLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273. Implications for Practice Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum-based chemotherapy remain elusive. In this single-arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression-free survival of 1.8 (95% confidence interval [CI], 0.4–15) months, and the median overall survival of 4.3 (95% CI, 1.7–15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer.
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- 2019
11. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) regulates the cell metabolism of pancreatic neuroendocrine tumors (pNET) and de-sensitizes pNET to mTOR inhibitors
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Shih Sheng Jiang, Yu Lin Chen, Yan Shen Shan, Hui You Lin, Hui Jen Tsai, Wen Chun Hung, Pei-Yi Chu, Ming Huang Chen, and Li-Tzong Chen
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0301 basic medicine ,medicine.medical_specialty ,mitochondrial OXPHOS ,Angiogenesis ,pancreatic neuroendocrine tumor ,03 medical and health sciences ,0302 clinical medicine ,PCK2 ,Internal medicine ,Medicine ,Glycolysis ,PI3K/AKT/mTOR pathway ,Gene knockdown ,business.industry ,glycolysis ,030104 developmental biology ,Endocrinology ,PEPCK-M ,Oncology ,Gluconeogenesis ,030220 oncology & carcinogenesis ,Cancer cell ,mTOR ,Cancer research ,business ,Phosphoenolpyruvate carboxykinase ,Research Paper - Abstract
mTOR pathway activation and hypervascularity have been identified as important characteristics of pancreatic neuroendocrine tumors (pNETs). Agents targeting angiogenesis and mTOR, such as sunitinib and everolimus (RAD001), have been shown to result in progression-free survival of approximately 11 months in patients with advanced pNETs. Novel treatment is needed to extend survival. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), which is encoded by PCK2, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. PEPCK-M has been demonstrated to potentiate cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK-C)-mediated gluconeogenesis and to play a critical role in the survival program initiated upon stress during metabolism in cancer cells. Elevated expression of PCK2 has been found in various tumors according to the results of The Cancer Genome Atlas project. However, the role of PEPCK-M aberration in cancers is not well understood. In the current study, we observed that 12 of 21 (57%) pNET patients had high expression of PEPCK-M in the tumors, whereas the normal islet cells had weak expression of PEPCK-M. Knockdown of PCK2 inhibited the proliferation of pNET cells and enhanced the sensitivity of pNET cells to mTOR inhibitors. Knockdown of PCK2 promoted glycolysis but reduced mitochondrial oxidative phosphorylation in pNET cells. The combination of mTOR inhibitors and an anti-glycolysis agent, 2-DG, synergistically or additively inhibited the proliferation of pNET cells, particularly for the cells with high expression of PEPCK-M. Therefore, targeting PEPCK-M or glycolysis combined with inhibiting mTOR is a potential therapeutic approach for the treatment of pNETs.
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- 2017
12. The regulatory role of aberrant Phosphatase and Tensin Homologue and Liver Kinase B1 on AKT/mTOR/c-Myc axis in pancreatic neuroendocrine tumors
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Hui Jen Tsai, Hsiu Chi Tu, Tsung Ming Chang, Pei-Yi Chu, Shih Sheng Jiang, Yu Lin Chen, Yan Shen Shan, Wen Chun Hung, Li-Tzong Chen, and Hui You Lin
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,PTEN ,medicine.medical_specialty ,LKB1 ,pancreatic neuroendocrine tumor ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Tensin ,skin and connective tissue diseases ,Mechanistic target of rapamycin ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Everolimus ,biology ,Kinase ,business.industry ,Molecular medicine ,c-Myc ,030104 developmental biology ,Endocrinology ,Oncology ,030220 oncology & carcinogenesis ,mTOR ,biology.protein ,Cancer research ,business ,Research Paper ,medicine.drug - Abstract
// Tsung-Ming Chang 1, * , Yan-Shen Shan 2, 3, * , Pei-Yi Chu 4, 1, 5, * , Shih Sheng Jiang 1 , Wen-Chun Hung 1 , Yu-Lin Chen 1 , Hsiu-Chi Tu 1 , Hui-You Lin 1 , Hui-Jen Tsai 1, 6, 7 and Li-Tzong Chen 1, 6, 7, 8 1 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan 2 Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan 3 Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan 4 Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan 5 School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 6 Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan 7 Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 8 Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan * These authors contributed equally to this work Correspondence to: Hui-Jen Tsai, email: hjtsai@nhri.org.tw Keywords: pancreatic neuroendocrine tumor, PTEN, LKB1, mTOR, c-Myc Received: June 15, 2017 Accepted: September 03, 2017 Published: September 16, 2017 ABSTRACT Pancreatic neuroendocrine tumor (pNET) is an uncommon type of pancreatic neoplasm. Low Phosphatase and Tensin Homologue (PTEN) expression and activation of the mechanistic target of rapamycin (mTOR) pathway have been noted in pNETs, and the former is associated with poor survival in pNET patients. Based on the results of the RADIANT-3 study, everolimus, an oral mTOR inhibitor, has been approved to treat advanced pNETs. However, the exact regulatory mechanism for the mTOR pathway in pNETs remains largely unknown. PTEN and liver kinase B1 (LKB1) are well-known for their regulatory role in the mTOR pathway. We evaluated the expression of PTEN and LKB1 in 21 pNET patients, and low PTEN and LKB1 expression levels were noted in 48% and 24% of the patients, respectively. Loss of PTEN and LKB1 synergistically promoted cell proliferation of pNET, attenuated the sensitivity of cells to mTOR inhibitors and enhanced c-Myc expression, which back-regulated PTEN, AKT, mTOR and its downstream effectors. For pNET cells with low expression levels of PTEN and LKB1, silencing the expression of c-Myc by shRNA reduced their proliferative rate, while adding either c-Myc inhibitor or AMP-activated protein kinase activator reversed their resistance to mTOR inhibitors in vitro and in vivo . Furthermore, high c-Myc expression was subsequently identified in 81% of pNETs, suggesting that up-regulation of c-Myc expression in pNETs may occur through PTEN/LKB1-dependent and PTEN/LKB1-independent regulation. The results delineated the regulation of PTEN and LKB1 on the AKT/mTOR/c-Myc axis and suggested that both c-Myc and mTOR are potential therapeutic targets for pNET.
- Published
- 2017
13. The B-cell-activating factor signalling pathway is associated withHelicobacter pyloriindependence in gastric mucosa-associated lymphoid tissue lymphoma without t(11;18)(q21;q21)
- Author
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Chia-Tung Shun, Ming-Feng Wei, Hui-Jen Tsai, Hsiao-Wei Lee, Li-Tzong Chen, Sung-Hsin Kuo, Ming-Shiang Wu, Chung-Wu Lin, Ann-Lii Cheng, Ping-Ning Hsu, and Kun-Huei Yeh
- Subjects
0301 basic medicine ,MALT lymphoma ,NF-κB ,Biology ,medicine.disease ,BCL10 ,Pathology and Forensic Medicine ,Lymphoma ,03 medical and health sciences ,chemistry.chemical_compound ,Transactivation ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,chemistry ,immune system diseases ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,medicine ,Gastric mucosa ,B-cell activating factor ,Autocrine signalling - Abstract
We previously reported that activation of the B cell-activating factor (BAFF) pathway upregulates NF-κB and induces BCL3 and BCL10 nuclear translocation in H. pylori (HP)-independent gastric diffuse large B-cell lymphoma (DLBCL) tumours with evidence of mucosa-associated lymphoid tissue (DLBCL [MALT]). However, the significance of BAFF expression in HP-independence of gastric low-grade MALT lymphomas (MALT lymphoma) without t(11;18)(q21;q21) remains unexplored. Sixty-four patients who underwent successful HP eradication for localized HP-positive gastric MALT lymphomas without t(11;18)(q21;q21) were studied. BAFF expression was significantly higher in the HP-independent group than in the HP-dependent group (22 of 26 [84.6%] versus 8 of 38 [21.1%]; p
- Published
- 2016
14. AUY922 effectively targets against activated B cell subtype of diffuse large B-cell lymphoma and low-grade lymphoma cells harboring genetic alteration-associated nuclear factor-κB activation
- Author
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Ann-Lii Cheng, Sung-Hsin Kuo, Neng Yao Shih, Li-Tzong Chen, Tsai Yun Chen, Kung Chao Chang, Hui Jen Tsai, Hui You Lin, Sheng Fung Lin, and Jeffrey S. Chang
- Subjects
Male ,Cancer Research ,Cell Survival ,Down-Regulation ,Antineoplastic Agents ,Apoptosis ,Biology ,Translocation, Genetic ,Mice ,BCL9 ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,HSP90 Heat-Shock Proteins ,B cell ,Cell Proliferation ,Chromosome Aberrations ,Chromosomes, Human, Pair 14 ,B-Lymphocytes ,Caspase 3 ,Cell growth ,NF-kappa B ,MALT lymphoma ,Cell Cycle Checkpoints ,Isoxazoles ,Resorcinols ,Hematology ,medicine.disease ,Xenograft Model Antitumor Assays ,Caspase 9 ,BCL10 ,Mitochondria ,Tumor Burden ,Lymphoma ,Enzyme Activation ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Grading ,Chromosomes, Human, Pair 18 ,REL ,Diffuse large B-cell lymphoma ,Signal Transduction - Abstract
Recurrent genetic alterations that are frequently observed in some low-grade lymphomas, such as activated B cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL) and mucosa-associated lymphoid tissue type lymphoma (MALT lymphoma) are usually associated with nuclear factor-κB (NF-κB) activation and confer resistance to therapy. In this study, we investigated the therapeutic efficacy and molecular mechanisms of AUY922, a novel Hsp90 inhibitor, in representative cell lines OCI-Ly3 (ABC-DLBCL) and MA-1 (a low-grade lymphoma cell line with t(14;18)/IgH-MALT1translocation) to explore its potential use in the treatment of refractory B-cell lymphoma. Our results showed that AUY922 effectively induced growth inhibition and apoptosis of OCI-Ly3 and MA-1 cells, which were accompanied by down-regulation of the expression levels of NF-κB and Bcl-2 family proteins, as well as molecules of multiple signaling pathways involving cell proliferation, growth and survival. The growth inhibitory effect of AUY922 was further confirmed in a mouse xenograft model. These findings indicate the potential use of AUY922 in B cell lymphomas.
- Published
- 2015
15. The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells
- Author
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Su Peng Yeh, Wen Chun Hung, Cheng Chin Kuo, You Syuan Lai, Jing Yi Chen, B. Linju Yen, Hui Jen Tsai, and H. Sunny Sun
- Subjects
0301 basic medicine ,Receptors, CXCR4 ,Stromal cell ,Primary Cell Culture ,Complement C5a ,Biology ,CXCR4 ,Article ,Glutarates ,03 medical and health sciences ,chemistry.chemical_compound ,Paracrine signalling ,0302 clinical medicine ,Paracrine Communication ,medicine ,Humans ,Myeloid Cells ,Phosphorylation ,Mitogen-Activated Protein Kinase 1 ,Multidisciplinary ,Mitogen-Activated Protein Kinase 3 ,Kinase ,Gene Expression Regulation, Leukemic ,Interleukin-6 ,Protein Stability ,Interleukin-8 ,NF-kappa B ,Myeloid leukemia ,NF-κB ,Mesenchymal Stem Cells ,Isocitrate Dehydrogenase ,NIMA-Interacting Peptidylprolyl Isomerase ,Haematopoiesis ,Junctional Adhesion Molecule B ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Bone marrow ,Reactive Oxygen Species ,Signal Transduction - Abstract
Mutations of isocitrate dehydrogenase 1 (IDH1) and IDH2 in acute myeloid leukemia (AML) cells produce the oncometabolite R-2-hydroxyglutarate (R-2HG) to induce epigenetic alteration and block hematopoietic differentiation. However, the effect of R-2HG released by IDH-mutated AML cells on the bone marrow microenvironment is unclear. Here, we report that R-2HG induces IκB kinase-independent activation of NF-κB in bone marrow stromal cells. R-2HG acts via a reactive oxygen species/extracellular signal-regulated kinase (ERK)-dependent pathway to phosphorylate NF-κB on the Thr254 residue. This phosphorylation enhances the interaction of NF-κB and the peptidyl-prolyl cis-trans isomerase PIN1 and increases the protein stability and transcriptional activity of NF-κB. As a consequence, R-2HG enhances NF-κB-dependent expression of cytokines including IL-6, IL-8 and complement 5a to stimulate proliferation of AML cells. In addition, R-2HG also upregulates vascular endothelial adhesion molecule 1 and CXCR4 in stromal cells to enhance the contact between AML and stromal cells and attenuates chemotherapy-induced apoptosis. More importantly, we validated the R-2HG-activated gene signature in the primary bone marrow stromal cells isolated from IDH-mutated AML patients. Collectively, our results suggest that AML cell-derived R-2HG may be helpful for the establishment of a supportive bone marrow stromal niche to promote AML progression via paracrine stimulation.
- Published
- 2016
16. BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT-Driven Myeloid Leukemia
- Author
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Joseph H. Butterfield, Hui You Lin, Weir-Torn Jiaang, Sheng Fung Lin, Neng Yao Shih, Hui Jen Tsai, Chiung-Tong Chen, John Tsu An Hsu, Li-Tzong Chen, and Tsai Yun Chen
- Subjects
0301 basic medicine ,Male ,Transcriptional Activation ,Cancer Research ,Myeloid ,medicine.drug_class ,Apoptosis ,Tyrosine-kinase inhibitor ,Translocation, Genetic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Proliferation ,Chemistry ,Cell Cycle ,Myeloid leukemia ,Imatinib ,medicine.disease ,Xenograft Model Antitumor Assays ,Mitochondria ,Tumor Burden ,Leukemia ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Mutation ,Cancer research ,Signal transduction ,Apoptosis Regulatory Proteins ,Tyrosine kinase ,medicine.drug ,Signal Transduction - Abstract
Acute myelogenous leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT–driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT–null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT–driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug–resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT–driven myeloid leukemia. Mol Cancer Ther; 15(10); 2323–33. ©2016 AACR.
- Published
- 2015
17. Bioimaging analysis of nuclear factor-κB activity in Philadelphia chromosome-positive acute lymphoblastic leukemia cells reveals its synergistic upregulation by tumor necrosis factor-α-stimulated changes to the microenvironment
- Author
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Seiichiro Kobayashi, Takaomi Ishida, Arinobu Tojo, Hui-Jen Tsai, Kazuo Umezawa, Sheng-Fung Lin, Kiyoko Izawa, and Toshiki Watanabe
- Subjects
Cancer Research ,Stromal cell ,Recombinant Fusion Proteins ,Transplantation, Heterologous ,Antineoplastic Agents ,Biology ,Piperazines ,Mice ,Downregulation and upregulation ,Bone Marrow ,Genes, Reporter ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Transgenes ,Cyclohexanones ,Gene Expression Regulation, Leukemic ,Tumor Necrosis Factor-alpha ,NF-kappa B ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Neoplasm Proteins ,Tumor Burden ,Transplantation ,Leukemia ,Pyrimidines ,Imatinib mesylate ,Oncology ,Apoptosis ,Cell culture ,Benzamides ,Luminescent Measurements ,Immunology ,Disease Progression ,Imatinib Mesylate ,Cancer research ,Tumor necrosis factor alpha ,Stromal Cells ,Spleen - Abstract
To gain an insight into the microenvironmental regulation of nuclear factor (NF)-κB activity in the progression of leukemia, we established a bioluminescent imaging model of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) cells transduced with a NF-κB/luciferase (Luc) reporter and cocultured with murine stromal cells and cytokines. Stromal cells alone did not augment Luc activity, taken as an index of NF-κB, but Luc activity was synergistically upregulated by the combination of stromal cells and tumor necrosis factor (TNF)-α. Dehydroxymethylepoxyquinomicin (DHMEQ), a specific inhibitor of NF-κB DNA binding, rapidly induced the apoptosis of Ph+ALL cells, indicating that NF-κB is necessary for the growth and survival of these cells. However, the DHMEQ-induced suppression of NF-κB activity and the apoptosis of leukemia cells were attenuated by the presence of stromal cells and TNF-α. In NOD-SCID mice transplanted with NF-κB/Luc reporter-containing Ph+ALL cell lines and monitored periodically during the progression of the leukemia, murine TNF-α was significantly expressed in lesions in which the leukemia cells emitted a significant NF-κB signal. These results support the notion that TNF-α also triggers microenvironmental upregulation of NF-κB activity in vivo. Collectively, the results indicated that TNF-α-stimulated microenvironment may contribute to the survival and progression of Ph+ALL cells through the synergistic upregulation of NF-κB activity.
- Published
- 2011
18. Establishment of a novel MALT lymphoma cell line, ma-1, from a patient with t(14;18)(q32;q21)-positive Helicobacter Pylori-Independent Gastric MALT Lymphoma
- Author
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Chung-Wu Lin, Huei-Jiuan Jeng, Ann-Lii Cheng, Wen-Hui Weng, Li-Tzong Chen, Ming-Shiang Wu, Ping-Ning Hsu, Kun-Huei Yeh, Sung-Hsin Kuo, Zi-Hua Chen, and Hui-Jen Tsai
- Subjects
Male ,Cancer Research ,Gene Dosage ,Biology ,Cell morphology ,Translocation, Genetic ,Helicobacter Infections ,Immunophenotyping ,Stomach Neoplasms ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Genetics ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,B cell ,Chromosomes, Human, Pair 14 ,Comparative Genomic Hybridization ,Helicobacter pylori ,medicine.diagnostic_test ,Lymphoma, Non-Hodgkin ,Spectral Karyotyping ,MALT lymphoma ,Lymphoma, B-Cell, Marginal Zone ,Middle Aged ,Flow Cytometry ,medicine.disease ,biology.organism_classification ,Immunohistochemistry ,Molecular biology ,digestive system diseases ,BCL10 ,Lymphoma ,medicine.anatomical_structure ,Immunology ,Chromosomes, Human, Pair 18 ,Microsatellite Repeats ,Comparative genomic hybridization ,Fluorescence in situ hybridization - Abstract
Although t(11;18)(q21;q21), t(1;14)(p22;q32), and a few other genetic mutations are specific markers for the Helicobacter pylori (HP)-independent status of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the molecular mechanisms responsible for HP-independence of gastric MALT lymphoma without such translocations and mutations remain uncharacterized. In the present study, we describe the establishment and characterization of a novel MALT lymphoma cell line, MA-1, which was derived from a gastric MALT lymphoma which was negative for both t(11;18)(q21;q21) and t(1;14)(p22;q32); the patient had failed HP eradication therapy and chemotherapy. The cell morphology and the immunophenotype of this cell line were similar to that of the original gastric MALT lymphoma. Comparative genomic hybridization analysis showed no significant gene copy number changes. Spectral karyotyping displayed a near-diploid chromosome content (482nXY), with at least 13 chromosome structural abnormalities. Furthermore, fluorescence in situ hybridization analyses disclosed the existence of three sub-clones, characterized by t(14;18)(q32;q21)/IGH-BCL2, t(14;18)(q32;q21)/IGH-MALT1, and the presence of both chromosomal translocations in the same cell, respectively; whereas amplification of the genes CRAD9, TRAF2, and BCL10 were not found. In conclusion, we have established the first human gastric MALT lymphoma cell line, which is characterized by unusual and complex chromosome translocations and will be useful to explore further the molecular mechanisms of HP-independence in gastric MALT lymphoma.
- Published
- 2011
19. A phase II study of weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer
- Author
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Yee Chao, Chang Hsien Lu, Li-Tzong Chen, Chung-Pin Li, Kuan Der Lee, Peng Chan Lin, C.-J. Yen, Jen-Shi Chen, Wen Pin Su, and Hui-Jen Tsai
- Subjects
Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Leucovorin ,cisplatin ,Administration, Oral ,Tegafur/uracil ,Docetaxel ,Tegafur ,Antimetabolite ,Drug Administration Schedule ,tegafur/uracil ,Stomach Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,heterocyclic compounds ,Neoplasm Metastasis ,Uracil ,Stomach cancer ,neoplasms ,Aged ,Cisplatin ,Chemotherapy ,business.industry ,gastric cancer ,Cancer ,Middle Aged ,medicine.disease ,digestive system diseases ,Surgery ,stomatognathic diseases ,Clinical Study ,Female ,Taxoids ,business ,therapeutics ,medicine.drug - Abstract
Background: Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression. Methods: Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m−2, followed by cisplatin 30 mg m−2 infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m−2 per day plus leucovorin 90 mg per day on days 1–14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment. Results: From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22–75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41–74%) and 53% (95% CI: 38–68%), respectively. The disease control rates in these populations were 85% (95% CI: 70–94%) and 82% (95% CI: 68–92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3–4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities. Conclusion: Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.
- Published
- 2010
20. Beware imposters: MA-1, a novel MALT lymphoma cell line, is misidentified and corresponds to Pfeiffer, a diffuse large B-cell lymphoma cell line-A reply: Despite the same 8-code STR, MA-1 and Pfeiffer are cytogenetically diverse
- Author
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Li-Tzong Chen, Sung-Hsin Kuo, Ann-Lii Cheng, Hui-Jen Tsai, Chi-Cheng Li, Wen-Hui Weng, and Kun-Huei Yeh
- Subjects
Cancer Research ,medicine.anatomical_structure ,Cell culture ,Immunology ,Genetics ,medicine ,Cancer research ,MALT lymphoma ,Biology ,medicine.disease ,Diffuse large B-cell lymphoma ,B cell ,Lymphoma - Published
- 2013
21. The regulatory role of PTEN and LKB1 on mTOR pathway in pancreatic neuroendocrien tumors
- Author
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Li-Tzong Chen, Wen-Chun Hung, Hui-Jen Tsai, Yan Shen Shan, Pei-Yi Chu, Tsung-Ming Chang, Hsu-Chi Tu, Shih Sheng Jiang, and Yu-Lin Chen
- Subjects
Hepatology ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,RPTOR ,Gastroenterology ,biology.protein ,Cancer research ,PTEN ,Medicine ,business ,PI3K/AKT/mTOR pathway - Published
- 2017
22. A phase I dose escalation study of SCB01A, a micro-tubular inhibitor with vascular disrupting activity, in patients with advanced solid tumors refractory to standard therapy
- Author
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Chia-Chi Lin, Chia Jui Yen, Wu Chou Su, Hui-Jen Tsai, Shang-Yin Wu, Nai-Jung Chiang, Her-Shyong Shiah, Kwang-Yu Chang, and Li-Tzong Chen
- Subjects
Cancer Research ,010405 organic chemistry ,business.industry ,Pharmacology ,01 natural sciences ,0104 chemical sciences ,Phase i study ,010404 medicinal & biomolecular chemistry ,Oncology ,Refractory ,Maximum tolerated dose ,Toxicity ,Dose escalation ,Medicine ,In patient ,business ,Standard therapy - Abstract
2531 Background: SCB01A is a novel anti-microtubular agent with vascular disrupting activity. The Phase I study aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety, and pharmacokinetic (PK) profiles of SCB01A in patients with advanced solid tumor. Methods: This was an open-label, phase I clinical trial with a rapid titration followed by a 3 x 3 study design. Eligible patients would receive a 3-hr intravenous infusion of SCB01A, every 21 days as one cycle. All adverse events were classified according to the CTCAE V4.0. DLT was defined as the occurrence of grade 3 with complications and grade 4 hematoloigcal, or ≥grade 3 non-hematological toxicities. Results: From June 2011 to November 2015, a total of 33 eligible patients were enrolled to eight dose levels: 2 mg/m2 (n = 1), 3 mg/m2 (n = 1), 4 mg/m2 (n = 6), 6.5 mg/m2 (n = 9, with 3 additional subjects were recruited for safety concern), 10 mg/m2 (n = 3), 16 mg/m2 (n = 3), 24 mg/m2 (n = 6) and 32 mg/m2 (n = 4). Six episodes of DLTs were observed in 5 patients (each one in dose levels of 4/6.5/24 mg/m2 and two in dose level of 32 mg/m2), including grade 4 blood creatine phosphokinase elevation (4 mg/m2), grade 3 gastric hemorrhage (6.5 mg/m2), grade 2 venous thrombosis (24 mg/m2), grade 3 peripheral neuropathy manifested as weakness of lower limbs, grade 3 aspartate aminotransferase elevation, and grade 3 hypertension (32 mg/m2). The MTD was determined to be 24 mg/m2. Pharmacokinetic profiles revealed a linear AUC-dose response with an average elimination half-life (t1/2) of 2.5 hours. Partial response was observed in one subject with buccal cancer. A total of 57.6% (19/33) subjects had stable disease for at least 2 cycles. Conclusions: SCB01A is safe and tolerable in patients with solid tumor. The MTD of SCB01A is 24 mg/m2 every 21 days, which deserves further development. Clinical trial information: NCT011159522.
- Published
- 2017
23. Myeloid Sarcoma Mimicking Nasopharyngeal Carcinoma
- Author
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Sheng-Fung Lin, Shih-Feng Cho, Yi-Chang Liu, and Hui-Jen Tsai
- Subjects
Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Adolescent ,business.industry ,Treatment outcome ,Nasopharyngeal Neoplasms ,medicine.disease ,Diagnosis, Differential ,Treatment Outcome ,Text mining ,Oncology ,Nasopharyngeal carcinoma ,X ray computed ,Myeloid sarcoma ,Humans ,Medicine ,Sarcoma ,Sarcoma, Myeloid ,Tomography, X-Ray Computed ,business - Published
- 2011
24. CagA and NFAT co-operatively participate in the lymphomagenesis of gastric MALT lymphoma
- Author
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Sow-Hsong Kuo, Y.-S. Zeng, K.-H. Yeh, L.-T. Chen, Hui-Jen Tsai, P.-N. Hsu, Chii-Wann Lin, A-L Cheng, and Ming-Shiang Wu
- Subjects
0301 basic medicine ,Gastric MALT Lymphoma ,business.industry ,NFAT ,Hematology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,CagA ,business - Published
- 2016
25. Efficacy of frontline antibiotics therapy in the treatment of Helicobacter pylori-negative gastric low-grade mucosa-associated lymphoid tissue lymphoma
- Author
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Li-Tzong Chen, Ming-Shiang Wu, Ming-Feng Wei, Jyh-Ming Liou, Hui-Jen Tsai, Hsiao-Wei Lee, Chung-Wu Lin, Ann-Lii Cheng, Kun-Huei Yeh, and Sung-Hsin Kuo
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,medicine.drug_class ,Mucosa-Associated Lymphoid Tissue Lymphoma ,Antibiotics ,Helicobacter pylori ,biology.organism_classification ,medicine.disease ,digestive system diseases ,Lymphoma ,Lymphatic system ,Oncology ,Antibacterial therapy ,immune system diseases ,hemic and lymphatic diseases ,Immunology ,medicine ,business - Abstract
e19024Background: Previous series reports revealed that certain proportions of Helicobacter pylori (HP)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma may respond to antibiotics...
- Published
- 2016
26. Phase I dose-escalation study of sorafenib plus S-1 in refractory solid tumors
- Author
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Her-Shyong Shiah, Jang Yang Chang, Kwang-Yu Chang, Wu Chou Su, Hui-Jen Tsai, Nai-Jung Chiang, and Li-Tzong Chen
- Subjects
Sorafenib ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Pharmacology ,medicine.disease ,Phase i study ,Refractory ,Internal medicine ,Toxicity ,Maximum dose ,Dose escalation ,Medicine ,Dosing ,business ,Thyroid cancer ,medicine.drug - Abstract
745 Background: S-1 is a new oral fluoropyrimidine-derived combo and has been shown activity in patients with various cancers in phase II/III studies. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenesis activities and has been approved for the first-line treatment of advanced HCC, RCC and radioactive iodine-resistant thyroid cancer. In xenograft mouse models, sorafenib showed its activity to enhance the cytotoxicity of chemotherapeutic agents. Therefore, a phase I dose-escalation study to determine the dose-limiting toxicity and maximum dose of S-1 in combination with standard dosing of sorafenib in patients with refractory solid tumors was conducted. Methods: Eligible patients would receive escalating dose (30, 35 and 40 mg/m2, twice daily) of S-1 in a standard 3+3 phase I study design. Treatment was consisted of continuous sorafenib 400 mg bid plus S-1 30-40mg/m2 bid, D1-14, every 21 days per cycle. DLTs were assessed during the first two cycles of treatment, and treatment would be continued until disease progression, the occurrence of unacceptable toxicity or consent withdrawal. Results: A total of 13 patients were included, 7 in 30 mg/m2 dose level and 6 in 35 mg/m2 dose level. DLT occurred in 2 of 6 patients with 35 mg/m2 twice daily, manifested as grade 3 skin rash and prolonged grade 2 hand-foot-skin reaction in one each; while there was no DLT observed in 30 mg/m2 cohort. Seven patients achieved durable tumor control, included one pancreatic neuroendocrine tumor patient who had a sustained PR for 27.9 months, and durable stable diseases (>6 months of progression-free survival) in 3 out of 4 colorectal cancer patients, 2 of 2 biliary tract cancer patients and 1 of 2 pancreatic cancer patients. Conclusions: The recommended dose of S-1 in this combination was 30mg/m2 bid. Preliminary results suggested sorafenib/S-1 combination is feasible and deserves for further exploration in refractory advanced gastrointestinal tract cancers. Clinical trial information: NCT01128998.
- Published
- 2016
27. JAK2V617F mutation is associated with special alleles in essential thrombocythemia
- Author
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Hui-Hua Hsiao, Jui-Feng Hsu, Sheng-Fung Lin, Hui-Jen Tsai, Yi-Chang Liu, and Ching-Ping Lee
- Subjects
Cancer Research ,Genetic Linkage ,Phenylalanine ,DNA Mutational Analysis ,Mutation, Missense ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Gene Frequency ,Leucine ,medicine ,SNP ,Humans ,Genetic Predisposition to Disease ,Jak2v617f mutation ,Genetic Testing ,Allele ,Alleles ,Genetics ,Janus kinase 2 ,biology ,Essential thrombocythemia ,Lysine ,Tryptophan ,Valine ,Hematology ,Janus Kinase 2 ,medicine.disease ,Oncology ,Amino Acid Substitution ,Healthy individuals ,Mutation (genetic algorithm) ,biology.protein ,Receptors, Thrombopoietin ,Thrombocythemia, Essential - Abstract
Janus kinase 2 mutation (JAK2V617F) has been identified in myeloproliferative neoplasms. Furthermore, special single nucleoside polymorphisms (SNPs) have been found to be associated with the JAK2V617F mutation. Therefore, the associations among JAK2V617F and special SNPs and the allelic location between them were investigated in patients with essential thrombocythemia (ET). A total of 61 patients with ET and 106 healthy individuals were enrolled. The PCR-RFLP method was applied to investigate the pattern of three SNPs, rs10974944, rs12343867, and rs12340895. Allele-specific PCR was used to examine the allelic location between rs10974944 and JAK2V617F. Among the patients with ET, 34 (55.7%, 34/61) were JAK2V617F positive (heterozygous) while the other 27 (44.3%, 27/61) were negative, and there were no MPLW515L/K mutations noted. The pattern of special SNPs in JAK2V617F(+) was significantly different from that in normal individuals (p 0.05), while there was no difference between JAK2V617F(-) patients and normal individuals. Allele-specific PCR showed high association of a cis-location between the special G-allele of rs10974944 and JAK2V617F(+). Based on this small numbered study, the results show the association between special SNPs and JAK2V617F mutation and a cis-location between the special G-allelic form of rs10974944 and the JAK2V617F mutation. These data highlight a close relationship between them in patients with ET.
- Published
- 2011
28. Plasma decorin predicts the presence of esophageal squamous cell carcinoma
- Author
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Hui-Jen Tsai, Shah-Hwa Chou, I-Chen Wu, Ming-Tsang Wu, Chun-Chi Huang, Ling-Hui Li, Yi-Ping Chou, Hung-Shun Lin, Deng-Chyang Wu, Yu-Kuei Chen, Shu-Yu Tai, and Chieh-Yu Lu
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Alcohol Drinking ,Esophageal Neoplasms ,Decorin ,Lower risk ,Gastroenterology ,Internal medicine ,Blood plasma ,Carcinoma ,medicine ,Biomarkers, Tumor ,Humans ,Osteopontin ,Areca ,Extracellular Matrix Proteins ,biology ,business.industry ,Smoking ,Case-control study ,Area under the curve ,Middle Aged ,medicine.disease ,biology.organism_classification ,Prognosis ,carbohydrates (lipids) ,Oncology ,Case-Control Studies ,biology.protein ,Carcinoma, Squamous Cell ,Female ,Proteoglycans ,business - Abstract
Using a microarray technique, we found decorin to be underexpressed, but osteopontin (OPN) to be overexpressed, in esophageal squamous cell carcinoma (ESCC). This study aims to examine whether plasma decorin and OPN plus personal substances use (tobacco, alcohol and areca) can serve as suitable clinical markers to predict the presence of ESCC. In total, 570 archived plasma specimens (275 patients and 295 controls) were collected from 2 medical centers in Taiwan between 2000 and 2008. Decorin and OPN protein levels were measured by ELISA. Means and standard deviation of plasma decorin were 5.6 + or - 3.6 ng/ml in case patients, which were significantly lower than those in controls (7.8 + or - 3.1, p < 0.0001). Plasma OPN levels in case patients were not significantly different from controls (p = 0.33). When compared to subjects with the lowest quartile of plasma decorin, those with the highest quartile one had a significantly lower risk to have ESCC (Adjusted OR = 0.03, p < 0.001). Receiver operator characteristic (ROC) analysis was performed for the combination of plasma decorin and 3 substances use (smoke, alcohol and areca) for the patients compared with the controls. The area under the curve was 88.6% and the optimal cut-point of ROC curve (any 3 factors) had 73.5% sensitivity and 90.2% specificity with approximately 82% of corrected classification. Plasma decorin, but not OPN, is a potential clinical marker for the detection of ESCC. When plasma decorin plus the use of the 3 substances are combined, this factor cluster could be used to detect the presence of ESCC.
- Published
- 2010
29. Heterogeneous cell origin of Helicobater pylori-dependent high-grade gastric lymphomas
- Author
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Ming-Shiang Wu, Chung-Wu Lin, Ann-Lii Cheng, Li-Tzong Chen, Hui-Jen Tsai, Hsiao-Wei Lee, Sung-Hsin Kuo, Kun-Huei Yeh, and Ping-Ning Hsu
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Cell ,medicine.disease ,Lymphoma ,medicine.anatomical_structure ,Lymphatic system ,Oncology ,immune system diseases ,hemic and lymphatic diseases ,medicine ,business ,neoplasms - Abstract
e19520 Background: We recently showed that gastric “pure” diffuse large B-cell lymphoma (DLBCL) as well as DLBCL with histologic evidence of mucosa-associated lymphoid tissue (DLBCL[MALT]) remains ...
- Published
- 2015
30. The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells
- Author
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Tsai Yun Chen, Wen-Chun Hung, Jing Yi Chen, You-Syuan Lai, and Hui-Jen Tsai
- Subjects
medicine.drug_class ,Cellular differentiation ,Immunoblotting ,Antineoplastic Agents ,Biology ,Piperazines ,Epigenesis, Genetic ,Histone H3 ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Cytotoxicity ,Cells, Cultured ,U937 cell ,Reverse Transcriptase Polymerase Chain Reaction ,Histone deacetylase inhibitor ,Myeloid leukemia ,Cell Differentiation ,Drug Synergism ,Hematology ,Methyltransferases ,DNA Methylation ,medicine.disease ,Bromodomain ,Repressor Proteins ,Leukemia ,Leukemia, Myeloid, Acute ,Oncology ,Cancer research ,Original Article - Abstract
Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.
- Published
- 2015
31. Association of helicobacter pylori CagA translocation with the expression of CagA-signaling transduction molecules in gastric mucosa-associated lymphoid tissue lymphoma
- Author
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Kun-Huei Yeh, Ping-Ning Hsu, Li-Tzong Chen, Sung-Hsin Kuo, Yi-Shin Tzeng, Ming-Shiang Wu, Chung-Wu Lin, Ann-Lii Cheng, and Hui-Jen Tsai
- Subjects
Cancer Research ,Chromosomal translocation ,Biology ,Helicobacter pylori ,bacterial infections and mycoses ,Signaling transduction ,medicine.disease ,biology.organism_classification ,digestive system ,Molecular biology ,digestive system diseases ,Lymphoma ,medicine.anatomical_structure ,Lymphatic system ,Oncology ,Immunology ,Gastric mucosa ,medicine ,bacteria ,CagA - Abstract
8571 Background: We previously reported that a direct contact of Helicobacter pylori (HP) with B cells results in CagA translocation into the latter, and the translocated CagA regulates intracellul...
- Published
- 2014
32. 1J373 Is a Promising Agent Against C-KIT driven Acute Myeloid Leukemia
- Author
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Weir-Torn Jiang, Hui-You Lin, Hui-Jen Tsai, Li-Tzong Chen, Tsu-An John Hsu, Chiung-Tong Chen, and Sheng-Fung Lin
- Subjects
medicine.drug_class ,Chemistry ,Immunology ,Myeloid leukemia ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tyrosine-kinase inhibitor ,Leukemia ,Imatinib mesylate ,hemic and lymphatic diseases ,medicine ,Cancer research ,Protein kinase B ,PI3K/AKT/mTOR pathway ,medicine.drug ,K562 cells - Abstract
Acute myeloid leukemia (AML) carrying t(8;21)(q22;q22) and inv(16)/t(16;16)(p13;q22) are classified as French-American-British (FAB) AML subtype M2 or monocytic with eosinophilic differentiation (M4Eo) by morphology and as core binding factor (CBF)-AML according to pathogenesis. CBF-AML accounts for approximately 15% of AML and frequently harbors c-KIT mutation (17∼46%). C-KIT mutated CBF-AML patients usually have higher baseline white blood cell count, higher relapse rate and shorter event free survival/overall survival after conventional chemotherapy than those without c-KIT mutation. It is conceived that c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Imatinib, a tyrosine kinase inhibitor suppressing c-KIT activation, has been used in c-KIT mutated AML, systemic mastocytosis (SM) and gastrointestinal stromal tumor (GIST). However, c-KIT exon17 D816V mutation, a frequent mutation of CBF-AML and SM, is associated with primary imatinib resistance. 1J373, a multi-targeted tyrosine kinase inhibitor, which was initially designed as a FLT3 inhibitor but later found to target c-KIT as well. It has been shown to effectively inhibit the proliferation of FLT3-ITD mutated leukemia cell lines, MV4;11 and MOLM-13, both in vitro and in vivo. (unpublished data) Among a series of myeloid leukemia cell lines without FLT3-ITD mutation, including THP-1, HL-60, K562, KG-1, and kasumi-1, the sensitivity to 1J373 is closely associated with the presence of constitutive c-KIT activation (Figure 1A). The IC50 of 1J373 for cells with (K562, KG-1 and kasumi-1) and without (THP-1 and HL-60) constitutive c-KIT activation was below 50 nM and beyond 1000 nM, respectively. 1J373 suppressed the phosphorylation of c-KIT for cell lines with constitutively activated c-KIT, which suggested that 1J373 may suppress the proliferation of KG-1, K562, and kasumi-1 by inhibiting c-KIT (Figure 1B).We further compared the efficacy of 1J373 and imatinib in kasumi-1, a cell line with t(8;21)/AML1-ETO and c-KIT exon 17 N822K mutation. At 1000nM of concentration, the phosphorylation of c-KIT was effectively inhibited by imatinib at 2-hour but partially recovered after 8 hours; while 1J373 treatment resulted in a sustained inhibition for 24 hours. The inhibition of c-KIT activation by both agents was accompanied with corresponding changes in the phosphorylation status of its downstream signaling pathway molecules, including PI3K, AKT, mTOR, and MAPK (Figure 2). 1J373 induced cell cycle arrest of kasumi-1 at G1 phase with increase of subG1 population time-dependently and induced apoptosis of kasumi-1 through activation of caspase 8 and 9, and upregulation of proapoptotic proteins Bax and Bak. The in vivo experiments are in progress. In conclusion, 1J373, a multi-targeted tyrosine kinase inhibitor, can effectively inhibit the proliferation and induce the apoptosis of c-KIT activated leukemia cells. It has the potential to be used in clinical practice to treat c-KIT driven, particularly c-KIT mutated, AML.Figure 1c-KIT and phosphorylated c-KIT expression in myeloid leukemia cell linesFigure 1. c-KIT and phosphorylated c-KIT expression in myeloid leukemia cell linesFigure 2c-KIT and its downstream signalings expression in kasumi-1 cells treated with imatinib and 1J373Figure 2. c-KIT and its downstream signalings expression in kasumi-1 cells treated with imatinib and 1J373 Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
33. Allo-SCT in a rare t(8;21) evolution of CML
- Author
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Chun-Yuan Lee, Shu-Kai Lin, Hui-Jen Tsai, H H Hsiao, and Yi-Hsueh Liu
- Subjects
Transplantation ,medicine.medical_specialty ,Hematology ,business.industry ,Cancer ,Chromosomal translocation ,Blastic Phase ,medicine.disease ,Somatic evolution in cancer ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,Cancer research ,Medicine ,Abnormality ,Stem cell ,business ,neoplasms ,Chronic myelogenous leukemia - Abstract
Although clonal evolution with an acquired additional chromosomal abnormality is one of the most common mechanisms of disease progression in CML, t(8;21) with AML1-ETO transcript has rarely been reported in the evolution of CML.1, 2, 3 We present here a case harboring an acquired t(8;21) abnormality in the blastic phase of CML after complete cytogenetic remission from imatinib therapy and demonstrate the successful treatment of this advanced status using allo-SCT.
- Published
- 2009
34. Detection of the Helicobacter pylori CagA protein in gastric mucosa-associated lymphoid tissue lymphoma cells: clinical and biological significance
- Author
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Ming-Shiang Wu, Yi-Shin Tzeng, Hsiu-Po Wang, Chung-Wu Lin, Ann-Lii Cheng, Ping-Ning Hsu, Hui-Jen Tsai, Chu Cy, Kun-Huei Yeh, Li-Tzong Chen, and Sung-Hsin Kuo
- Subjects
Pathology ,medicine.medical_specialty ,digestive system ,antibiotics ,medicine ,Gastric mucosa ,CagA ,MALT lymphoma ,biology ,business.industry ,Stomach ,food and beverages ,Hematology ,Helicobacter pylori ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,digestive system diseases ,Lymphoma ,Lymphatic system ,medicine.anatomical_structure ,Oncology ,Cancer research ,Immunohistochemistry ,Original Article ,business ,stomach - Abstract
We previously reported that CagA can be translocated into B cells in Helicobacter pylori (HP) coculture media, and the translocation appears biologically significant as activation of the relevant cellular pathways was noticed. In this study, we further explore if CagA can be detected in malignant B cells of HP-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Expression of CagA was evaluated by immunohistochemistry. CagA expression was further confirmed by western blot analysis. The association between CagA expression in malignant B cells and tumor response to HP eradication therapy (HPE) was evaluated in 64 stage IE gastric MALT lymphoma patients. We detected CagA expression in 31 (48.4%) of 64 patients: 26 (68.4%) of the 38 HP-dependent cases and 5 (19.2%) of the 26 HP-independent cases (P
- Published
- 2013
35. Effective treatment of aggressive B-cell lymphomas by downregulated NIK-induced noncanonical NF-κB pathway activation through inhibition of BAFF
- Author
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Sung-Hsin Kuo, Ann-Lii Cheng, Li-Tzong Chen, Kun-Huei Yeh, Hsiao-Wei Lee, and Hui-Jen Tsai
- Subjects
Cancer Research ,Tnf family ,NF-κB ,Biology ,chemistry.chemical_compound ,medicine.anatomical_structure ,Oncology ,chemistry ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Cancer research ,Effective treatment ,Signal transduction ,B-cell activating factor ,Autocrine signalling ,B cell - Abstract
e13554 Background: We recently reported that autocrine BAFF (B cell–activating factor belonging to the TNF family) signal transduction pathway contributes to H. pylori-independent growth of gastric diffuse large B-cell lymphoma (DLBCL) (Blood 2008;112:2927-34; Ann Hematol 2010;89:431-6). In this study, we sought to investigate whether activation of BAFF signaling pathway can promote the survival and proliferation of aggressive B-cell lymphoma. Methods: Seven aggressive NHL cell lines (EBV-negative Burkitt’s lymphoma (Ramos), EBV-positive Burkitt’s lymphoma (Raji), EBV-negative undifferentiated lymphoma (MC116), activated B cell (ABC)-like DLBCL (OCI-Ly3, OCI-Ly10), and germinal center B cell (GCB)-like DLBCL (OCI-Ly7, and Pfeiffer) were used in this study. Cell cycle was analyzed by flow cytometry. The DNA-binding activity of NF-kB was determined by the luciferase assay. Expression of non-canonical NF-κB signatures-related proteins (BAFF, BAFF-R, NIK, cIAP1, TRAF2, cIAP1/2, TRAF3, IKKa, p100, p52 and RelB, BCL10, BCL3, and STAT3) was assessed by immunoblotting. Results: Our results showed that in GCB-DLBCL cell lines, activation of BAFF induced recruitment and degradation of TRAF3, which resulted in NIK kinase accumulation, BCL10 Ser138 phosphorylation, IKKa phosphorylation, and NF-kB p100 processing, thereby resulting in continuous activation of non-canonical NF-kB pathway. This phenomenon also resulted in BCL3 nuclear translocation and STAT3 activation, and subsequently activated STAT3 downstream-regulated genes (BCL2, survivin, and cyclin D1). Furthermore, we found that inhibition of BAFF by short hairpin RNA (shRNA) suppressed the growth of ABC-DLBCL cells and Burkitt lymphoma cells through the down-regulation of BAFF/BAFF-R/TRAF3/NIK/BCL3/NF-kB signaling pathway. Conclusions: Our results indicate that constitutive BAFF signaling activates NIK-induced non-canonical NF-kB signaling pathway in aggressive B-cell lymphoma, and inhibition of BAFF is particularly effective in the treatment of this subgroup of tumors.
- Published
- 2013
36. AUY922, a Novel HSP90 Inhibitor Effective Against ABC-DLBCL and MALT Lymphoma Cells Harboring Genetic Alteration-Associated NF-κB Activation
- Author
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A-L Cheng, Hui-Jen Tsai, Sow-Hsong Kuo, and L.-T. Chen
- Subjects
business.industry ,Genetic Alteration ,MALT lymphoma ,HSP90 Heat-Shock Proteins ,Hematology ,medicine.disease ,BCL10 ,Hsp90 inhibitor ,Oncology ,Cancer research ,Medicine ,Abc dlbcl ,business ,Nf κb activation - Published
- 2013
37. Detection of Caga Expression in Gastric Mucosa-Associated Lymphoid Tissue Lymphoma—Biologic Significance and Clinical Implication
- Author
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Chun-Nan Lin, Kun-Tu Yeh, Ming-Shiang Wu, P.-N. Hsu, Hui-Jen Tsai, Sow-Hsong Kuo, Hsei-Wei Wang, L.-T. Chen, Yi-Shin Tzeng, and A-L Cheng
- Subjects
biology ,business.industry ,Cancer ,MALT lymphoma ,Hematology ,Helicobacter pylori ,bacterial infections and mycoses ,biology.organism_classification ,medicine.disease ,digestive system ,digestive system diseases ,Lymphoma ,Lymphatic system ,medicine.anatomical_structure ,Oncology ,immune system diseases ,hemic and lymphatic diseases ,Gastric mucosa ,medicine ,Cancer research ,CagA ,Immunohistochemistry ,business - Abstract
Background We recently reported that a direct contact of Helicobacter pylori (HP) with B cells resulted in CagA translocation into the cells (Cancer Res 2010;70:5740-8). The translocated CagA further activates extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), and up-regulates the expressions of Bcl-2 and Bcl-xL. In this study, we sought to verify if CagA exists in the malignant B cells of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Methods Expression of CagA protein, phospho-SHP-2, phospho-ERK, phospho-p38MAPK, Bcl-2 and Bcl-xL in a series of 26 gastric MALT lymphoma was determined by immunohistochemistry. Western blot analysis was done to confirm immunohistochemical detection of CagA and biopsies from non-gastric MALT lymphoma served as negative controls. The association of CagA expression and the tumor response to HP-eradication (HPE) therapy was evaluated in 77 stage IE/IIE1 low-grade gastric MALT lymphoma patients. Results The expression of CagA was detected in 35 (45.5%) of 77 patients. CagA expression was closely associated with the expression phospho-SHP-2 (P = .016), phospho-ERK (P Conclusion CagA protein can be translocated into malignant B cells of MALT lymphoma. The expression of CagA in lymphoma cells appears to be biologically and clinically significant. Disclosure All authors have declared no conflicts of interest.
- Published
- 2012
38. Tumor Necrosis Factor-α Contributes to Microenvironmental up- Regulation of NF-κB Activity in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Implication for a Novel Therapeutic Target
- Author
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Takaomi Ishida, Kiyoko Itoh, Seiichiro Kobayashi, Kazuo Umezawa, Hui-Jen Tsai, and Arinobu Tojo
- Subjects
Stromal cell ,Chemistry ,Cell growth ,Immunology ,Cell ,Cell Biology ,Hematology ,Philadelphia chromosome ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Cell culture ,Apoptosis ,Cancer research ,medicine ,Tumor necrosis factor alpha ,Bone marrow - Abstract
Constitutively activated NF-κB has been demonstrated in primary blast cells and cell lines derived from Philadelphia chromosome (Ph- positive acute lymphoblastic leukemia(Ph- ALL). In our previous study, we have shown the essential role for NF-κB in growth and survival of Ph- ALL cells. To gain insight into the microenvironmental (cytokines and/or stromal cell) regulation of NF-κB activity in Ph- ALL, we lentivirally transduced Ph- ALL cells, IMS-PhL1 and Sup-B15 cells, with NF-κB/luciferase (kB/Luc) reporter construct and established a bioluminescence imaging model of Ph- ALL for in vitro and in vivo analysis. In in vitro study, we checked NF-κB/Luc activity by luminoter. It showed that NF-κB activity of Ph- ALL cells was significantly up-regulated by TNFa stimulation and synergistically augmented by seeding them onto a layer of murine HESS5 stromal cells, which singly didn’t change NF-κB activity in Ph- ALL cells. DHMEQ, a specific inhibitor of nuclear translocation of p65, eradicated constitutive and TNFa inducible NF-κB activity of Ph- ALL cells and induced their substantial apoptosis dose-dependently. However, the inhibitory effect of DHMEQ on TNFa induced NF-κB activity as well as viability of Ph- ALL was alleviated in the presence of HESS5. This alleviatory effect of DHMEQ induced NF-κB suppression by HESS5 was overcame by addition of TNFa inhibitor, Etanercept, in a dose of less than 1ug/ml. (Fig.1) Taken together, TNFa plays an essential role in up-regulation of NF-κB activity in the absence or presence of HESS5 cells. When Ph- ALL cells were treated with TPCA-1, an IKK-2 inhibitor, the TNFa induced NF-κB activity in Ph- ALL cells was suppressed even in the presence of HESS5 cells. Cell proliferation assay also showed inhibitory effect on proliferation of Ph- ALL cells by TPCA-1. In in vivo study, we transplanted Ph- ALL cells into NOD-Scid mice and periodically monitored the NF-κB activity of Ph- ALL cells by a CCD camera. Intriguingly, strong signal was detected in liver, stomach and ovary in addition to bone marrow, which was the predominant site of leukemic cell infiltration. QR-PCR analysis and immunohistochemistry staining for mouse tissue verified tumor infiltration up-regulate murine TNFa production in these tissues. It suggests the essential role of TNFa in the up-regulation of NF-κB signaling in mouse model. However high dose Etanercept, 1mg, subcutaneous injection into Ph- ALL cells transplanted mouse didn’t show significant reduction of NF-κB activity and partial response of NF-κB suppression was seen in the mouse injected with 5mg of Etanercept intraperitoneally. (Fig.2) This result suggests that factors other than TNFa may contribute to in vivo maintenance and/or up-regulation of NF-κB activity in Ph- ALL cells. In conclusion, TNFa-dependent and independent pathways are involved in microenvironmental up-regulation of NF-κB activity, which contribute to survival, expansion and presumably drug-resistance of Ph- ALL cells. The present bioimaging model helps us to dissect the regulatory mechanism of NF-κB signal in Ph- ALL and the results suggest us microenvironment as a novel therapeutic target in the treatment of Ph- ALL. Fig. 1 NF-κB activity of Sup-B15 cells treated with DHMEQ, TNFα and Etanercept(22hrs) Fig. 1. NF-κB activity of Sup-B15 cells treated with DHMEQ, TNFα and Etanercept(22hrs) Fig. 2 In vivo imaging of NF-κB activity in Sup-B15 cells treated with Etanercept Fig. 2. In vivo imaging of NF-κB activity in Sup-B15 cells treated with Etanercept
- Published
- 2008
39. Downregulation of Circadian Genes, PER1, PER2, and PER3, in Chronic Myeloid Leukemia
- Author
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Lin Sheng-Fung, Tyen-Po Chen, Shih-Bin Tseng, Ming-Yu Yang, Yi-Chang Liu, Ta-Chih Liu, Hui-Jen Tsai, Jan-Gowth Chang, and Hui-Hua Hsiao
- Subjects
Immunology ,Circadian clock ,Myeloid leukemia ,Cell Biology ,Hematology ,Methylation ,Biology ,Biochemistry ,Molecular biology ,PER2 ,PER3 ,CpG site ,Cancer research ,Circadian rhythm ,PER1 - Abstract
Circadian rhythm is present in all eukaryotic and some prokaryotic life forms. This time-keeping system is organized in a hierarchical fashion and composed of a self-sustained central pacemaker in the suprachiasmatic nuclei of the anterior hypothalamus and peripheral oscillators in most body cells. A recent study demonstrated that mice deficient in the clock gene mPer2 are cancer prone and display a deregulated temporal expression genes involved in cell cycle regulation, such as c-Myc, Cyclin D1, Cyclin A, and Mdm-2. These mice display salivary gland hyperplasia, and a large portion of them develops lymphomas. The results revealed that Per2 is an essential circadian gene and it is associated with proliferation control in mammals. In a more recent study, it was demonstrated that an age-dependent decay of the circadian clock both at the behavioral and the molecular levels was observed in mPer1−/−mCry2−/− double-mutant mice. To gain further insights into the roles of circadian genes in chronic myeloid leukemia (CML), we analyzed peripheral blood from 21 healthy individuals and 35 CML patients (18 in blastic crisis and 17 in chronic phase) by real-time quantitative RT-PCR for the expression of circadian genes PER1, PER2, and PER3. In blastic crisis cases, the expression levels of all three PER genes were significantly impaired than in healthy individuals (PER1, 1:5.97, p < 0.005; PER2, 1:13.51, p < 0.0001; PER3, 1:2181.33; p < 0.0001); whereas, in chronic phase, only the expression levels of PER2 and PER3 were significantly impaired (PER1, 1:1.23, p > 0.5; PER2, 1:2.47, p < 0.05; PER3, 1:14.22; p < 0.0001). Mutational analysis of the whole gene and methylation analysis of CpGs sites at the promoter area were further performed to investigate the possible mechanisms. No mutation was found within the coding regions of the three PER genes in all CML cases. Methylation analysis using methylation-specific PCR and direct sequencing showed no methylation in the promoter areas of both PER1 and PER2 genes. In contrast, most of the CpG sites were methylated in the promoter area of PER3 gene in CML cases and none of these CpG sites were methylated in healthy individual cases. In addition, the methylated CpG frequencies of PER3 gene differed in patients at blastic crisis and at chronic phase (CpG, 8.24 ± 0.73 vs. 4.48 ± 0.48, p < 0.0001; T/CpG, 10.47 ± 0.67 vs. 14.67 ± 0.46, p < 0.0001; TG, 1.24 ± 0.32 vs. 0.81 ± 0.16, p > 0.05). Demethylation by treatment of hypermethylated K562 cells with 5′-aza-2′-deoxycytidine resulted in partial reactivation of PER3 expression. Our results suggest that the downregulated PER3 expression in CML was due to the inactivation of PER3 gene by methylation and the differential expression was correlated to the ratio of methylated CpG sites at the promoter region. We hope to explore the role of circadian genes in the tumorigenesis of leukemia and to establish circadian genes as novel and useful markers for diagnosis and references for therapies in leukemia.
- Published
- 2004
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