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Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002) Issue CLINICAL CANCER RESEARCH 2022, Volume 28 Issue 4 637-645 Author Hua Xin / Bi Xi-wen / Zhao Jian-Li / Shi Yan-Xia / Lin Ying / Wu Zhi-Yong / Zhang Yuan-Qi / Zhang Le-Hong / Zhang An-Qing / Huang Heng / Liu Xin-Mei / Xu Fei / Guo Ying / Xia Wen / Hong Ruo-Xi / Jiang Kui-Kui / Xue Cong / An Xin / Zhong Yong-Yi / Wang Shu-Sen / Huang Jia-Jia / Yuan Zhong-Yu Abstract Purpose: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2(+)) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. Patients and Methods: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. Results: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. Conclusions: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR(+)HER2(+) MBC. Cite this article as: [1]Hua Xin, Bi Xi-wen, Zhao Jian-Li, et al.Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002)[J].CLINICAL CANCER RESEARCH,2022,28(4):637-645.  Full text link
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| Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication Issue BLOOD CANCER JOURNAL 2021, Volume 11 Issue 2 Author Lu Pin / Wang Shengchun / Franzen Carrie A. / Venkataraman Girish / McClure Rebecca / Li Lei / Wu Wenjun / Niu Nifang / Sukhanova Madina / Pei Jianming / Baldwin Donald A. / Nejati Reza / Wasik Mariusz A. / Khan Nadia / Tu Yifan / Gao Juehua / Chen Yihua / Ma Shuo / Larson Richard A. / Wang Y. Lynn Abstract Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients' actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease. Cite this article as: [1]Lu Pin, Wang Shengchun, Franzen Carrie A., et al.Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication[J].BLOOD CANCER JOURNAL,2021,11(2).  Full text link
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| Efficacy and safety of GLS-010 (zimberelimab) in patients with relapsed or refractory classical Hodgkin lymphoma: A multicenter, single-arm, phase II study Issue EUROPEAN JOURNAL OF CANCER 2022, Volume 164 117-126 Author Lin Ningjing / Zhang Mingzhi / Bai Hai / Liu Hui / Cui Jie / Ke Xiaoyan / Zhang Huilai / Liu Lihong / Yan Dongmei / Jiang Yongsheng / Zang Aimin / Qi Junyuan / Wang Li / Liu Zhuogang / Xu Bing / Zhang Ying / Zhang Zhihui / Zhao Xielan / Hu Chunhong / Yang Shenmiao / Zhou Hui / Shi Jinsheng / Shao Zonghong / Xiang Ying / Zhu Jiman / Song Yuqin / Zhu Jun Keywords Hodgkin lymphoma / Treatment response / Response / PD-1 / Monoclonal antibody Abstract Background: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL).Methods: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483).Results: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n Z 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4 .7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. Conclusions: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.(c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Cite this article as: [1]Lin Ningjing, Zhang Mingzhi, Bai Hai, et al.Efficacy and safety of GLS-010 (zimberelimab) in patients with relapsed or refractory classical Hodgkin lymphoma: A multicenter, single-arm, phase II study[J].EUROPEAN JOURNAL OF CANCER,2022,164:117-126.  Full text link
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| Dietary Fats High in Linoleic Acids Impair Antitumor T-cell Responses by Inducing E-FABP-Mediated Mitochondrial Dysfunction Issue CANCER RESEARCH 2021, Volume 81 Issue 20 5296-5310 Author Jin Rong / Hao Jiaqing / Yi Yanmei / Yin Di / Hua Yuan / Li Xiaohong / Bao Hanmei / Han Xianlin / Egilmez Nejat K. / Sauter Edward R. / Li Bing Abstract The most recent American Dietary Guidelines (2020-2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear. Here we demonstrated that high-fat diets (HFD) rich either in OA or LA induced a similar degree of murine obesity, but the LA-rich HFD specifically promoted mammary tumor growth. LA impaired antitumor T-cell responses by promoting naive T-cell apoptosis and inhibiting TNF alpha production. While exogenous OA and LA were taken up by T cells with similar efficacy, only LA induced significant mitochondrial reactive oxygen species production and lipid peroxidation. Importantly, naive T cells predominantly expressed epidermal fatty acid binding protein (E-FABP), which is central in facilitating LA mitochondrial transport and cardiolipin incorporation. Genetic depletion of E-FABP rescued LA-impaired T-cell responses and suppressed LA-rich HFD-associated mammary tumor growth. Collectively, these data suggest that dietary oils high in LA promote mammary tumors by inducing E-FABP-mediated T-cell dysfunction. Significance: These findings suggest that modulation of dietary oil composition and inhibition of E-FABP activity may represent novel strategies to enhance T-cell function in the prevention and treatment of obesity-associated cancers. [GRAPHICS] . Cite this article as: [1]Jin Rong, Hao Jiaqing, Yi Yanmei, et al.Dietary Fats High in Linoleic Acids Impair Antitumor T-cell Responses by Inducing E-FABP-Mediated Mitochondrial Dysfunction[J].CANCER RESEARCH,2021,81(20):5296-5310.  Full text link
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| Chemically synthesized cinobufagin suppresses nasopharyngeal carcinoma metastasis ENKUR to stabilize Issue CANCER LETTERS 2022, Volume 531 57-70 Author Hou Rentao / Liu Xiong / Yang Huiling / Deng Shuting / Cheng Chao / Liu Jiahao / Li Yonghao / Zhang Yewei / Jiang Jingwen / Zhu Zhibo / Su Yun / Wu Liyang / Xie Yingying / Li Xiaoning / Li Wenmin / Liu Zhen / Fang Weiyi Keywords Cancer cell metastasis / Cinobufagin / ENKUR / P53 / Nasopharyngeal carcinoma Abstract Clinically, the metastasis of tumor cells is the key factor of death in patients with cancer. In this study, we used a model of metastatic nasopharyngeal carcinoma (NPC) to explore the effects of a new chemical, cinobufagin (CB), combined with cisplatin (DDP). We observed that chemically synthesized CB strongly decreased the metastasis of NPC. Furthermore, a better therapeutic effect was shown when CB was combined with DDP. Molecular analysis revealed that CB induced ENKUR expression by deregulating the PI3K/AKT pathway and suppressing c-Jun, an oncogenic transcriptional factor that binds to the ENKUR promoter and negatively modulated its expression in NPC. ENKUR as a tumor suppressor binds to MYH9 and decreases its expression by recruiting beta-catenin via its enkurin domain to prevent its nuclear accumulation, which therefore suppresses c-Jun-induced MYH9 expression. Subsequently, downregulated MYH9 reduces the enlistment of E3 ligase UBE3A and thus decreases the UBE3A-mediated ubiquitination degradation of p53, a key tumor suppressor that decreases epithelialmesenchymal transition (EMT). Clinical sample analysis demonstrated that the ENKUR expression level was significantly reduced in NPC tissues. Its decreased expression substantially promoted clinical progression and reflected poor prognosis for patients with NPC. This study demonstrated that CB induced ENKUR to repress the beta-catenin/c-Jun/MYH9 signal and thus decreased UBE3A-mediated p53 ubiquitination degradation. As a result, the EMT signal was inactivated to suppress NPC metastasis. Cite this article as: [1]Hou Rentao, Liu Xiong, Yang Huiling, et al.Chemically synthesized cinobufagin suppresses nasopharyngeal carcinoma metastasis ENKUR to stabilize[J].CANCER LETTERS,2022,531:57-70.  Full text link
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| Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3-mediated N6-methyladenosine modification of ICAM2 mRNA in fibroblast-like synoviocytes Issue CLINICAL AND TRANSLATIONAL MEDICINE 2022, Volume 12 Issue 12 Author Chen Jian / Lin Xian / He Juan / Liu Dandan / He Lianhua / Zhang Miaomiao / Luan Huijie / Hu Yiping / Tao Cheng / Wang Qingwen Keywords artemisitene / fibroblast-like synoviocytes / ICAM2 / METTL3 / rheumatoid arthritis Abstract BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease. We previously revealed that the natural compound artemisitene (ATT) exhibits excellent broad anticancer activities without toxicity on normal tissues. Nevertheless, the effect of ATT on RA is undiscovered. Herein, we aim to study the effect and potential mechanism of ATT on RA management. MethodsA collagen-induced arthritis (CIA) mouse model was employed to confirm the anti-RA potential of ATT. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, cell cycle and apoptosis analysis, immunofluorescence, migration and invasion assays, quantitative real-time PCR (RT-qPCR), Western blot, RNA-sequencing (RNA-seq) analysis, plasmid construction and lentivirus infection, and methylated RNA immunoprecipitation and chromatin immunoprecipitation assays, were carried out to confirm the effect and potential mechanism of ATT on RA management. ResultsATT relieved CIA in mice. ATT inhibited proliferation and induced apoptosis of RA-fibroblast-like synoviocytes (FLSs). ATT restrained RA-FLSs migration and invasion via suppressing epithelial-mesenchymal transition. RNA-sequencing analysis and bioinformatics analysis identified intercellular adhesion molecule 2 (ICAM2) as a promoter of RA progression in RA-FLSs. ATT inhibits RA progression by suppressing ICAM2/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/p300 pathway in RA-FLSs. Moreover, ATT inhibited methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine methylation of ICAM2 mRNA in RA-FLSs. Interestingly, p300 directly facilitated METTL3 transcription, which could be restrained by ATT in RA-FLSs. Importantly, METTL3, ICAM2 and p300 expressions in synovium tissues of RA patients were related to clinical characteristics and therapy response. ConclusionsWe provided strong evidence that ATT has therapeutic potential for RA management by suppressing proliferation, migration and invasion, in addition to inducing apoptosis of RA-FLSs through modulating METTL3/ICAM2/PI3K/AKT/p300 feedback loop, supplying the fundamental basis for the clinical application of ATT in RA therapy. Moreover, METTL3, ICAM2 and p300 might serve as biomarkers for the therapy response of RA patients. Cite this article as: [1]Chen Jian, Lin Xian, He Juan, et al.Artemisitene suppresses rheumatoid arthritis progression via modulating METTL3-mediated N6-methyladenosine modification of ICAM2 mRNA in fibroblast-like synoviocytes[J].CLINICAL AND TRANSLATIONAL MEDICINE,2022,12(12).  Full text link
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| ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway Issue CANCER LETTERS 2020, Volume 472 70-80 Author Wang Nuozhou / Li Ming-Yue / Liu Yi / Yu Jianqing / Ren Jianwei / Zheng Zhiyuan / Wang Shanshan / Yang Shucai / Yang Sheng-li / Liu Li-ping / Hu Bao-guang / Chong Charing C. N. / Merchant Juanita L. / Lai Paul B. S. / Chen George Gong Keywords Hepatocellular carcinoma / Liver cancer sternness / Recurrence / Notch1 / ZBP-89 Abstract Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer sternness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC sternness via inhibiting the Notch1 signaling. Cite this article as: [1]Wang Nuozhou, Li Ming-Yue, Liu Yi, et al.ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway[J].CANCER LETTERS,2020,472:70-80.  Full text link
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| The miR-1185-2-3p-GOLPH3L pathway promotes glucose metabolism in breast cancer by stabilizing p53-induced SERPINE1 Issue JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 2021, Volume 40 Issue 1 Author Xu Youqin / Chen Wancheng / Liang Jing / Zeng Xiaoqi / Ji Kaiyuan / Zhou Jianlong / Liao Shijun / Wu Jiexian / Xing Kongyang / He Zilong / Yang Yang / Liu Qianzhen / Zhu Pingyi / Liu Yuchang / Li Li / Liu Minfeng / Chen Wenxiao / Huang Wenhua Keywords Tumorigenesis / Glucose metabolism / Glycosylation / miRNA / p53-induced transcription Abstract Background Phosphatidylinositol-4-phosphate-binding protein GOLPH3L is overexpressed in human ductal carcinoma of the breast, and its expression levels correlate with the prognosis of breast cancer patients. However, the roles of GOLPH3L in breast tumorigenesis remain unclear. Methods We assessed the expression and biological function of GOLPH3L in breast cancer by combining bioinformatic prediction, metabolomics analysis and RNA-seq to determine the GOLPH3L-related pathways involved in tumorigenesis. Dual-luciferase reporter assay and coimmunoprecipitation (Co-IP) were used to explore the expression regulation mechanism of GOLPH3L. Results We demonstrated that knockdown of GOLPH3L in human breast cancer cells significantly suppressed their proliferation, survival, and migration and suppressed tumor growth in vivo, while overexpression of GOLPH3L promoted aggressive tumorigenic activities. We found that miRNA-1185-2-3p, the expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, is directly involved in suppressing the expression of GOLPH3L. Metabolomics microarray analysis and transcriptome sequencing analysis revealed that GOLPH3L promotes central carbon metabolism in breast cancer by stabilizing the p53 suppressor SERPINE1. Conclusions In summary, we discovered a miRNA-GOLPH3L-SERPINE1 pathway that plays important roles in the metabolism of breast cancer and provides new therapeutic targets for human breast cancer. Cite this article as: [1]Xu Youqin, Chen Wancheng, Liang Jing, et al.The miR-1185-2-3p-GOLPH3L pathway promotes glucose metabolism in breast cancer by stabilizing p53-induced SERPINE1[J].JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,2021,40(1).  Full text link
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