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cancer Biology & Medicine 2024年第9期21卷 754-768页

作者： Lina Hu Xuanye Zhang Shengbing Zang sun yat-sen university cancer center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Pathology Sun Yat-sen University Cancer Center Department of Medical Oncology Sun Yat-sen University Cancer Center

Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA) among various cancers with unique aberrant profiles and pathogenic effects, especially in peripheral T-cell lymphoma(PTCL). The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type, thereby leading to different functional and biological properties, which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors. However, the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated. Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways. The promising potential of targeting RHOA as a therapeutic modality is also outlined. This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

关键词： Drug target Ras homolog family member A mutation pathogenesis peripheral T-cell lymphoma personalized medicine

Sintilimab(anti-PD-1 antibody)plus chidamide(histone deacetylase inhibitor)in relapsed or refractory extranodal natural killer T-cell lymphoma(SCENT):a phase Ⅰb/Ⅱ study

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2765-2773页

作者： Yan Gao Haixia He Xueping Li Liling Zhang Wei Xu Ru Feng Wenyu Li Yin Xiao Xinxiu Liu Yu Chen Xiaoxiao Wang Bing Bai Huijing Wu Qingqing Cai Zhiming Li Jibin Li Suxia Lin Yanxia He Liqin Ping Cheng Huang Jiaying Mao Xiujin Chen Baitian Zhao Huiqiang Huang State Key Laboratory of Oncology in South China&Collaborative Innovation center of cancer Medicine Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhouChina Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhouChina Department of Radiation Oncology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina Department of Hematology Sun Yat-sen University Cancer CenterGuangzhouChina cancer center Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina Department of Hematology The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjingChina Department of Hematology Nanfang HospitalSouthern Medical UniversityGuangzhouChina Department of Lymphoma Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhouChina Department of pathology Guangdong General HospitalGuangdong Academy of Medical SciencesGuangzhouChina Department of Medical Oncology Hubei Cancer CenterWuhanChina Department of Clinical Research Sun Yat-sen University Cancer CenterGuanzhouChina Department of Pathology Sun Yat-sen University Cancer CenterGuangzhouChina

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma(RR-ENKTL),however,the complete response(CR)rate and the duration of response(DOR)need to be *** phase 1b/2 study investigated the safety and efficacy of sintilimab,a fully human anti-PD-1 antibody,plus chidamide,an oral subtype-selective histone deacetylase inhibitor in 38 patients with *** objective response rate(ORR)of combination treatment was 80%.Patients received escalating doses of chidamide,administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 *** dose-limiting events were observed,RP2D of chidamide was 30 mg twice a ***-nine patients were enrolled in phase *** the intention-to-treat population(n=37),overall response rate was 59.5% with a complete remission rate of 48.6%.The median DOR,progression-free survival(PFS),and overall survival(OS)were 25.3,23.2,and 32.9 months,*** most common grade 3 or higher treatment-emergent adverse events(AEs)were neutropenia(28.9%)and thrombocytopenia(10.5%),immune-related AEs were reported in 18(47.3%)*** biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic ***3 mutation shows an unfavorable *** outcome of anticipate ORR was not achieved,sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first *** is a promising therapeutic option for this population.

关键词： killer lymphoma doses

Nanomedicine targeting ferroptosis to overcome anticancer therapeutic resistance

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Science China(Life Sciences) 2024年第1期67卷 19-40页

作者： Jing Cai Xiaoding Xu Phei Er Saw Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Nanhai Translational Innovation center of Precision Immunology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityFoshan 528200China

A potential reason for the failure of tumor therapies is treatment *** to chemotherapy,radiotherapy,and immunotherapy continues to be a major obstacle in clinic,resulting in tumor recurrence and *** major mechanisms of therapy resistance are inhibitions of cell deaths,like apoptosis and necrosis,through drug inactivation and excretion,repair of DNA damage,tumor heterogeneity,or changes in tumor microenvironment,*** studies have shown that ferroptosis play a major role in therapies resistance by inducing phospholipid peroxidation and iron-dependent cell *** ferroptosis inducers in combination with clinical treatment techniques have been used to enhance the effect in tumor ***,versatile ferroptosis nanoinducers exhibit an extensive range of functions in reversing therapy resistance,including directly triggering ferroptosis and feedback ***,we provide a detailed description of the design,mechanism,and therapeutic application of ferroptosis-mediated synergistic tumor *** also discuss the prospect and challenge of nanomedicine in tumor therapy resistance by regulating ferroptosis and combination therapy.

关键词： ferroptosis cancer therapy therapy resistance nanoinducers

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Development of antibody-drug conjugates in cancer:Overview and prospects

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cancer Communications 2024年第1期44卷 3-22页

作者： Dan-Yun Ruan Hao-Xiang Wu Qi Meng Rui-Hua Xu Department of Clinical Research Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen UniversityGuangzhouGuangdongP.R.China Research Unit of Precision Diagnosis and Treatment for Gastrointestinal cancer Chinese Academy of Medical SciencesGuangzhouGuangdongP.R.China Department of Medical Oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen UniversityGuangzhouGuangdongP.R.China

In recent years,remarkable breakthroughs have been reported on antibody-drug conjugates(ADCs),with 15 ADCs successfully entering the market over the past *** substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs,demonstrating their efficacy in treating awide array of ***,there is still an unmet clin-ical need forwider application,better efficacy,and fewer side effects of *** ADC generally comprises an antibody,a linker and a payload,and the combina-tion has profound effects on drug structure,pharmacokinetic profile and ***,optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side *** this review,we comprehen-sively reviewed the current development and the prospects of ADC,provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China,highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies,and also discussed the new related technologies,possibility of next-generation ADCs and the directions of clinical research.

关键词： companies breakthrough payload

N6-methyladenosine facilitates mitochondrial fusion of colorectal cancer cells via induction of GSH synthesis and stabilization of OPA1 mRNA

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National Science Review 2024年第3期11卷 72-91页

作者： Jiawang Zhou Haisheng Zhang Ke Zhong Lijun Tao Yu Lin Guoyou Xie Yonghuang Tan You Wu Yunqing Lu Zhuojia Chen Jiexin Li Xin Deng Qin Peng Zigang Li Hongsheng Wang Guangdong Provincial Key Laboratory of New Drug Design and Evaluation School of Pharmaceutical Sciences Sun Yat-sen University sun yat-sen university cancer center State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine Department of Biomedical Sciences City University of Hong Kong Institute of Systems and Physical Biology Shenzhen Bay Laboratory

Mitochondria undergo fission and fusion that are critical for cell survival and cancer development, while the regulatory factors for mitochondrial dynamics remain elusive. Herein we found that RNA m6A accelerated mitochondria fusion of colorectal cancer（CRC） cells. Metabolomics analysis and function studies indicated that m6A triggered the generation of glutathione（GSH） via the upregulation of RRM2B——a p53-inducible ribonucleotide reductase subunit with anti-reactive oxygen species potential. This in turn resulted in the mitochondria fusion of CRC cells. Mechanistically, m6A methylation of A1240 at 3 UTR of RRM2B increased its m RNA stability via binding with IGF2BP2. Similarly, m6A methylation of A2212 at the coding sequence（CDS） of OPA1——an essential GTPase protein for mitochondrial inner membrane fusion——also increased m RNA stability and triggered mitochondria fusion. Targeting m6A through the methyltransferase inhibitor STM2457 or the dm6ACRISPR system significantly suppressed mitochondria fusion. In vivo and clinical data confirmed the positive roles of the m6A/mitochondrial dynamics in tumor growth and CRC progression. Collectively, m6A promoted mitochondria fusion via induction of GSH synthesis and OPA1 expression, which facilitated cancer cell growth and CRC development.

关键词： m6A mitochondrial fusion glutathione OPA1 colorectal cancer

The burgeoning importance of PIWI-interacting RNAs in cancer progression

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Science China(Life Sciences) 2024年第4期67卷 653-662页

作者： Xinpei Deng Tianle Liao Jindong Xie Da Kang Yiwei He Yuying sun Zhangling Wang Yongluo Jiang Xuan Miao Yixuan Yan Hailin Tang Lewei Zhu Yutian Zou Peng Liu State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510060China School of Medicine Sun Yat-sen UniversityShenzhen 518107China Key Laboratory of Cardiovascular and Cerebrovascular Medicine Nanjing Medical UniversityNanjing 211166China Guanghua School of Stomatology Sun Yat-sen UniversityGuangzhou 510062China The First People’s Hospital of Foshan Foshan 528000China

PIWI-interacting RNAs(pi RNAs)are a class of small noncoding RNA molecules that specifically bind to piwi protein family members to exert regulatory functions in germ *** studies have found that pi RNAs,as tissue-specific molecules,both play oncogenic and tumor suppressive roles in cancer progression,including cancer cell proliferation,metastasis,chemoresistance and ***,the atypical manifestation of pi RNAs and PIWI proteins in various malignancies presents a promising strategy for the identification of novel biomarkers and therapeutic targets in the diagnosis and management of ***,the precise functions of pi RNAs in cancer progression and their underlying mechanisms have yet to be fully *** review aims to examine current research on the biogenesis and functions of pi RNA and its burgeoning importance in cancer progression,thereby offering novel perspectives on the potential utilization of pi RNAs and piwi proteins in the management and treatment of advanced cancer.

关键词： PIWI-interacting RNAs/piRNAs cancer progression metastasis chemoresistance stemness

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Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system

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World Journal of Gastroenterology 2024年第6期30卷 607-609页

作者： Bai-Wei Zhao Ying-Jia Chen Ruo-Peng Zhang Yong-Ming Chen Bo-Wen Huang Department of gastric Surgery Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerGuangzhou 510060Guangdong ProvinceChina Health Science center Peking UniversityBeijing 100191China

The present letter to the editor is related to the study titled‘Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells’.Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

关键词： Angiotensin-converting enzyme 2 Hepatic stellate cells Liver fibrosis Angiotensin II Angiotensin 1-7 Renin-angiotensin system

Choline suppresses hepatocellular carcinoma progression by attenuating AMPK/mTOR-mediated autophagy via choline transporter SLC5A7 activation

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Hepatobiliary Surgery and Nutrition 2024年第3期13卷 393-411,I0001,I0002页

作者： Chen Wang Zhao-Yan Liu Wen-Ge Huang Zhi-Jun Yang Qiu-Ye Lan Ai-Ping Fang Meng-Jun Hou Xiao-Lin Luo Yao-Jun Zhang Si Chen Hui-Lian Zhu Department of Nutrition School of Public HealthSun Yat-sen UniversityGuangzhouChina Guangdong Provincial Key Laboratory of Food Nutrition and HealthSchool of Public HealthSun Yat-sen UniversityGuangzhouChina center of Experimental Animals Sun Yat-sen UniversityGuangzhouChina Experimental and Teaching center for Public Health School of Public HealthSun Yat-sen UniversityGuangzhouChina Department of Hepatobiliary Oncology Sun Yat-sen University Cancer CenterGuangzhouChina

Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-associated *** evidence suggests that autophagy plays a critical role in HCC tumorigenesis,metastasis,and *** is an essential nutrient related to prolonged survival and reduced risk of ***,it remains unclear whether this phenomenon is mediated by ***:Two HCC cell lines(HUH-7 and Hep3B)were used in the present *** growth was evaluated by cell counting kit 8(CCK-8),colony formation,and in vivo mouse xenografts *** motility was calculated by wound healing and transwell *** were measured by transmission electron microscope(TEM),and autophagy flux was detected by mRFP-GFP-labeled LC3 *** mRNA level of genes was measured by quantitative real-time polymerase chain reaction(qRT-PCR).The protein levels were detected by Western blotting(WB).Results:We found that choline inhibited the proliferation,migration,and invasion of HCC cells by downregulating autophagy in vitro and in *** expression of the solute carrier family 5 member 7(SLC5A7),a specific choline transporter,correlated with better HCC *** further discovered that choline could promote SLC5A7 expression,upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway,and attenuate ***,we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in ***:Our findings provide novel insights into choline-mediated autophagy in HCC,providing the foothold for its future application in HCC treatment.

关键词： Hepatocellular carcinoma(HCC) autophagy choline solute carrier family 5 member 7(SLC5A7)

Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2119-2136页

作者： Li Peng Yanyi Jiang Hengxing Chen Yongqiang Wang Qiusheng Lan Shuiqin Chen Zhanwang Huang Jingyuan Zhang Duanqing Tian Yuntan Qiu Diankui Cai Jiangyun Peng Daning Lu Xiaoqing Yuan Xianzhu Yang Dong Yin Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Medical Research center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Hefei Institutes of Physical Science Chinese Academy of SciencesHefei 230031China Department of Gastrointestinal Surgery Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Hepatobiliary Surgery Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China School of Biomedical Sciences and Engineering South China University of TechnologyGuangzhou International CampusGuangzhou 511442China

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug ***,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of *** is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor *** this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA ***,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in ***,we identified KRAS signaling as a common pathway downstream of EHF and ***,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in *** conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS *** of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

关键词： EHF AJUBA KRAS pathway Enhancer Core transcriptional regulatory circuitry Gastroesophageal adenocarcinoma gastric adenocarcinoma Esophageal adenocarcinoma Transcription factor Coactivator Lipid nanoparticles

Improving the Conversion Success Rate of Hepatocellular Carcinoma: Focus on the Use of Combination Therapy with a High Objective Response Rate

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Journal of Clinical and Translational Hepatology 2024年第3期12卷 298-304页

作者： Qi-Feng Chen Song Chen Minshan Chen Ning Lyu Ming Zhao Department of Minimally Invasive Interventional Therapy Liver Cancer Study and Service GroupSun Yat-sen University Cancer CenterGuangzhouGuangdongChina State Key Laboratory of Oncology in South China GuangzhouGuangdongChina Department of Liver Surgery Sun Yat-sen University Cancer CenterGuangzhouGuangdongChina

The high mortality rate in hepatocellular carcinoma(HCC)is partially due to the fact that a significant number of patients are diagnosed at an intermediate or advanced stage,with surgical treatment options *** therapy,which involves both locoregional and systemic treatments,has the potential to downstage tumors in selected patients with initially unresectable HCC,thereby making surgical treatment a possibility and potentially increasing long-term *** optimize the conversion rate,it is necessary to maximize successful conversions and clearly define the target population for conversion treatment through a collaborative *** this review article,we summarize the clinical experience and evidence for conversion therapy in patients with‘potentially resectable’HCC from four perspectives:1)defining the target population for conversion therapy,2)selecting the appropriate conversion strategy,placing emphasis on the utilization of combination therapy that exhibits a significant objective response rate,3)determining the timing and urgency of surgical resection,4)promoting the adoption of a multidisciplinary team *** authors are optimistic that with the continuous progress in treatment and a deeper understanding of HCC,the success rate of HCC conversion therapy will increase,and the overall survival of HCC patients will be prolonged.

关键词： Hepatocellular carcinoma Conversion therapy Conversion rate Targeted population Combination therapy