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Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study

Research 2024年第3期2023卷 473-485页

作者： Wei Huang Yizhen Pang Qiufang Liu Chenyi Liang Shuxian An Qianyun Wu You Zhang Gang Huang Haojun Chen Jianjun Liu Weijun Wei Department of Nuclear Medicine Institute of Clinical Nuclear MedicineRenj HospitalSchool of Medicine Shanghai Jiao Tong UniversityShanghai 200127China Department of Nuclear Medicine and Minnan PET center Xiamen Cancer CenterXiamen Key Laboratory of Radiation OncologyThe First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen 361003China Department of Nuclear Medicine Fudan University Shanghai Cancer CenterFudan UniversityShanghai 200032China

Fibroblast activation protein (FAP) is among the most popular targets in nuclear medicine imaging and cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3 peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with 68Ga and 177Lu was assessed in several tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased tumor uptake, and decreased kidney accumulation. Our findings indicated that [68Ga]Ga-DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models, including pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [68Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction. In summary, we developed [68Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.

关键词： DOTA expressing labeled

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Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin

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Science China(Life Sciences) 2024年第6期67卷 1226-1241页

作者： Zhengyang Guo Jiaqi Huang Xiao Huo Chen Huang Xiaotong Yu Yan Sun Yanfang Li Tianhui He Hongyan Guo Jianling Yang Lixiang Xue Cancer center of Peking University Third Hospital Beijing 100191China center of Basic Medical Research Institute of Medical Innovation and ResearchPeking University Third HospitalBeijing 100191China Peking University Third Hospital Cancer center Department of Radiation OncologyPeking University Third HospitalBeijing 100191China Department of Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed *** ovarian cancer,multiple metabolic enzymes of lipid metabolism are abnormally expressed,resulting in metabolism *** a characteristic pathway in polyunsaturated fatty acid(PUFA)metabolism,arachidonic acid(AA)metabolism is disturbed in ovarian ***,we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related *** 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms(TCGA,ICGC,and GSE17260).The high association between the risk subgroups and clinical characteristics indicated a good performance of the *** data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian *** of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian ***,our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis,which contributes to the reduction of tumor-infiltrating CD8+T cells and immune escape in ovarian *** findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.

关键词： ovarian cancer polyunsaturated fatty acids prognostic risk model LTA4H tumor immunity CCL5

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Clinical practice guidelines for full-cycle standardized management of bone health in breast cancer patients

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Cancer Innovation 2024年第1期3卷 1-28页

作者： Committee of Full-cycle Standardized Management of Bone Health in breast Cancer Patients Fei Ma 不详 Department of Medical oncology National Cancer CenterNational Clinical Research Center for CancerCancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Bone health management for breast cancer spans the entire cycle of patient care,including the prevention and treatment of bone loss caused by early breast cancer treatment,the adjuvant application of bone-modifying agents to improve prognosis,and the diagnosis and treatment of advanced bone *** good bone health management means formulating appropriate treatment strategies and dealing with adverse drug reactions,and will help to improve patients'quality of life and survival *** breast Cancer Expert Committee of the National Cancer center for Quality Control organized relevant experts to conduct an in-depth discussion on the full-cycle management of breast cancer bone health based on evidence-based medicine,and put forward reasonable suggestions to guide clinicians to better deal with health issues in bone health clinics.

关键词： bone health bone-modifying drugs breast cancer guidelines

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CircMYBL2 facilitates hepatocellular carcinoma progression by regulating E2F1 expression

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oncology Research 2024年第6期32卷 1129-1139页

作者： JUNZHE YI BINBIN LI XIAOMIN YIN LINGRUI LIU CAILU SONG YING ZHAO MANBO CAI HAILIN TANG DONG CHEN NING LYU State Key Laboratory of oncology in South China Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou510060China Department of Medical oncology The Third People’s Hospital of YongzhouYongzhou425000China Department of Radiotherapy The First Affiliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyang421001China center of Hepato-Pancreato-Biliary Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhou510080China

Circular RNAs(circRNAs)have been recognized as pivotal regulators in tumorigenesis,yet the biological functions as well as molecular mechanisms of the majority of circRNAs in hepatocellular carcinoma(HCC)remain *** sought to unveil the expression profile and biological role of circMYBL2 in *** microarray analyses were conducted to probe the expression profile of circMYBL2 in HCC cells,and qRT‒PCR analysis was then performed in HCC cell lines and tissues,revealing significant upregulation of *** experiments were conducted to evaluate the biological function of circMYBL2 in HCC ***,bioinformatics analysis,qRT‒PCR analysis,luciferase reporter assays,and western blot analysis were employed to investigate the interplay among circMYBL2,miR-1205,and ***2 was found to exhibit marked upregulation in tumor tissues as well as HCC cell *** expression of circMYBL2 increased the proliferation and migration of HCC cells,whereas circMYBL2 knockdown elicited contrasting ***,our results indicated that circMYBL2 promoted E2F1 expression and facilitated HCC progression by sponging *** findings revealed that circMYBL2 contributed to HCC progression through the circMYBL2/miR-1205/E2F1 axis,suggesting the potential of circMYBL2 as a novel target for HCC treatment or a prognostic biomarker for HCC.

关键词： Circular RNAs circMYBL2 miR-1205 E2F1 Hepatocellular carcinoma

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Clinical benefit and safety profile of cross-line therapy with CDK4/6 inhibitors: a retrospective study of HR+/HER2–advanced breast cancer

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Cancer Biology & Medicine 2024年第10期 934-950页

作者： Qi Zhao Mingxia Jiang Jiaxuan Liu Mengqi Zhang Maiyue He Shihan Zhou Jiani Wang Hongnan Mo Bo Lan Peng Yuan Pin Zhang Fei Ma Qiao Li Binghe Xu Department of Medical oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College

Objective: CDK4/6 inhibitors(CDK4/6is) in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC) and have transformed the therapeutic landscape. Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects. Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)± ***: This retrospective study enrolled 82 patients with HR+/HER2± ABC who were treated with cross-line CDK4/6is(abemaciclib, palbociclib, ribociclib, and dalpiciclib) after progression with another CDK4/6i. The primary endpoint was progressionfree survival(PFS) according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included toxicity, objective response rate, disease control rate, and overall survival. Adverse events(AEs) were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events, as promulgated by the U.S. Department of Health and Human ***: Eighty-two HR+/HER2± ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled. The median age of the patients was 60 years. The median PFS of all patients was 7.6 months(95% CI, 5.9-9.2). Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS. Notably, patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months. The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i, then to a subsequent CDK4/6i merits further investigation. Hematologic toxicity was the most common grade ≥ 3 AEs. No instances of fatal safety events were ***: Cro

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Integrative analyses identified gap junction beta‐2 as a prognostic biomarker and therapeutic target for breast cancer

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Cancer Innovation 2024年第4期3卷 43-56页

作者： Di Zhang Lixi Li Fei Ma Department of Medical oncology Qilu Hospital of Shandong UniversityJinanChina Department of Medical oncology Qilu HospitalCheeloo College of MedicineShandong UniversityJinanChina Department of Medical oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Background:Increasing evidence has shown that connexins are involved in the regulation of tumor development,immune escape,and drug *** study investigated the gene expression patterns,prognostic values,and potential mechanisms of connexins in breast ***:We conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our *** mRNA expressions in breast cancer and matched normal tissues were compared,and multiomics studies were ***:Gap junction beta‐2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes,and its high expression was associated with poor *** tumor membrane of the gap junction beta‐2 mutated group was positive,and the corresponding protein was *** mutation and copy number variation of gap junction beta‐2 are rare in breast *** gap junction beta‐2 transcription level in the p110αsubunit of the phosphoinositide 3‐kinase mutant subgroup was higher than that in the wild‐type *** junction beta‐2 was associated with the phosphoinositide 3‐kinase‐Akt signaling pathway,extracellular matrix–receptor interaction,focal adhesion,and proteoglycans in ***,gap junction beta‐2 overexpression may be associated with phosphoinositide 3‐kinase and histone deacetylase inhibitor resistance,and its expression level correlated with infiltrating CD8+T cells,macrophages,neutrophils,and dendritic ***:Gap junction beta‐2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.

关键词： breast cancer connexin gap junction beta‐2 phosphoinositide 3‐kinase‐Akt‐mTOR pathway prognosis

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Gastric cancer secreted miR 214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells

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oncology Research 2024年第3期32卷 489-502页

作者： WEIXUE WANG TONGTONG WANG YAN ZHANG TING DENG HAIYANG ZHANG YI BA Department of GI Medical oncology Tanjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerTianjin Key Iaboratory of Digestive CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China

Diferent from necrosis,apoptosis,autophagy and other forms of cell death,ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated ftty acids under the action of iron divalent or lipoxygenase,leading to cell *** is currently used in the third line standard treatment of advanced gastric cancer,targeting the anti-angiogenesis ***,Apatinib mediated ferroptosis in vascular endothelial cells has not been reported *** exosomes can be taken up into target cells to regulate tumor development,but the mechanism related to vascular endothelial cell ferroptosis has not yet been ***,we show that exosomes secreted by gastric cancer cells carry miR-214.3p into vascular endothelial cells and directdy target zinc finger protein A20 to negatively regulate ACSL4,a key enzyme of lipid peroxidation during frroptosis thereby inhibiting ferroptosis in vascular endothelial cells and reducing the eficiency of *** conclusion,inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib,thereby promoting the antiangiogenic efect of Apatinib,suggesting a potential combination therapy for advanced gastric cancer.

关键词： Cellular ferroptosis Exosome Tyrosine kinase inhibitor Gastrointestinal tumors miRNA

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ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis

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Cancer Biology & Medicine 2024年第7期21卷 606-635页

作者： Shirong Tan Xiangyu Sun Haoran Dong Mozhi Wang Litong Yao Mengshen Wang Ling Xu Yingying Xu Department of breast Surgery The First Affliated Hospital of China Medical UniversityShenyang 110000China Department of Thyroid and breast Surgery Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221000China Department of Medical oncology The First Hospital of China Medical UniversityShenyang 110000China

Objective:Mitochondrial fatty acid oxidation is a metabolic pathway whose dysregulation is recognized as a critical factor in various cancers,because it sustains cancer cell survival,proliferation,and *** acyl-Co A synthetase long-chain(ACSL)family is known to activate long-chain fatty acids,yet the specific role of ACSL3 in breast cancer has not been ***:We assessed the prognostic value of ACSL3 in breast cancer by using data from tumor ***-of-function and lossof-function assays were also conducted to determine the roles and downstream regulatory mechanisms of ACSL3 in vitro and in ***:ACSL3 expression was notably downregulated in breast cancer tissues compared with normal tissues,and this phenotype correlated with improved survival *** experiments revealed that ACSL3 knockdown in breast cancer cells promoted cell proliferation,migration,and epithelial±mesenchymal ***,ACSL3 was found to inhibitβ-oxidation and the formation of associated byproducts,thereby suppressing malignant behavior in breast ***,ACSL3 was found to interact with YES proto-oncogene 1,a member of the Src family of tyrosine kinases,and to suppress its activation through phosphorylation at *** decrease in activated YES1 consequently inhibited YAP1 nuclear colocalization and transcriptional complex formation,and the expression of its downstream genes in breast cancer cell ***:ACSL3 suppresses breast cancer progression by impeding lipid metabolism reprogramming,and inhibiting malignant behaviors through phospho-YES1 mediated inhibition of YAP1 and its downstream *** findings suggest that ACSL3 may serve as a potential biomarker and target for comprehensive therapeutic strategies for breast cancer.

关键词： breast cancer lipid metabolism ACSL3 YAP metastasis

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The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype,promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

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Cellular & Molecular Immunology 2024年第1期21卷 60-79页

作者： Fan Luo Han Li Wenjuan Ma Jiaxin Cao Qun Chen Feiteng Lu Miaozhen Qiu Penghui Zhou Zengfei Xia Kangmei Zeng Jianhua Zhan Ting Zhou Qiuyun Luo Wentao Pan Lin Zhang Chaozhuo Lin Yan Huang Li Zhang Dajun Yang Hongyun Zhao State Key Laboratory of oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhouChina Ascentage Pharma(Suzhou)Co Ltd 218 Xinghu StreetSuzhouJiangsu ProvinceChina

The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T *** the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer *** found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse *** single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy ***,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine *** a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell *** immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on ***,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

关键词： BCL-2 APG-2575 ICIs Macrophages NLRP3

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Single-cell transcriptomic Atlas of aging macaque ocular outflow tissues

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Protein & Cell 2024年第8期15卷 594-611页

作者： Jian Wu Chaoye Wang Shuhui Sun Tianmin Ren Lijie Pan Hongyi Liu Simeng Hou Shen Wu Xuejing Yan Jingxue Zhang Xiaofang Zhao Weihai Liu Sirui Zhu Shuwen Wei Chi Zhang Xu Jia Qi Zhang Ziyu Yu Yehong Zhuo Qi Zhao Chenlong Yang Ningli Wang Beijing Institute of Ophthalmology Beijing Tongren Eye CenterBeijing Tongren HospitalCapital Medical UniversityBeijing Key Laboratory of Ophthalmology and Visual SciencesBeijing 100730China State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510060China State Key Laboratory of oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Department of Neurosurgery Peking University Third HospitalCenter for Precision Neurosurgery and Oncology of Peking University Health Science CenterBeijing 100191China Spencer center for Vision Research Byers Eye InstituteSchool of MedicineStanford UniversityPalo AltoCA 94304USA

The progressive degradation in the trabecular meshwork(TM)is related to age-related ocular diseases like primary open-angle ***,the molecular basis and biological significance of the aging process in TM have not been fully ***,we established a dynamic single-cell transcriptomic landscape of aged macaque TM,wherein we classified the outflow tissue into 12 cell subtypes and identified mitochondrial dysfunction as a prominent feature of TM ***,we divided TM cells into 13 clusters and performed an in-depth analysis on cluster O,which had the highest aging score and the most significant changes in cell proportions between the two ***,we found that the APOE gene was an important differentially expressed gene in cluster O during the aging process,highlighting the close relationship between cell migration and extracellular matrix regulation,and TM *** work further demonstrated that silencing the APOE gene could increase migration and reduce apoptosis by releasing the inhibition on the PI3K-AKT pathway and downregulating the expression of extracellular matrix components,thereby increasing the aqueous outflow rate and maintaining intraocular pressure within the normal *** work provides valuable insights for future clinical diagnosis and treatment of glaucoma.

关键词： single-cell transcriptomic atlas macaque trabecular meshwork ocular outflow tissue aging

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