Cellular Oncology最新文献

{"title":"Marine derived macrolide bryostatin 4 inhibits the TGF-β signaling pathway against acute erythroleukemia.","authors":"Yan-Yu Kou, Jie Liu, Yung-Ting Chang, Li-Yun Liu, Fan Sun, Yi-Lin Li, Jia-Rong Leng, Hou-Wen Lin, Fan Yang","doi":"10.1007/s13402-024-00968-0","DOIUrl":"10.1007/s13402-024-00968-0","url":null,"abstract":"<p><strong>Purpose: </strong>Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) with an extremely poor prognosis when treated with available drugs. Therefore, new investigational agents capable of inducing remission are urgently required.</p><p><strong>Methods: </strong>Bioinformatics analysis, western blot and qRT-PCR were used to reveal the potential biological mechanism of bryostatin 4 (B4), an antineoplastic macrolide derived from the marine bryozoan Bugula neritina. Then, in vivo experiments were conducted to evaluate the role of transforming growth factor (TGF)-β signaling in the progression of AEL.</p><p><strong>Results: </strong>Our results revealed that the proliferation of K562 cells and TF-1 cells was significantly inhibited by B4 at IC₅₀ values of 37 nM and 52 nM, respectively. B4 inhibited TGF-β signaling and its downstream pathway targets, particularly the phosphorylation of Smad2, Smad3, Ras, C-RAF, ERK1/2, and MEK. B4 also played an important role in cell invasion and migration in K562 cells and TF-1 cells by reducing the protein levels of the mesenchymal cell marker vimentin. Moreover, Flow cytometry and western blot analyses demonstrated that B4 induced apoptosis and initiated G0/G1 phase arrest by modulating mitochondrial dysfunction and cyclin-dependent kinase (CDK) expression.</p><p><strong>Conclusion: </strong>These findings indicated that B4 could inhibit the proliferation, migration, invasion, and TGF-β signaling pathways of AEL cells, thus suggesting that B4 possesses therapeutic potential as a treatment for AEL.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1863-1878"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HVEM in acute lymphocytic leukemia facilitates tumour immune escape by inhibiting CD8⁺ T cell function.","authors":"Yujia Liu, Lixiang Wang, Yiyi Li, Cheng Zhong, Xiumei Wang, Xinyu Wang, Zijin Xia, Jing Liao, Chunliu Huang, Chengzhou Mao, Yongyi Feng, Congzhou Luo, Wenhao Mai, Hongrui Song, Hongyu Li, Lin Bao, Danchun Chen, Yue Sheng, Hui Zhang, Xiaolei Wei, Jun Chen, Wei Yi","doi":"10.1007/s13402-024-00959-1","DOIUrl":"10.1007/s13402-024-00959-1","url":null,"abstract":"<p><strong>Purpose: </strong>Leukaemia remains a major contributor to global mortality, representing a significant health risk for a substantial number of cancer patients. Despite notable advancements in the field, existing treatments frequently exhibit limited efficacy or recurrence. Here, we explored the potential of abolishing HVEM (herpes virus entry mediator, TNFRSF14) expression in tumours as an effective approach to treat acute lymphoblastic leukaemia (ALL) and prevent its recurrence.</p><p><strong>Methods: </strong>The clinical correlations between HVEM and leukaemia were revealed by public data analysis. HVEM knockout (KO) murine T cell lymphoblastic leukaemia cell line EL4 were generated using CRISPR-Cas9 technology, and syngeneic subcutaneous tumour models were established to investigate the in vivo function of HVEM. Immunohistochemistry (IHC), RNA-seq and flow cytometry were used to analyse the tumour immune microenvironment (TIME) and tumour draining lymph nodes (dLNs). Immune functions were investigated by depletion of immune subsets in vivo and T cell functional assays in vitro. The HVEM mutant EL4 cell lines were constructed to investigate the functional domain responsible for immune escape.</p><p><strong>Results: </strong>According to public databases, HVEM is highly expressed in patients with ALL and acute myeloid leukemia (AML) and is negatively correlated with patient prognosis. Genetic deletion of HVEM in EL4 cells markedly inhibited tumour progression and prolonged the survival of tumour-bearing mice. Our experiments proved that HVEM exerted its immunosuppressive effect by inhibiting antitumour function of CD8⁺ T cell through CRD1 domain both in vivo and in vitro. Additionally, we identified a combination therapy capable of completely eradicating ALL tumours, which induces immune memory toward tumour protection.</p><p><strong>Conclusions: </strong>Our study reveals the potential mechanisms by which HVEM facilitates ALL progression, and highlights HVEM as a promising target for clinical applications in relapsed ALL therapy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1779-1796"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of β-catenin signaling.","authors":"Mei-Na Cai, Dong-Mei Chen, Xin-Ru Chen, Yu-Rong Gu, Chun-Hong Liao, Le-Xin Xiao, Jia-Liang Wang, Bing-Liang Lin, Yue-Hua Huang, Yi-Fan Lian","doi":"10.1007/s13402-024-00972-4","DOIUrl":"10.1007/s13402-024-00972-4","url":null,"abstract":"<p><strong>Background: </strong>Liver cancer stem cells (CSCs) contribute to tumor initiation, progression, and recurrence in hepatocellular carcinoma (HCC). The Wnt/β-catenin pathway plays a crucial role in liver cancer stemness, progression, metastasis, and drug resistance, but no clinically approved drugs have targeted this pathway efficiently so far. We aimed to elucidate the role of COLEC10 in HCC stemness.</p><p><strong>Methods: </strong>The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases were employed to search for the association between COLEC10 expression and HCC stemness. Colony formation, sphere formation, side population, and limiting dilution tumor initiation assays were used to identify the regulatory role of COLEC10 overexpression in the stemness of HCC cell lines. Wnt/β-catenin reporter assay and immunoprecipitation were performed to explore the underlying mechanism.</p><p><strong>Results: </strong>COLEC10 level was negatively correlated with HCC stemness. Elevated COLEC10 led to decreased expressions of EpCAM and AFP (alpha-fetoprotein), two common markers of liver CSCs. Overexpression of COLEC10 inhibited HCC cells from forming colonies and spheres, and reduced the side population numbers in vitro, as well as the tumorigenic capacity in vivo. Mechanically, we demonstrated that overexpression of COLEC10 suppressed the activity of Wnt/β-catenin signaling by upregulating Wnt inhibitory factor WIF1 and reducing the level of cytoplasmic β-catenin. COLEC10 overexpression promoted the interaction of β-catenin with the component of destruction complex CK1α. In addition, KLHL22 (Kelch Like Family Member 22), a reported E3 ligase adaptor predicted to interact with CK1α, could facilitate COLEC10 monoubiquitination and degradation.</p><p><strong>Conclusion: </strong>COLEC10 inhibits HCC stemness by downregulating the Wnt/β-catenin pathway, which is a promising target for liver CSC therapy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1897-1910"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupting YAP1-mediated glutamine metabolism induces synthetic lethality alongside ODC1 inhibition in osteosarcoma.","authors":"Hongsheng Wang, Yining Tao, Jing Han, Jiakang Shen, Haoran Mu, Zhuoying Wang, Jinzeng Wang, Xinmeng Jin, Qi Zhang, Yuqin Yang, Jun Lin, Mengxiong Sun, Xiaojun Ma, Ling Ren, Amy K LeBlanc, Jing Xu, Yingqi Hua, Wei Sun","doi":"10.1007/s13402-024-00967-1","DOIUrl":"10.1007/s13402-024-00967-1","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;Osteosarcoma, a highly malignant primary bone tumor primarily affecting adolescents, frequently develops resistance to initial chemotherapy, leading to metastasis and limited treatment options. Our study aims to uncover novel therapeutic targets for metastatic and recurrent osteosarcoma.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this study, we proved the potential of modulating the YAP1-regulated glutamine metabolic pathway to augment the response of OS to DFMO. We initially employed single-cell transcriptomic data to gauge the activation level of polyamine metabolism in MTAP-deleted OS patients. This was further substantiated by transcriptome sequencing data from recurrent and non-recurrent patient tissues, confirming the activation of polyamine metabolism in progressive OS. Through high-throughput drug screening, we pinpointed CIL56, a YAP1 inhibitor, as a promising candidate for a combined therapeutic strategy with DFMO. In vivo, we utilized PDX and CDX models to validate the therapeutic efficacy of this drug combination. In vitro, we conducted western blot analysis, qPCR analysis, immunofluorescence staining, and PuMA experiments to monitor alterations in molecular expression, distribution, and tumor metastasis capability. We employed CCK-8 and colony formation assays to assess the proliferative capacity of cells in the experimental group. We used flow cytometry and reactive oxygen probes to observe changes in ROS and glutamine metabolism within the cells. Finally, we applied RNA-seq in tandem with metabolomics to identify metabolic alterations in OS cells treated with a DFMO and CIL56 combination. This enabled us to intervene and validate the role of the YAP1-mediated glutamine metabolic pathway in DFMO resistance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Through single-cell RNA-seq data analysis, we pinpointed a subset of late-stage OS cells with significantly upregulated polyamine metabolism. This upregulation was further substantiated by transcriptomic profiling of recurrent and non-recurrent OS tissues. High-throughput drug screening revealed a promising combination strategy involving DFMO and CIL56. DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839. This underscores the significant potential of targeting the YAP1-mediated glutamine metabolic pathway to enhance efficacy of DFMO.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an \"One-two Punch\" therapy of metastatic and recurrent oste","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1845-1861"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tertiary lymphoid structures and their therapeutic implications in cancer.","authors":"Xun Chen, Pan Wu, Ziqi Liu, Tiansheng Li, Jie Wu, Zhaoyang Zeng, Wenjia Guo, Wei Xiong","doi":"10.1007/s13402-024-00975-1","DOIUrl":"10.1007/s13402-024-00975-1","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates formed by the structured accumulation of immune cells such as B cells and T cells in non-lymphoid tissues induced by infection, inflammation, and tumors. They play a crucial role in the immune response, particularly in association with tumor development, where they primarily exert anti-tumor immune functions during tumorigenesis. Current research suggests that TLSs inhibit tumor growth by facilitating immune cell infiltration and are correlated with favorable prognosis in various solid tumors, serving as an indicator of immunotherapy effectiveness to some extent. Therefore, TLSs hold great promise as a valuable biomarker. Most importantly, immunotherapies aimed to prompting TLSs formation are anticipated to be potent adjuncts to current cancer treatment. This review focuses on the formation process of TLSs and their potential applications in cancer therapy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1579-1592"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM28 promotes tumor growth and metastasis in breast cancer by targeting the BRD7 protein for ubiquitination and degradation.","authors":"Changning Xue, Hanbing Meng, Weihong Niu, Mengna Li, Jianxia Wei, Shipeng Chen, Lemei Zheng, Yumei Duan, Hongyu Deng, Faqing Tang, Songqing Fan, Ming Tan, Wei Xiong, Ming Zhou","doi":"10.1007/s13402-024-00981-3","DOIUrl":"10.1007/s13402-024-00981-3","url":null,"abstract":"<p><strong>Purpose: </strong>Bromodomain-containing protein 7 (BRD7) is downregulated and functions as a tumor suppressor in many types of cancers including breast cancer, and the dysregulation of BRD7 expression is closely related to the development and progression of breast cancer. Whereas little attention has been focused on the regulation of BRD7 protein levels in breast cancer, which needs to be further elucidated.</p><p><strong>Methods: </strong>The protein stability of BRD7 in breast cancer cells and BRD7 protein level in breast cancer tissues was examined by Western Blotting. The potential E3 ubiquitin ligase proteins that interact with the BRD7 was screened by coimmunoprecipitation combined with mass spectrometry analysis in MDA-MB-231 cells. We proved the interaction between BRD7 and tripartite motif containing 28 (TRIM28) through Co-Immunoprecipitation (Co-IP) and immunofluorescence assays. Co-IP and ubiquitination assay were used to explore the specific binding domain between BRD7 and TRIM28 and the ubiquitination site of BRD7. The effects of TRIM28 on the BRD7 protein stability and ubiquitination level was investigated by qPCR, Western Blot and Co-IP assay. CCK-8 and clone formation assays were carried out to assess the effect of TRIM28 on proliferation ability of breast cancer ells. Transwell assay and wound healing assay were used to investigate the effect of TRIM28 on breast cancer cell invasion and migration. Flow cytometry was used to detect the effect of TRIM28 on cell cycle and apoptosis of breast cancer cells. In addition, we confirmed effect of TRIM28 on tumor growth and metastasis by xenograft and metastatic mouse models. We designed some recovery assays to explore the role of recovery BRD7 in TRIM28-mediated promotion of malignant progression of breast cancer in vivo and in vitro. Finally, the clinical significance of TRIM28 and BRD7 was proved by immunohistochemistry.</p><p><strong>Results: </strong>In this study, we demonstrated that BRD7 was an unstable protein and might be regulated by ubiquitination in breast cancer; furthermore, we found that the Coiled-Coil region of TRIM28 could directly bind to N-terminal of BRD7, and TRIM28 mediates BRD7 ubiquitination and degradation dependent on K21 by acting as a potential E3 ubiquitin ligase. Moreover, TRIM28 promoted cell proliferation, migration, invasion, xenograft tumor growth and metastasis, thus playing an oncogenic role in breast cancer. Furthermore, the restoration of BRD7 expression in breast cancer significantly reversed the promotional effects of TRIM28 on malignant progression both in vitro and in vivo. In addition, TRIM28 was highly expressed in the biopsy tissues of breast cancer, and its expression was negatively correlated with BRD7 expression and positively correlated with TNM stage and poor prognosis of BC patients.</p><p><strong>Conclusions: </strong>Our findings provide a novel mechanism by which TRIM28 significantly facilitates BRD7 ubiquitination and deg","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1973-1993"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PSMD2 overexpression as a biomarker for resistance and prognosis in renal cell carcinoma treated with immune checkpoint and tyrosine kinase inhibitors.","authors":"Xianglai Xu, Jiahao Wang, Ying Wang, Yanjun Zhu, Jiajun Wang, Jianming Guo","doi":"10.1007/s13402-024-00977-z","DOIUrl":"10.1007/s13402-024-00977-z","url":null,"abstract":"<p><strong>Background: </strong>Integrated immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) are now the recommended first-line therapy to manage renal cell carcinoma (mRCC). Proteasome 26S subunit non-ATPase 2 (PSMD2) overexpression in tumors has been correlated with tumor progression. Currently, mRCC lacks an established biomarker for the combination of ICI+TKI.</p><p><strong>Methods: </strong>This study involved RNA sequencing of RCC patients from two cohorts treated with ICI+TKI (ZS-MRCC and JAVELIN-Renal-101). We utilized immunohistochemistry alongside flow cytometry, aiming at assessing immune cell infiltration and functionality in high-risk localized RCC samples. Response and progression-free survival (PFS) were evaluated relying upon RECIST criteria.</p><p><strong>Results: </strong>PSMD2 was significantly overexpressed in advanced RCC and among non-responders to ICI+TKI therapy. Overexpressed PSMD2 was correlated with poor PFS in the ZS-MRCC and JAVELIN-101 cohorts. Multivariate Cox analysis validated PSMD2 as an independent PFS predictor. PSMD2 overexpression was related to a reduction in CD8⁺ T cells, especially GZMB⁺ CD8⁺ T cells, besides an increase in PD1⁺ CD4⁺ T cells. Additionally, tumors with high PSMD2 levels showed enhanced T cell exhaustion levels and a higher regulatory T cell presence. A Machine Learning (ML) model based on PSMD2 expression and other screened factors was subsequently developed to predict the effectiveness of ICI+TKI.</p><p><strong>Conclusions: </strong>Elevated PSMD2 expression is linked to resistance and decreased PFS in mRCC patients undergoing ICI+TKI therapy. High PSMD2 levels are also associated with impaired function and increased exhaustion of tumor-infiltrating lymphocytes. An ML model incorporating PSMD2 expression could potentially identify patients who may have a higher likelihood of benefiting from ICI+TKI.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1943-1956"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted gene delivery systems for T-cell engineering.","authors":"Fengling Wang, Yong Huang, JiaQian Li, Weilin Zhou, Wei Wang","doi":"10.1007/s13402-024-00954-6","DOIUrl":"10.1007/s13402-024-00954-6","url":null,"abstract":"<p><p>T lymphocytes are indispensable for the host systems of defense against pathogens, tumors, and environmental threats. The therapeutic potential of harnessing the cytotoxic properties of T lymphocytes for antigen-specific cell elimination is both evident and efficacious. Genetically engineered T-cells, such as those employed in CAR-T and TCR-T cell therapies, have demonstrated significant clinical benefits in treating cancer and autoimmune disorders. However, the current landscape of T-cell genetic engineering is dominated by strategies that necessitate in vitro T-cell isolation and modification, which introduce complexity and prolong the development timeline of T-cell based immunotherapies. This review explores the complexities of gene delivery systems designed for T cells, covering both viral and nonviral vectors. Viral vectors are known for their high transduction efficiency, yet they face significant limitations, such as potential immunogenicity and the complexities involved in large-scale production. Nonviral vectors, conversely, offer a safer profile and the potential for scalable manufacturing, yet they often struggle with lower transduction efficiency. The pursuit of gene delivery systems that can achieve targeted gene transfer to T cell without the need for isolation represents a significant advancement in the field. This review assesses the design principles and current research progress of such systems, highlighting the potential for in vivo gene modification therapies that could revolutionize T-cell based treatments. By providing a comprehensive analysis of these systems, we aim to contribute valuable insights into the future development of T-cell immunotherapy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1537-1560"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma.","authors":"Xiangke Xin, Xiaojian Zhu, Yang Yang, Na Wang, Jue Wang, Jinhuan Xu, Jia Wei, Liang Huang, Miao Zheng, Yi Xiao, Chunrui Li, Yang Cao, Fankai Meng, Lijun Jiang, Yicheng Zhang","doi":"10.1007/s13402-024-00940-y","DOIUrl":"10.1007/s13402-024-00940-y","url":null,"abstract":"<p><strong>Introduction: </strong>Chimeric antigen receptor (CAR)-T cells obtained long-term durability in about 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Maintenance therapy after CAR-T is necessary, and PD1 inhibitor is one of the important maintenance therapy options.</p><p><strong>Methods: </strong>A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with autologous hematopoietic stem cell transplantation (ASCT) from March 2019 to July 2022 were assessed for eligibility for two trials. There were 81 patients on PD1 inhibitor maintenance therapy.</p><p><strong>Results: </strong>In the CD19/22 CAR-T therapy trial, the PD1 inhibitor maintenance group indicated superior objective response rate (ORR) (82.9% vs 60%; P = 0.04) and 2-year progression-free survival (PFS) (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. The estimated 2-year overall survival (OS) was comparable in the two groups (60.1% vs 45.1%; P = 0.112). No difference was observed in the peak expansion levels of CD19 CAR-T and CD22 CAR-T between the two groups. The persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. In the CD19/22 CAR-T therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups. The peak expansion levels and duration of CD19 and CD22 CAR-T were not statistically different between the two groups. During maintenance treatment with PD1 inhibitor, all adverse events were manageable. In the multivariable analyses, type and R3m were independent predictive factors influencing the OS of r/r B-NHL with PD1 inhibitor maintenance after CAR-T therapy.</p><p><strong>Conclusion: </strong>PD1 inhibitor maintenance following CD19/22 CAR-T therapy obtained superior response and survival in r/r B-NHL, but not in the trial of CD19/22 CAR-T cell therapy combined with ASCT.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1425-1440"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140337440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma.","authors":"Tingyu Liu, Xin Yue, Xue Chen, Ru Yan, Chong Wu, Yunzhi Li, Xianzhang Bu, Hui Han, Ran-Yi Liu","doi":"10.1007/s13402-024-00927-9","DOIUrl":"10.1007/s13402-024-00927-9","url":null,"abstract":"<p><strong>Purpose: </strong>Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application.</p><p><strong>Methods: </strong>We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc. RESULTS: From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect.</p><p><strong>Conclusion: </strong>Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1277-1294"},"PeriodicalIF":4.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139933708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}