Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-24DOI: 10.1016/j.xcrm.2025.102199
Ziwei Zhou, Si Chen, Jianli Zhao, Xin Du, Haibin Yin, Chao Zhou, Hai Hu, Yunfang Yu, Yinghua Zhu, Herui Yao
{"title":"EGFR TKIs suppress MUC1 glycosylation through the PI3K/AKT/SP1/C1GALT1 pathway to enhance TnMUC1 CAR-T efficacy in EGFR-mutant NSCLC.","authors":"Ziwei Zhou, Si Chen, Jianli Zhao, Xin Du, Haibin Yin, Chao Zhou, Hai Hu, Yunfang Yu, Yinghua Zhu, Herui Yao","doi":"10.1016/j.xcrm.2025.102199","DOIUrl":"10.1016/j.xcrm.2025.102199","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for EGFR-mutant cancer (non-small cell lung cancer [NSCLC]), achieving an objective response rate (ORR) of approximately 60%-70%. However, optimizing their therapeutic efficacy remains a challenge. NSCLC cells express the tumor-specific hypoglycosylated Thomsen-nouvelle (Tn) mucin 1 (MUC1) antigen, making them suitable targets for TnMUC1 chimeric antigen receptor (CAR)-T cell therapy. This study shows that EGFR TKIs enhance the efficacy of TnMUC1 CAR-T cell therapy in EGFR-mutant NSCLC, both in vitro and in vivo. EGFR TKIs upregulate TnMUC1 by reducing MUC1 glycosylation, thereby improving TnMUC1 CAR-T cell recognition and cytotoxicity. Specifically, EGFR TKIs modulate TnMUC1-related glycosyltransferases, with core1-beta1,3-galactosyltransferase 1 (C1GALT1) identified as a key enzyme downregulated by EGFR TKIs, suggesting C1GALT1 as a potential therapeutic target.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102199"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-24DOI: 10.1016/j.xcrm.2025.102201
Nicolas Huyghe, Elena Benidovskaya, Tariq Masoodi, Isabelle Sinapi, Astrid De Cuyper, Fazulur Vempalli, Simon Beyaert, Caroline Bouzin, Finoula Maestre Osorio, Luigi Ferraro, Nicolas van Baren, Raphaël Helaers, Pierre Goffette, Benoit Ghaye, Aline van Maanen, Marie-Laure Castella, Michele Ceccarelli, Davide Bedognetti, Jérôme Galon, Wouter R L Hendrickx, Javier Carrasco, Marc Van den Eynde
{"title":"Impact of the tumor immune contexture in microsatellite-stable metastatic colorectal cancer treated with avelumab, cetuximab, and irinotecan.","authors":"Nicolas Huyghe, Elena Benidovskaya, Tariq Masoodi, Isabelle Sinapi, Astrid De Cuyper, Fazulur Vempalli, Simon Beyaert, Caroline Bouzin, Finoula Maestre Osorio, Luigi Ferraro, Nicolas van Baren, Raphaël Helaers, Pierre Goffette, Benoit Ghaye, Aline van Maanen, Marie-Laure Castella, Michele Ceccarelli, Davide Bedognetti, Jérôme Galon, Wouter R L Hendrickx, Javier Carrasco, Marc Van den Eynde","doi":"10.1016/j.xcrm.2025.102201","DOIUrl":"10.1016/j.xcrm.2025.102201","url":null,"abstract":"<p><p>The treatment of patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) remains a significant clinical challenge. Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), induces immunogenic cell death, potentially synergizing with immune checkpoint inhibitors. The phase 2, proof-of-concept, single-arm AVETUXIRI trial (ClinicalTrials.gov: NCT03608046) evaluates the safety and efficacy of cetuximab, irinotecan (a topoisomerase I inhibitor), and avelumab (an anti-programmed cell death ligand 1 [PD-L1]) in 57 patients with RAS wild-type or mutated MSS mCRC refractory to chemotherapy and anti-EGFR mAbs. Exploratory objectives include investigating the tumor immune microenvironment within mCRC biopsies performed during the trial and correlating it with treatment activity. A manageable safety profile is observed. Although the overall efficacy endpoints are not met, biomarkers associated with clinical efficacy are identified. Patients exhibiting a high Immunoscore, strong cytotoxic and T cell proximity to tumor cells, and a high genetic immunoediting score within mCRC biopsies before treatment demonstrate significant therapeutic survival benefit, independent of RAS tumor mutation status.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102201"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-07-08DOI: 10.1016/j.xcrm.2025.102234
Yongzhi Yang, Yangyang Guo, Yan Ding, Jinming Li, Lei Liang, Debing Shi, Xinxiang Li, Yanlei Ma
{"title":"Perioperative administration of CBM588 in colorectal cancer radical surgery: A single-center, randomized controlled trial.","authors":"Yongzhi Yang, Yangyang Guo, Yan Ding, Jinming Li, Lei Liang, Debing Shi, Xinxiang Li, Yanlei Ma","doi":"10.1016/j.xcrm.2025.102234","DOIUrl":"10.1016/j.xcrm.2025.102234","url":null,"abstract":"<p><p>Clostridium butyricum MIYAIRI 588 (CBM588) has been used to treat gastrointestinal disorders and recently found to enhance efficacy of checkpoint inhibitor in solid tumors. However, limited studies spotlight the role of CBM588 in perioperative management of colorectal cancer (CRC) radical surgery. Here, we report a phase 4, open-label, randomized controlled trial (ChiCTR2000033883) to assess the safety and short-term efficacy of CBM588 as a perioperative, adjunctive therapy. The primary efficacy indicator is postoperative intestinal function assessed by time to first flatus, recovery time of defecation, and first intake of delicate fluid and semi-fluid. Secondary outcomes are incidence of postoperative complications and immune status. We find that perioperative administration of CBM588 significantly benefits recovery of intestinal function, lowers risk of infectious complications, and enhances systemic immunity by increasing circulating T cells. CBM588 serves as a promising probiotic with favorable tolerability in CRC patients undergoing radical surgery.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102234"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-27DOI: 10.1016/j.xcrm.2025.102207
Jongjun Won, Grace Yoojin Lee, Sungyang Jo, Jihyun Lee, Sangjin Lee, Jae Seung Kim, Changhwan Sung, Jungsu S Oh, Kyum-Yil Kwon, Soo Bin Park, Joonsang Lee, Jieun Yum, Sun Ju Chung, Namkug Kim
{"title":"Enhancing 3D dopamine transporter imaging as a biomarker for Parkinson's disease via self-supervised learning with diffusion models.","authors":"Jongjun Won, Grace Yoojin Lee, Sungyang Jo, Jihyun Lee, Sangjin Lee, Jae Seung Kim, Changhwan Sung, Jungsu S Oh, Kyum-Yil Kwon, Soo Bin Park, Joonsang Lee, Jieun Yum, Sun Ju Chung, Namkug Kim","doi":"10.1016/j.xcrm.2025.102207","DOIUrl":"10.1016/j.xcrm.2025.102207","url":null,"abstract":"<p><p>Accurate diagnosis and precise estimation of disease progression states are crucial for developing effective treatment plans for patients with parkinsonism. Although various deep learning-based computer-aided diagnostic models have demonstrated benefits, they have been relatively underexplored in parkinsonism owing to limited data and lack of external validation. We introduce the hierarchical wavelet diffusion autoencoder (HWDAE), a generative self-supervised model trained with 1,934 dopamine transporter positron emission tomography (DAT PET) images. HWDAE learns relevant disease traits during generative training, prior to supervision with human labels, as evidenced by its ability to synthesize realistic images representing different disease states of Parkinson's disease. The pretrained HWDAE is subsequently adapted for two differential diagnostic tasks and one disease progression estimation task, tested on images from two medical centers. Our training approach introduces a paradigm for deep learning research utilizing PET and expands the potential of DAT PET as a biomarker for Parkinson's disease.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102207"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-06-30DOI: 10.1016/j.xcrm.2025.102206
Sang-Yeon Lee, Seungbok Lee, Seongyeol Park, Sung Ho Jung, Yejin Yun, Won Hoon Choi, Ju Hyuen Cha, Hongseok Yun, Sangmoon Lee, Myung-Whan Suh, Moo Kyun Park, Jae-Jin Song, Byung Yoon Choi, Jun Ho Lee, Tong Mook Kang, Young Seok Ju, June-Young Koh, Jong-Hee Chae
{"title":"Comprehensive genetic profiling of sensorineural hearing loss using an integrative diagnostic approach.","authors":"Sang-Yeon Lee, Seungbok Lee, Seongyeol Park, Sung Ho Jung, Yejin Yun, Won Hoon Choi, Ju Hyuen Cha, Hongseok Yun, Sangmoon Lee, Myung-Whan Suh, Moo Kyun Park, Jae-Jin Song, Byung Yoon Choi, Jun Ho Lee, Tong Mook Kang, Young Seok Ju, June-Young Koh, Jong-Hee Chae","doi":"10.1016/j.xcrm.2025.102206","DOIUrl":"10.1016/j.xcrm.2025.102206","url":null,"abstract":"<p><p>Despite the advent of next-generation sequencing, diagnosing genetic disorders remains challenging. We perform comprehensive genomic profiling of 394 families (752 individuals) with sensorineural hearing loss (SNHL) using a systematic multi-tiered approach, from single-gene analysis to whole-genome sequencing (WGS), complemented by functional assays and bioinformatic analysis. Our strategy achieves a cumulative diagnostic yield of 55.6% (219 families), with automated WGS analysis identifying pathogenic variants in an additional 20 families, primarily structural variants. Comparative analysis reveals higher frequencies of single pathogenic alleles in recessive genes within our cohort compared to controls. Subsequent analysis, including in silico predictions and in vitro validation, identifies three deep intronic pathogenic variants on opposite alleles. These findings demonstrate the value of comprehensive genomic analysis in resolving undiagnosed cases. Finally, we map the genome-phenome landscape of SNHL at the level of inner ear function. Our results highlight WGS as a transformative tool for precision medicine in genetic diseases.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102206"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-07-01DOI: 10.1016/j.xcrm.2025.102209
Zihan Zhang, Bin Ma, Buyao Li, Zhiwei Li, Min Gao, Hailong Zhao, Rui Peng, Jiang Hu, Yu Wang, Wei You, Xun Gui, Rui Wang, Xiaoqing Hu, Beidi Chen, Yuanjie Zhang, Yanyun Hao, Xiaolin Sun, Peishi Rao, Liang Zhang, Ming Lu, Demin Zhou, Yun Yang, Mi Deng, Lei Miao
{"title":"Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in vivo CAR-T therapy for inflamm-aging.","authors":"Zihan Zhang, Bin Ma, Buyao Li, Zhiwei Li, Min Gao, Hailong Zhao, Rui Peng, Jiang Hu, Yu Wang, Wei You, Xun Gui, Rui Wang, Xiaoqing Hu, Beidi Chen, Yuanjie Zhang, Yanyun Hao, Xiaolin Sun, Peishi Rao, Liang Zhang, Ming Lu, Demin Zhou, Yun Yang, Mi Deng, Lei Miao","doi":"10.1016/j.xcrm.2025.102209","DOIUrl":"10.1016/j.xcrm.2025.102209","url":null,"abstract":"<p><p>mRNA-based in vivo chimeric antigen receptor (CAR)-T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery methods require antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identify cardiolipin-like di-phosphoramide lipids that improve T cell transfection without targeting ligands, both in vitro and in vivo. The T cell-favored tropism is likely due to the lipid's packing, shape, and rigidity. Encapsulating circular RNA further prolongs mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we deliver mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single-cell sequencing in humans confirms uPAR's relevance to senescence and inflammation in RA. To facilitate clinical translation, we screen and humanize single-chain variable fragments (scFvs) against uPAR, establishing a PL40 mRNA-encoded humanized uPAR CAR with potential for treating aging-inflamed disorders.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102209"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Augment proteasome inhibitor efficacy activates CD8<sup>+</sup> T cell-mediated antitumor immunity in breast cancer.","authors":"Dongyang Tang, Shiqi Lin, Jingbo Zhou, Josh Haipeng Lei, Fangyuan Shao, Heng Sun, Xiangpeng Chu, Ling Li, Lin He, Yunfeng Qiao, Xiaoling Xu, Chu-Xia Deng","doi":"10.1016/j.xcrm.2025.102211","DOIUrl":"10.1016/j.xcrm.2025.102211","url":null,"abstract":"<p><p>Although three proteasome inhibitors are used for liquid tumor treatment, their effectiveness against solid tumors remains inadequate. To address this issue, we employ a drug combination strategy and discover that ammonium tetrathiomolybdate (TM) and AMD3100 can sensitize solid cancer cell lines to proteasome inhibitors. Mechanistically, we find that TM and AMD3100 reduce proteasome activity by decreasing the protein level of PSMB5. This reduction occurs through the activation of the AMP-activated protein kinase (AMPK) pathway, which inhibits STAT3 phosphorylation. Notably, our in vivo studies reveal that drug combinations retard tumor growth dependent on CD8<sup>+</sup> T cells. The combination of bortezomib with TM or AMD3100 induces cancer cell antigen presentation and the production of CCL5, which together stimulate the recruitment and generation of cytotoxic CD8<sup>+</sup> T cells. This study identifies synergistic lethal pairs that enhance the effectiveness of bortezomib-centered therapy for breast cancer treatment in a way relied on intact immune system.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102211"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-07-07DOI: 10.1016/j.xcrm.2025.102232
Sijing Li, Omar Motiño, Flavia Lambertucci, Jonathan Pol, Hui Chen, Long Pan, Sylvère Durand, Federica Rossin, Claudia Campani, Lucie Poupel, Christophe Klein, Léa Montégut, María Pérez-Lanzón, Gerasimos Anagnostopoulos, Uxia Nogueira-Recalde, Alexandra Cerone, Fanny Aprahamian, Yanbing Dong, Manuela Lizarralde-Guerrero, Enfu Xue, Peng Liu, Liwei Zhao, Hui Pan, Vincent Carbonnier, Sylvie Lachkar, Ester Gloria Saavedra Díaz, Li Sun, Chantal Desdouets, Sabine Colnot, Oliver Kepp, Isabelle Martins, Laurence Zitvogel, Mauro Piacentini, Jean-Charles Nault, Maria Chiara Maiuri, Jessica Zucman-Rossi, Guido Kroemer
{"title":"Neutralization of acyl coenzyme A binding protein for the experimental prevention and treatment of hepatocellular carcinoma.","authors":"Sijing Li, Omar Motiño, Flavia Lambertucci, Jonathan Pol, Hui Chen, Long Pan, Sylvère Durand, Federica Rossin, Claudia Campani, Lucie Poupel, Christophe Klein, Léa Montégut, María Pérez-Lanzón, Gerasimos Anagnostopoulos, Uxia Nogueira-Recalde, Alexandra Cerone, Fanny Aprahamian, Yanbing Dong, Manuela Lizarralde-Guerrero, Enfu Xue, Peng Liu, Liwei Zhao, Hui Pan, Vincent Carbonnier, Sylvie Lachkar, Ester Gloria Saavedra Díaz, Li Sun, Chantal Desdouets, Sabine Colnot, Oliver Kepp, Isabelle Martins, Laurence Zitvogel, Mauro Piacentini, Jean-Charles Nault, Maria Chiara Maiuri, Jessica Zucman-Rossi, Guido Kroemer","doi":"10.1016/j.xcrm.2025.102232","DOIUrl":"10.1016/j.xcrm.2025.102232","url":null,"abstract":"<p><p>Acyl coenzyme A binding protein (ACBP encoded by diazepam binding inhibitor DBI) is involved in non-malignant liver diseases. Here, we show that DBI mRNA and circulating ACBP/DBI levels are increased in patients with hepatocellular carcinoma (HCC). We investigated its role in hepatocarcinogenesis in mice, inhibiting ACBP/DBI by three methods: (1) inducible whole-body or liver-specific knockout of DBI, (2) a point mutation of the ACBP/DBI receptor (GABRG2), and (3) induction of autoantibodies neutralizing ACBP/DBI. ACBP/DBI plays a major pro-carcinogenic role in HCC induced by intrahepatic transplantation of HCC cell lines, transgenic co-expression of the two oncogenes Myc and Ctnnb1, and chronic challenge with a Western-style diet together with either carbon tetrachloride (CCl<sub>4</sub>) or diethylnitrosamine. ACBP/DBI inhibition normalizes HCC-associated gene expression, reducing oncogenic alterations in cell cycle-, immunomodulatory-, and ferroptosis-regulatory genes. ACBP/DBI inhibition increases HCC responses to PD-1 blockade and sensitizes HCC to the therapeutic induction of ferroptosis. Hence, ACBP/DBI constitutes an actionable target involved in HCC pathogenesis.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102232"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-07-15Epub Date: 2025-07-07DOI: 10.1016/j.xcrm.2025.102218
Shalini Nath, Sally Claridge, Genesis Lara Granados, Majd Al Assaad, Eric Park, Julie-Ann Cavallo, Ufuoma Nuwere, Maame Esi Ackon, Lamberto De Boni, Stacey Baker, E Premkumar Reddy, Stephanie V Blank, Olivier Elemento, Rachel Brody, Benjamin D Hopkins
{"title":"Unlocking the therapeutic potential of rigosertib as a selective therapy for ovarian cancer.","authors":"Shalini Nath, Sally Claridge, Genesis Lara Granados, Majd Al Assaad, Eric Park, Julie-Ann Cavallo, Ufuoma Nuwere, Maame Esi Ackon, Lamberto De Boni, Stacey Baker, E Premkumar Reddy, Stephanie V Blank, Olivier Elemento, Rachel Brody, Benjamin D Hopkins","doi":"10.1016/j.xcrm.2025.102218","DOIUrl":"10.1016/j.xcrm.2025.102218","url":null,"abstract":"<p><p>Precision oncology seeks to exploit tumor-specific drug sensitivities. Traditionally, this is accomplished through the identification and targeting of highly recurrent mutations. This paradigm falls short in ovarian cancer where the oncogenic alterations are more diverse, necessitating an alternate approach for the identification of tumor-specific vulnerabilities. To address this, we have used a functional modeling approach, integrating drug screening with a Kinome Atlas-based assessment of signaling, to nominate a therapeutic regimen for ovarian tumors. This approach identifies a small-molecule RAS mimetic, rigosertib, as a tumor-selective agent and leads us to identify the combination of rigosertib with phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibition as effective combinations that prevent rigosertib-induced survival signaling while inducing regressions in ovarian cancer xenografts. These data support further exploration of these combinations for the treatment of ovarian cancer.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102218"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yanzhi Feng, Etienne Leveille, Jae H Park, Markus Müschen
{"title":"Moving cellular therapies to the front line for Ph<sup>+</sup> B cell acute lymphoblastic leukemia.","authors":"Yanzhi Feng, Etienne Leveille, Jae H Park, Markus Müschen","doi":"10.1016/j.xcrm.2025.102184","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102184","url":null,"abstract":"<p><p>Chemotherapy-free regimens have gained increasing attention as frontline treatments for B cell acute lymphoblastic leukemia (B-ALL) due to the limitations of chemotherapy. Zhang and colleagues conducted the first trial incorporating CAR-T into Ph<sup>+</sup> B-ALL frontline treatment, demonstrating remarkable efficacy and tolerability.<sup>1</sup>.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 7","pages":"102184"},"PeriodicalIF":11.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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