Cancer discovery最新文献

筛选
英文 中文
A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer. 一种塑料EMP1 +到LGR5 +的细胞状态转换作为KRAS-G12D药物抑制转移性结直肠癌的旁路。
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-21 DOI: 10.1158/2159-8290.cd-25-0679
Alessia Centonze,Adrià-Jaume Roura,Meritxell Novillo-Font,Cristina Giordano,Xavier Hernando-Momblona,Montserrat Llanses,Paula Prats,Marta Sevillano,Débora Cabot,Mireia Novell,Gabriel Pabst,Florian Andersch,Adrià Cañellas-Socias,Chong Zhang,Nikolaos-Nikiforos Giakoumakis,Hugh Sparks,Chris Dunsby,Julien Colombelli,Asunción Fernández-Barral,Elena Sancho,Camille Stephan-Otto Attolini,Alberto Muñoz,Antonio Barbachano,Héctor G Palmer,Jordi Martínez-Quintanilla,Johannes Zuber,Cristina Blaj,Elsa Quintana,Carme Cortina,Marc A Marti-Renom,Eduard Batlle
{"title":"A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.","authors":"Alessia Centonze,Adrià-Jaume Roura,Meritxell Novillo-Font,Cristina Giordano,Xavier Hernando-Momblona,Montserrat Llanses,Paula Prats,Marta Sevillano,Débora Cabot,Mireia Novell,Gabriel Pabst,Florian Andersch,Adrià Cañellas-Socias,Chong Zhang,Nikolaos-Nikiforos Giakoumakis,Hugh Sparks,Chris Dunsby,Julien Colombelli,Asunción Fernández-Barral,Elena Sancho,Camille Stephan-Otto Attolini,Alberto Muñoz,Antonio Barbachano,Héctor G Palmer,Jordi Martínez-Quintanilla,Johannes Zuber,Cristina Blaj,Elsa Quintana,Carme Cortina,Marc A Marti-Renom,Eduard Batlle","doi":"10.1158/2159-8290.cd-25-0679","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0679","url":null,"abstract":"Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here we show that a selective, covalent small molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical CRC models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor-prognosis-associated Emp1⁺ transcriptional state to a WNT-driven Lgr5⁺ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5⁺ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"1 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339263","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}
引用次数: 0
p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program. p53通过TSC2/ tfeb依赖性衰老程序驱动肺癌消退。
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-21 DOI: 10.1158/2159-8290.cd-25-0525
Mengxiong Wang,Kathryn T Bieging-Rolett,Alyssa M Kaiser,Colleen A Brady,John H Lockhart,Sofia Ferreira,Kha T Nguyen,Arati Rajeevan,Simone A Evans,Tianyu Zhao,Nitin Raj,Arielle Elkrief,Sam E Tischfield,Marc Ladanyi,Michael G Ozawa,Nam Q Bui,Christopher T Chen,Elsa R Flores,Laura D Attardi
{"title":"p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.","authors":"Mengxiong Wang,Kathryn T Bieging-Rolett,Alyssa M Kaiser,Colleen A Brady,John H Lockhart,Sofia Ferreira,Kha T Nguyen,Arati Rajeevan,Simone A Evans,Tianyu Zhao,Nitin Raj,Arielle Elkrief,Sam E Tischfield,Marc Ladanyi,Michael G Ozawa,Nam Q Bui,Christopher T Chen,Elsa R Flores,Laura D Attardi","doi":"10.1158/2159-8290.cd-25-0525","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0525","url":null,"abstract":"Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"39 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331636","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}
引用次数: 0
Rethinking Cancer Drug Development through Tumor-Agnostic Precision Medicine. 通过肿瘤不可知论精准医学重新思考癌症药物开发。
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-17 DOI: 10.1158/2159-8290.cd-25-1457
Vivek Subbiah
{"title":"Rethinking Cancer Drug Development through Tumor-Agnostic Precision Medicine.","authors":"Vivek Subbiah","doi":"10.1158/2159-8290.cd-25-1457","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1457","url":null,"abstract":"Tumor-agnostic therapies represent a revolutionary shift from century-old anatomic classifications to molecular-driven cancer treatment, in which therapeutic decisions are based on what drives the tumor rather than where it arises. This perspective calls for a transformative acceleration of tissue-agnostic drug development from today's 10 approvals to 50 to 100 within 25 years to eliminate therapeutic inequities and ensure every patient receives the right therapy based on their tumor's molecular identity, not anatomic accident.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"64 1","pages":"OF1-OF7"},"PeriodicalIF":28.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305451","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}
引用次数: 0
Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed/Refractory NK/T-cell Lymphoma. 在复发/难治性NK/ t细胞淋巴瘤中,DNMT抑制剂引发病毒拟态可增强PD-1免疫治疗
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-15 DOI: 10.1158/2159-8290.cd-25-0587
Cheng Huang,Yan Gao,Jianfeng Chen,Jing Han Hong,Yue Jiang,Kelila Xin Ye Chai,Yingxi Li,Peili Wang,Yali Wang,Jiuping Gao,Xian Zeng,Rong Xiao,Haixia He,Peiyong Guan,Jason Yongsheng Chan,Jing Quan Lim,Anand D Jeyasekharan,Huang Dachuan,Jin-Xin Bei,Bin Tean Teh,Soon Thye Lim,Qiang Yu,Choon Kiat Ong,Huiqiang Huang,Jing Tan
{"title":"Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed/Refractory NK/T-cell Lymphoma.","authors":"Cheng Huang,Yan Gao,Jianfeng Chen,Jing Han Hong,Yue Jiang,Kelila Xin Ye Chai,Yingxi Li,Peili Wang,Yali Wang,Jiuping Gao,Xian Zeng,Rong Xiao,Haixia He,Peiyong Guan,Jason Yongsheng Chan,Jing Quan Lim,Anand D Jeyasekharan,Huang Dachuan,Jin-Xin Bei,Bin Tean Teh,Soon Thye Lim,Qiang Yu,Choon Kiat Ong,Huiqiang Huang,Jing Tan","doi":"10.1158/2159-8290.cd-25-0587","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0587","url":null,"abstract":"Anti-PD-1 immunotherapy has demonstrated significant antitumor efficacy in relapsed or refractory NK/T-cell lymphoma (R/R NKTL), but resistance remains a substantial challenge. In this study, we evaluate DNA methyltransferase (DNMT) inhibitors combined with anti-PD-1 mAb in 21 patients with R/R NKTL for whom prior immunotherapy failed. This combination therapy achieved an objective response rate of 66.7% (14/21), with a complete response rate of 47.6% (10/21) and a 2-year overall survival rate of 50.2%. Preclinical models revealed that anti-PD-1 resistance was linked to the absence of CD8+ T-cell infiltration and suppressed IFN pathways. DNMT inhibitors reversed these effects, restoring CD8+ T-cell activities and tumor sensitivity to PD-1 blockade. Mechanistically, DNMT inhibitors triggered DNA demethylation of endogenous retroviral elements, activating viral mimicry via upregulated endogenous nucleic acids and type I IFN signaling. These findings underscore DNMT inhibitors' role in overcoming PD-1 resistance and support their combination with anti-PD-1 as a promising strategy for R/R NKTL.SIGNIFICANCEResistance to anti-PD-1 immunotherapy remains a substantial challenge in R/R NKTL. In this study, we reported that combining DNMT inhibitors with anti-PD-1 mAb achieves a high complete response rate of 47.6% in immunotherapy-R/R NKTL patients. Mechanistically, DNMT inhibitors potentiate anti-PD-1 efficacy by triggering viral mimicry, remodeling the immune microenvironment and augmenting antitumor immunity.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"8 1","pages":"OF1-OF18"},"PeriodicalIF":28.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288500","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}
引用次数: 0
Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer. 西伐替尼,一种对肺癌有活性的可逆HER2抑制剂。
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-15 DOI: 10.1158/2159-8290.cd-25-0605
Franziska Siegel,Stephan Siegel,Kristýna Kotýnková,Gizem Karsli Uzunbas,Daniel Korr,Haruna Tomono,Sawyer Andersen,Daniel Denney,Markus Berger,Volker K Schulze,Timothy A Lewis,Bethany Kaplan,Sven Golfier,Jérémie Mortier,Roman C Hillig,Ulf Boemer,Kirstin Petersen,Knut Eis,Sybil Williams,Dominik Rüttinger,Andrew D Cherniack,Herbert H Loong,Koichi Goto,Paolo Grassi,Matthew Meyerson,Heidi Greulich
{"title":"Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer.","authors":"Franziska Siegel,Stephan Siegel,Kristýna Kotýnková,Gizem Karsli Uzunbas,Daniel Korr,Haruna Tomono,Sawyer Andersen,Daniel Denney,Markus Berger,Volker K Schulze,Timothy A Lewis,Bethany Kaplan,Sven Golfier,Jérémie Mortier,Roman C Hillig,Ulf Boemer,Kirstin Petersen,Knut Eis,Sybil Williams,Dominik Rüttinger,Andrew D Cherniack,Herbert H Loong,Koichi Goto,Paolo Grassi,Matthew Meyerson,Heidi Greulich","doi":"10.1158/2159-8290.cd-25-0605","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0605","url":null,"abstract":"Exon 20 insertions of HER2, encoded by ERBB2, and other activating HER2 mutations occur in 2-4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR-HER2 inhibitor that is selective with respect to wild-type EGFR. Here, we report the preclinical activity of sevabertinib in lung cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"91 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288321","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}
引用次数: 0
Glucocorticoids Unleash Immune-dependent Melanoma Control through Inhibition of the GARP/TGF β Axis 糖皮质激素通过抑制GARP/TGF β轴释放免疫依赖性黑色素瘤控制
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-14 DOI: 10.1158/2159-8290.cd-24-1224
Charles H. Earnshaw, Poppy Dunn, Shih-Chieh Chiang, Agrin Moeini, Maria A. Koufaki, Eduardo Bonavita, Massimo Russo, Laetitia Nebot-Bral, Kimberley Hockenhull, Erin Richardson, Anna Pidoux, Charlotte R. Bell, Alexander R. Baker, Richard Reeves, Robert Sellers, Sudhakar Sahoo, Victoria Fife, Matthew G. Roberts, Theophile Bigirumurame, Caroline Dive, Julia Newton-Bishop, Jérémie Nsengimana, Christopher E.M. Griffiths, Santiago Zelenay
{"title":"Glucocorticoids Unleash Immune-dependent Melanoma Control through Inhibition of the GARP/TGF β Axis","authors":"Charles H. Earnshaw, Poppy Dunn, Shih-Chieh Chiang, Agrin Moeini, Maria A. Koufaki, Eduardo Bonavita, Massimo Russo, Laetitia Nebot-Bral, Kimberley Hockenhull, Erin Richardson, Anna Pidoux, Charlotte R. Bell, Alexander R. Baker, Richard Reeves, Robert Sellers, Sudhakar Sahoo, Victoria Fife, Matthew G. Roberts, Theophile Bigirumurame, Caroline Dive, Julia Newton-Bishop, Jérémie Nsengimana, Christopher E.M. Griffiths, Santiago Zelenay","doi":"10.1158/2159-8290.cd-24-1224","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1224","url":null,"abstract":"Half of patients with advanced melanoma fail to benefit from immune checkpoint blockade, and novel treatments are urgently required. Testing topical medications for anticancer activity in an immunotherapy-resistant murine melanoma model, we found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumor cells to downregulate the expression of glycoprotein A repetitions predominant (GARP). This inhibited TGF β signaling and unleashed CTL killing. In agreement, GCs stimulated tumor control in multiple cancer models but only if the tumors also responded to pharmacologic inhibition of TGF β signaling. Furthermore, patients with melanoma with high GC receptor expression or signaling showed improved prognosis and lower TGF β signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF β axis emerges as a GC-sensitive cancer cell–intrinsic immune-evasive mechanism. Significance: This study uncovers a surprising role for GCs in triggering CD8+ T cell–dependent tumor control through downregulation of GARP and thus TGF β signaling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"86 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145289190","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}
引用次数: 0
Screening for Tumor Microtube-Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression 肿瘤微管靶向药物筛选鉴定PKC调节剂作为胶质母细胞瘤进展的多能抑制剂
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-09 DOI: 10.1158/2159-8290.cd-24-0414
Daniel D. Azorín, Dirk C. Hoffmann, Nils R. Hebach, Erik Jung, David Hausmann, Miriam Ratliff, Ling Hai, Sandra Horschitz, Ammar Jabali, Matthias Osswald, Matthia A. Karreman, Tobias Kessler, Susann Wendler, Chanté D. Mayer, Cathrin Löb, Pascal Lehnert, Gina Cebulla, Denise Reibold, Rajiv K. Khajuria, Pino Bordignon, Andreas E. Moor, Tim Holland-Letz, Jill Reckless, Nigel Ramsden, David Grainger, Anna Kreshuk, Philipp Koch, Wolfgang Wick, Sophie Heuer, Frank Winkler
{"title":"Screening for Tumor Microtube-Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression","authors":"Daniel D. Azorín, Dirk C. Hoffmann, Nils R. Hebach, Erik Jung, David Hausmann, Miriam Ratliff, Ling Hai, Sandra Horschitz, Ammar Jabali, Matthias Osswald, Matthia A. Karreman, Tobias Kessler, Susann Wendler, Chanté D. Mayer, Cathrin Löb, Pascal Lehnert, Gina Cebulla, Denise Reibold, Rajiv K. Khajuria, Pino Bordignon, Andreas E. Moor, Tim Holland-Letz, Jill Reckless, Nigel Ramsden, David Grainger, Anna Kreshuk, Philipp Koch, Wolfgang Wick, Sophie Heuer, Frank Winkler","doi":"10.1158/2159-8290.cd-24-0414","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0414","url":null,"abstract":"Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TMs), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. Here, we developed a combined, comprehensive in vitro/in vivo anti-TM drug screening approach, including machine-learning-based analysis tools. Two Protein Kinase C (PKC) modulators robustly inhibited TM formation and pacemaker tumor cell-driven, TM-mediated glioblastoma cell network communication. Since TM-unconnected tumor cells exhibited increased sensitivity to cytotoxic therapy, the PKC activator TPPB was combined with radiotherapy, and long-term intravital 2-photon microscopy paired with spatially resolved multiomics revealed anti-TM and anti-tumor effects. TPPB treatment also decreased the expression of tweety family member 1 (TTYH1), a key driver of invasive TMs. Our study establishes a novel screening pipeline for anti-TM drug development, identifies a TM master regulator pathway, and supports the approach of TM targeting for efficient brain tumor therapies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"26 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246868","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}
引用次数: 0
HIF-2-dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear Cell Renal Cell Carcinoma. 侵袭性透明细胞肾细胞癌中PTHrP和副肿瘤性高钙血症的hif -2依赖性调节。
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-09 DOI: 10.1158/2159-8290.cd-25-0638
Arijit Mal,Bingqing Xie,Zane Gray,Charlotte Small,Susmita G Ramanand,Yunpeng Gao,Vanina Toffessi Tcheuyap,Sashi Debnath,Alana Christie,Jeffrey Miyata,Brooklyn Jackson,Hua Zhong,Boning Gao,Jay Lohrey,Naim M Maalouf,Sangeetha M Reddy,John D Minna,Ivan Pedrosa,Xiankai Sun,Ram S Mani,Payal Kapur,James Brugarolas
{"title":"HIF-2-dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear Cell Renal Cell Carcinoma.","authors":"Arijit Mal,Bingqing Xie,Zane Gray,Charlotte Small,Susmita G Ramanand,Yunpeng Gao,Vanina Toffessi Tcheuyap,Sashi Debnath,Alana Christie,Jeffrey Miyata,Brooklyn Jackson,Hua Zhong,Boning Gao,Jay Lohrey,Naim M Maalouf,Sangeetha M Reddy,John D Minna,Ivan Pedrosa,Xiankai Sun,Ram S Mani,Payal Kapur,James Brugarolas","doi":"10.1158/2159-8290.cd-25-0638","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0638","url":null,"abstract":"Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a TG with paraneoplastic polycythemia). As in TGs, paraneoplastic HC in patients was associated with clear cell (cc)RCC (and sarcomatoid/rhabdoid differentiation) and was rapidly corrected by PT2977/belzutifan, which unlike bisphosphonates, downregulated PTHrP. Our data supports evaluating HIF-2 antagonists for ccRCC patients with paraneoplastic HC, which may serve as a predictive biomarker.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"111 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246871","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}
引用次数: 0
Association between Medicaid Expansion and 5-Year Survival among Individuals Diagnosed with Cancer. 医疗补助扩大与癌症患者5年生存率的关系
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-08 DOI: 10.1158/2159-8290.cd-25-1244
Elizabeth J Schafer,Christopher J Johnson,Fabio Y Moraes,Xuesong Han,Jingxuan Zhao,Ahmedin Jemal
{"title":"Association between Medicaid Expansion and 5-Year Survival among Individuals Diagnosed with Cancer.","authors":"Elizabeth J Schafer,Christopher J Johnson,Fabio Y Moraes,Xuesong Han,Jingxuan Zhao,Ahmedin Jemal","doi":"10.1158/2159-8290.cd-25-1244","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1244","url":null,"abstract":"Medicaid expansion is associated with improvements in access to early detection and treatment services, and 2-year overall survival (OS) among individuals with cancer. However, the association with improvements in longer-term survival remains understudied. A difference-in-differences (DD) approach was used to examine changes in 5-year cause-specific survival and OS following Medicaid expansion. A total of 1,423,983 cancer cases diagnosed between 2007 and 2008 and 2014 and 2015 among adults 18 to 59 years of age residing in 26 expansion and 12 non-expansion states were included. Improvements in cause-specific survival were significantly greater in expansion states among individuals residing in rural [DD: 2.55 percentage point (ppt); 95% confidence interval (CI), 0.23-4.86] and high-poverty communities (DD: 1.54 ppt; 95% CI, 0.30-2.77), non-Hispanic White individuals (DD: 0.37 ppt; 95% CI, 0.05-0.70), and those with pancreatic (DD: 2.60 ppt; 95% CI, 0.86-4.34), lung (DD: 1.32 ppt; 95% CI, 0.30-2.34), and colorectal cancers (DD: 1.31 ppt; 95% CI, 0.26-2.37). Results were similar for OS. These findings underscore the importance of Medicaid expansion in mitigating disparities in survival outcomes.SIGNIFICANCEImprovements in 5-year cause-specific survival and OS were greater in Medicaid expansion than non-expansion states among individuals residing in rural and high-poverty communities and among individuals diagnosed with cancers that generally have a worse prognosis, emphasizing the importance of Medicaid expansion in mitigating disparities in survival outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"209 1","pages":"OF1-OF6"},"PeriodicalIF":28.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240927","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}
引用次数: 0
Recurrent immunogenic neoantigens and their cognate T-cell receptors in treatment-resistant metastatic prostate cancer. 复发性免疫原性新抗原及其同源t细胞受体在治疗抵抗性转移性前列腺癌中的作用。
IF 28.2 1区 医学
Cancer discovery Pub Date : 2025-10-08 DOI: 10.1158/2159-8290.cd-24-1213
Nofar Gumpert,Shira Sagie,Claudia Arnedo-Pac,Tomer Babu,Chen Weller,Abel Gonzalez-Perez,Yuan Wang,Lucas Michel Todó,Ronen Levy,Xi Chen,Polina Greenberg,Maria Dayan-Rubinov,Elizabeta Yakubovich,Talya Wasserman-Bartov,Mirie Zerbib,Jianhui Gong,Ryan J Rebernick,Anna Oliveira Tercero,Laura Agundez Muriel,Gil Benedek,Merav Kedmi,Roni Oren,Shifra Ben-Dor,Yishai Levin,Olga G Troyanskaya,Aslı D Munzur,Alexander W Wyatt,Marcin P Cieslik,David A Quigley,Eliezer M Van Allen,Niroshana Anandasabapathy,Joaquin Mateo,Xinbo Yang,Francisco Martínez-Jiménez,Nuria Lopez-Bigas,Yardena Samuels
{"title":"Recurrent immunogenic neoantigens and their cognate T-cell receptors in treatment-resistant metastatic prostate cancer.","authors":"Nofar Gumpert,Shira Sagie,Claudia Arnedo-Pac,Tomer Babu,Chen Weller,Abel Gonzalez-Perez,Yuan Wang,Lucas Michel Todó,Ronen Levy,Xi Chen,Polina Greenberg,Maria Dayan-Rubinov,Elizabeta Yakubovich,Talya Wasserman-Bartov,Mirie Zerbib,Jianhui Gong,Ryan J Rebernick,Anna Oliveira Tercero,Laura Agundez Muriel,Gil Benedek,Merav Kedmi,Roni Oren,Shifra Ben-Dor,Yishai Levin,Olga G Troyanskaya,Aslı D Munzur,Alexander W Wyatt,Marcin P Cieslik,David A Quigley,Eliezer M Van Allen,Niroshana Anandasabapathy,Joaquin Mateo,Xinbo Yang,Francisco Martínez-Jiménez,Nuria Lopez-Bigas,Yardena Samuels","doi":"10.1158/2159-8290.cd-24-1213","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1213","url":null,"abstract":"New approaches that generate long-lasting therapeutic responses in therapy-resistant metastatic cancer patients are urgently needed. To address this challenge, we developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neopeptides derived from Androgen Receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCRs) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y specific TCRs are highly specific and kill prostate cancer cells presenting AR neo-peptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for mCRPC patients. Moreover, SpotNeoMet offers a systematic route to identify 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"51 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241055","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}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信