Cancer discovery最新文献

{"title":"Pan-cancer analysis of oncogenic MET fusions reveals distinct pathogenomic subsets with differential sensitivity to MET-targeted therapy","authors":"Christopher A. Febres-Aldana, Morana Vojnic, Igor Odintsov, Tom Zhang, Ryan Cheng, Catherine Z. Beach, Daniel Lu, Marissa S. Mattar, Andrea M. Gazzo, Leo Gili, Manju Harshan, Ali Ameri, Stephen Machnicki, Xiuying Xiao, William W. Lockwood, Xiao-yan Zhou, Qianlan Yao, Alexander Drilon, Natasha Rekhtman, Nameeta Shah, Anqi Li, Zebing Liu, Soo-Ryum Yang, Monika A. Davare, Marc Ladanyi, Romel Somwar","doi":"10.1158/2159-8290.cd-24-0417","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0417","url":null,"abstract":"MET fusions (MET-Fs) are oncogenic drivers that remain poorly characterized. Analysis of 56 MET-F-positive tumors from an institutional cohort of 91,119 patients (79,864 DNA-seq plus 11,255 RNA-seq) uncovered two forms of MET-F pathobiology. The first group featured 5’ partners with homodimerization domains fused in-frame with MET-tyrosine kinase domain (TKD), primarily originated from translocations, frequently excluded MET exon 14, mediated oncogenesis through cytoplasmic aggregation and constitutive activation, and were markedly sensitive to MET tyrosine kinase inhibitors (TKI) in pre-clinical models and patients with lung cancer. The second group lacked partner homodimerization motifs and retained MET transmembrane and extracellular domains. Their pathogenesis involved intrachromosomal rearrangements, resulting in partner selection for promoter hijacking and fusion allele amplification. Membrane-bound fusions were enriched in gliomas with RTK co-alterations. We provide a framework to comprehend the heterogeneous landscape of MET-Fs, supporting that fusion oncogenicity and MET-TKI sensitivity are determined by structural topology and pathogenomic context.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"53 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443172","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":"High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non–Small Cell Lung Cancer in Patients","authors":"Ling Cai, Nia G. Hammond, Alpaslan Tasdogan, Massar Alsamraae, Chendong Yang, Robert B. Cameron, Peiran Quan, Ashley Solmonson, Wen Gu, Panayotis Pachnis, Mayher Kaur, Brianna K. Chang, Qin Zhou, Christopher T. Hensley, Quyen N. Do, Luiza Martins Nascentes Melo, Jessalyn M. Ubellacker, Akash Kaushik, Maia G. Clare, Isabel N. Alcazar, Katarzyna Kurylowicz, Joseph D. Marcuccilli, Gabriele Allies, Andrea Kutritz, Joachim Klode, Vijayashree Ramesh, Thomas J. Rogers, Aparna D. Rao, Hannah E. Crentsil, Hong Li, Fang Brister, Phyllis McDaniel, Xiaohong Xu, Bret M. Evers, Lauren G. Zacharias, Jessica Sudderth, Jian Xu, Thomas P. Mathews, Dwight Oliver, John D. Minna, John Waters, Sean J. Morrison, Kemp H. Kernstine, Brandon Faubert, Ralph J. DeBerardinis","doi":"10.1158/2159-8290.cd-23-1319","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-23-1319","url":null,"abstract":"In patients with non–small cell lung cancer (NSCLC), the relationship between tumor metabolism and clinical outcomes is unknown. Here, 13C-labeled nutrients were intraoperatively infused into more than 90 patients with surgically resectable pulmonary lesions, and metabolic properties of resected tumors were correlated with survival. In NSCLCs infused with 13C-glucose, high 13C enrichment in tricarboxylic acid (TCA) cycle intermediates conferred a HR of 3.8 for early death, typically with metastasis. To test whether these features reflect requirements for metastasis, we generated patient-derived xenografts that spontaneously metastasize to multiple organs. Treatment with an electron transport chain (ETC) inhibitor reduced glucose-derived TCA cycle labeling but did not suppress subcutaneous tumor growth. However, ETC blockade reduced the abundance of circulating cancer cells and suppressed xenograft metastatic burden in distant organs. Our data demonstrate that isotope labeling can identify metabolic properties associated with metastasis in patients and that blocking the ETC suppresses metastasis in mice. Significance: Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"80 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435288","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":"Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small Molecule Reactivator.","authors":"Anna M Puzio-Kuter, Lizhong Xu, Mary Kate McBrayer, Romyr Dominique, Hongju H Li, Bruce J Fahr, Alyssa M Brown, Amy E Wiebesiek, Brandon M Russo, Chris L Mulligan, Hong Yang, Josh Battaglia, Kimberly A Robell, Dafydd H Thomas, Kuo-Sen Huang, Alexander Solovyov, Benjamin D Greenbaum, Jonathan D Oliner, Thomas W Davis, Melissa L Dumble, Melissa L Johnson, Shunbin Xiong, Peirong Yang, Guillermina Lozano, Marc M Fellous, Binh T Vu, Alison M Schram, Arnold J Levine, Masha V Poyurovsky","doi":"10.1158/2159-8290.CD-24-1421","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1421","url":null,"abstract":"<p><p>Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. Here, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing anti-proliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild type p53 program. These compounds demonstrate potent anti-tumor activity in preclinical models as single agents and in combination with immunotherapy. Currently, rezatapopt is being evaluated in a registrational Phase 2 clinical trial for patients with advanced solid tumors harboring the TP53 Y220C mutation.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405675","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":"Predisposition Footprints in the Somatic Genome of Wilms Tumors.","authors":"Taryn D Treger, Jenny Wegert, Anna Wenger, Tim H H Coorens, Reem Al-Saadi, Paul G Kemps, Jonathan Kennedy, Conor Parks, Nathaniel D Anderson, Angus Hodder, Aleksandra Letunovska, Hyunchul Jung, Toochi Ogbonnah, Mi K Trinh, Henry Lee-Six, Guillaume Morcrette, Marry M van den Heuvel-Eibrink, Jarno Drost, Ruben van Boxtel, Eline J M Bertrums, Bianca F Goemans, Evangelia Antoniou, Dirk Reinhardt, Heike Streitenberger, Barbara Ziegler, Jack Bartram, John C Hutchinson, Gordan M Vujanic, Christian Vokuhl, Tanzina Chowdhury, Rhoikos Furtwängler, Norbert Graf, Kathy Pritchard-Jones, Manfred Gessler, Sam Behjati","doi":"10.1158/2159-8290.CD-24-0878","DOIUrl":"10.1158/2159-8290.CD-24-0878","url":null,"abstract":"<p><p>Approximately 10% of children with cancer harbor a mutation in a predisposition gene. In children with the kidney cancer Wilms tumor, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumorigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumor, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA sequencing, and genome-wide methylation, validating our findings in an independent cohort. Tumor development differed in children harboring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high-risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumorigenesis, suggesting a variant-specific approach to managing children merits consideration. Significance: Tumors that arise in children with a cancer predisposition may develop through the same mutational pathways as sporadic tumors. We examined this question in the childhood kidney cancer, Wilms tumor. We found that certain predispositions dictate the genetic development of tumors, with clinical implications for these children. See related commentary by Brzezinski and Malkin, p. 258.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"286-298"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hidden in Plain Sight: Clinical Imaging of the Tumor Microenvironment with PET.","authors":"Timothy H Witney","doi":"10.1158/2159-8290.CD-24-1673","DOIUrl":"10.1158/2159-8290.CD-24-1673","url":null,"abstract":"<p><p>PET imaging enables the spatiotemporal assessment of tumor biomarkers. In this issue, Kong and colleagues describe the clinical PET imaging of tumor-associated fibroblasts, which improved the diagnostic accuracy and management of a subset of patients with medullary thyroid carcinoma. See related article by Kong et al., p. 316.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"264-266"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363593","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":"Strengthening Asian/Asian American, Native Hawaiian, and Pacific Islander Leadership in Cancer Research.","authors":"Lawrence W Wu, Ryan H Moy","doi":"10.1158/2159-8290.CD-24-1618","DOIUrl":"10.1158/2159-8290.CD-24-1618","url":null,"abstract":"<p><p>Individuals in the United States from Asian and Asian American, Native Hawaiian, and Pacific Islander (AANHPI) backgrounds face a distinct set of cancer-related disparities. In this study, in conjunction with the American Association for Cancer Research Asian/AANHPI Task Force, we highlight the unique disparities faced by AANHPI patients and professionals, and we offer actionable recommendations on how to strengthen AANHPI leadership in cancer research.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"267-270"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363598","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":"Stromal KITL/SCF maintains pancreas tissue homeostasis and restrains tumor progression","authors":"M. Kathrina. Oñate, Chet Oon, Sohinee Bhattacharyya, Vivien Low, Canping Chen, Xiaofan Zhao, Frank Arnold, Ziqiao Yan, Sneha Pramod, Yan Hang, Yu-Jui Ho, Scott W. Lowe, Seung K. Kim, Zheng Xia, Mara H. Sherman","doi":"10.1158/2159-8290.cd-24-1079","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1079","url":null,"abstract":"Components of normal tissue architecture serve as barriers to tumor progression. Inflammatory and wound-healing programs are requisite features of solid tumorigenesis, wherein alterations to immune and non-immune stromal elements enable loss of homeostasis during tumor onset. The precise mechanisms by which normal stromal cell states limit tissue plasticity and tumorigenesis, and which are lost during tumor progression, remain largely unknown. Here we show that healthy pancreatic mesenchyme expresses the paracrine signaling molecule KITL, also known as stem cell factor, and identify loss of stromal KITL during tumorigenesis as tumor-promoting. Genetic inhibition of mesenchymal KITL in the contexts of health, injury, and cancer together indicate a role for KITL signaling in maintenance of pancreas tissue architecture, such that loss of the stromal KITL pool increased tumor growth and reduced survival of tumor-bearing mice. Together, these findings implicate loss of mesenchymal KITL as a mechanism for establishing a tumor-permissive microenvironment.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"60 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258398","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":"Tumor-Intrinsic Kinome Landscape of Pancreatic Cancer Reveals New Therapeutic Approaches.","authors":"Yi Xu, Xianlu L Peng, Michael P East, Ian C McCabe, Grace C Stroman, Madison R Jenner, Priscilla S Chan, Ashley B Morrison, Emily C Shen, Silvia G Hererra, Chinmaya U Joisa, Naim U Rashid, Alina C Iuga, Shawn M Gomez, Lisa Miller-Phillips, Stefan Boeck, Volker Heinemann, Michael Haas, Steffen Ormanns, Gary L Johnson, Jen Jen Yeh","doi":"10.1158/2159-8290.CD-23-1480","DOIUrl":"10.1158/2159-8290.CD-23-1480","url":null,"abstract":"<p><strong>Significance: </strong>We provide a comprehensive tumor-intrinsic kinome landscape that provides a roadmap for the use of kinase inhibitors in PDAC treatment approaches.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"346-362"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTR-FAPI PET Enables Precision Management of Medullary Thyroid Carcinoma.","authors":"Ziren Kong, Zhu Li, Xi-Yang Cui, Jian Wang, Mengxin Xu, Yang Liu, Junyi Chen, Song Ni, Zongmin Zhang, Xiaowei Fan, Jiazhao Huang, Yansong Lin, Yuning Sun, Yuqin He, Xinfeng Lin, Tianyu Meng, Han Li, Yixuan Song, Boshizhang Peng, Changming An, Chenyan Gao, Nan Li, Chen Liu, Yiming Zhu, Zhi Yang, Zhibo Liu, Shaoyan Liu","doi":"10.1158/2159-8290.CD-24-0897","DOIUrl":"10.1158/2159-8290.CD-24-0897","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but current clinical practice fails to localize the disease in 29% to 60% of patients. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]fluorodeoxyglucose ([18F]FDG) PET-CT in 50 patients with MTC. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, P = 0.0002). This improved detection was attributed to increased tumor uptake (maximum standardized uptake value = 11.71 ± 9.16 vs. 2.55 ± 1.73, P < 0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared with [18F]FDG (96.7% vs. 43.3%, P < 0.0001). Notably, the management of 32% of patients was altered following [68Ga]Ga-CTR-FAPI PET-CT, and the surgical plan was changed for 66.7% of patients. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared with [18F]FDG PET-CT, enabling precision management of patients with MTC. Significance: In this first-in-class clinical trial of CTR, [68Ga]Ga-CTR-FAPI demonstrated an improved patient-based detection rate (98%), tumor uptake (maximum standardized uptake value = 11.71 ± 9.16), and pathology-validated diagnostic accuracy (96.7%) compared with the currently approved method in MTC treatment. It directly altered management in 32% of patients, enabling precision diagnosis and management of MTC. See related commentary by Witney, p. 264.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"316-328"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knudson's \"Two-Hit\" Hypothesis and Cancer Predisposition: A Bit More Complicated but Still Going Strong.","authors":"Jack J Brzezinski, David Malkin","doi":"10.1158/2159-8290.CD-24-1662","DOIUrl":"10.1158/2159-8290.CD-24-1662","url":null,"abstract":"<p><p>This study by Treger and colleagues is a comprehensive evaluation of the genome and epigenome of tumors and constitutional tissue from children with Wilms tumor predisposition syndromes that demonstrates that the molecular features of Wilms tumors are dependent on the constitutional milieu of the patient in which they develop. See related article by Treger et al., p. 286.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"258-260"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363595","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}