Cancer discoveryPub Date : 2024-12-20DOI: 10.1158/2159-8290.CD-24-1366
Tanjina Kader, Jia-Ren Lin, Clemens B Hug, Shannon Coy, Yu-An Chen, Ino de Bruijn, Natalie Shih, Euihye Jung, Roxanne J Pelletier, Mariana Lopez Leon, Gabriel Mingo, Dalia K Omran, Jong Suk Lee, Clarence Yapp, Baby A Satravada, Ritika Kundra, Yilin Xu, Sabrina Chan, Juliann B Tefft, Jeremy L Muhlich, Sarah H Kim, Stefan M Gysler, Judith Agudo, James R Heath, Nikolaus Schultz, Charles W Drescher, Peter K Sorger, Ronny Drapkin, Sandro Santagata
{"title":"Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.","authors":"Tanjina Kader, Jia-Ren Lin, Clemens B Hug, Shannon Coy, Yu-An Chen, Ino de Bruijn, Natalie Shih, Euihye Jung, Roxanne J Pelletier, Mariana Lopez Leon, Gabriel Mingo, Dalia K Omran, Jong Suk Lee, Clarence Yapp, Baby A Satravada, Ritika Kundra, Yilin Xu, Sabrina Chan, Juliann B Tefft, Jeremy L Muhlich, Sarah H Kim, Stefan M Gysler, Judith Agudo, James R Heath, Nikolaus Schultz, Charles W Drescher, Peter K Sorger, Ronny Drapkin, Sandro Santagata","doi":"10.1158/2159-8290.CD-24-1366","DOIUrl":"10.1158/2159-8290.CD-24-1366","url":null,"abstract":"<p><p>High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863423","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}
Cancer discoveryPub Date : 2024-12-18DOI: 10.1158/2159-8290.cd-24-0916
Sally L. George, Claire Lynn, Reda Stankunaite, Debbie Hughes, Carolin M. Sauer, Jane Chalker, Saira Waqar Ahmed, Minou Oostveen, Paula Z. Proszek, Lina Yuan, Ridwan Shaikh, Sabri Jamal, Ama Brew, Jennifer Tall, Tony Rogers, Steven C. Clifford, Josef Vormoor, Janet M. Shipley, Deborah A. Tweddle, Chris Jones, Courtney Willis, G.A. Amos Burke, Aditi Vedi, Lisa Howell, Robert Johnston, Helen Rees, Madeleine Adams, Angela Jesudason, Milind Ronghe, Martin Elliott, Emma Ross, Guy Makin, Quentin Campbell-Hewson, Richard G. Grundy, Jennifer Turnbull, Shaun Wilson, Victoria Lee, Juliet C. Gray, Sara Stoneham, Susanne A. Gatz, Lynley V. Marshall, Paola Angelini, John Anderson, George D. Cresswell, Trevor A. Graham, Bissan Al-Lazikani, Isidro Cortes-Ciriano, Pamela Kearns, J. Ciaran Hutchinson, Darren Hargrave, Thomas S. Jacques, Michael Hubank, Andrea Sottoriva, Louis Chesler
{"title":"Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states","authors":"Sally L. George, Claire Lynn, Reda Stankunaite, Debbie Hughes, Carolin M. Sauer, Jane Chalker, Saira Waqar Ahmed, Minou Oostveen, Paula Z. Proszek, Lina Yuan, Ridwan Shaikh, Sabri Jamal, Ama Brew, Jennifer Tall, Tony Rogers, Steven C. Clifford, Josef Vormoor, Janet M. Shipley, Deborah A. Tweddle, Chris Jones, Courtney Willis, G.A. Amos Burke, Aditi Vedi, Lisa Howell, Robert Johnston, Helen Rees, Madeleine Adams, Angela Jesudason, Milind Ronghe, Martin Elliott, Emma Ross, Guy Makin, Quentin Campbell-Hewson, Richard G. Grundy, Jennifer Turnbull, Shaun Wilson, Victoria Lee, Juliet C. Gray, Sara Stoneham, Susanne A. Gatz, Lynley V. Marshall, Paola Angelini, John Anderson, George D. Cresswell, Trevor A. Graham, Bissan Al-Lazikani, Isidro Cortes-Ciriano, Pamela Kearns, J. Ciaran Hutchinson, Darren Hargrave, Thomas S. Jacques, Michael Hubank, Andrea Sottoriva, Louis Chesler","doi":"10.1158/2159-8290.cd-24-0916","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0916","url":null,"abstract":"We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"29 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849169","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}
Cancer discoveryPub Date : 2024-12-12DOI: 10.1158/2159-8290.CD-24-0878
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, J Ciaran Hutchinson, Gordan M Vujanic, Christian Vokuhl, Tanzina Chowdhury, Rhoikos Furtwängler, Norbert Graf, Kathy Pritchard-Jones, Manfred Gessler, Sam Behjati
{"title":"Predisposition footprints in the somatic genome of Wilms tumours.","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, J Ciaran 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":"https://doi.org/10.1158/2159-8290.CD-24-0878","url":null,"abstract":"<p><p>Ten percent of children with cancer harbour a mutation in a predisposition gene. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumourigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukaemias), utilising WGS, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed in children harbouring 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 tumourigenesis, suggesting a variant specific approach to managing children merits consideration.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer discoveryPub Date : 2024-12-09DOI: 10.1158/2159-8290.cd-24-0559
Lisa N. Chesner, Fanny Polesso, Julie N. Graff, Jessica E. Hawley, Alexis K. Smith, Arian Lundberg, Rajdeep Das, Tanushree Shenoy, Martin Sjöström, Faming Zhao, Ya-Mei Hu, Simon Linder, William S. Chen, Reed M. Hawkins, Raunak Shrestha, Xiaolin Zhu, Adam Foye, Haolong Li, Lisa M. Kim, Megha Bhalla, Thomas O'loughlin, Duygu Kuzuoglu-Ozturk, Junjie T. Hua, Michelle L. Badura, Scott Wilkinson, Shana Y. Trostel, Andries M. Bergman, Davide Ruggero, Charles G. Drake, Adam G. Sowalsky, Lawrence Fong, Matthew R. Cooperberg, Wilbert Zwart, Xiangnan Guan, Alan Ashworth, Zheng Xia, David A. Quigley, Luke A. Gilbert, Felix Y. Feng, Amy E. Moran
{"title":"Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer","authors":"Lisa N. Chesner, Fanny Polesso, Julie N. Graff, Jessica E. Hawley, Alexis K. Smith, Arian Lundberg, Rajdeep Das, Tanushree Shenoy, Martin Sjöström, Faming Zhao, Ya-Mei Hu, Simon Linder, William S. Chen, Reed M. Hawkins, Raunak Shrestha, Xiaolin Zhu, Adam Foye, Haolong Li, Lisa M. Kim, Megha Bhalla, Thomas O'loughlin, Duygu Kuzuoglu-Ozturk, Junjie T. Hua, Michelle L. Badura, Scott Wilkinson, Shana Y. Trostel, Andries M. Bergman, Davide Ruggero, Charles G. Drake, Adam G. Sowalsky, Lawrence Fong, Matthew R. Cooperberg, Wilbert Zwart, Xiangnan Guan, Alan Ashworth, Zheng Xia, David A. Quigley, Luke A. Gilbert, Felix Y. Feng, Amy E. Moran","doi":"10.1158/2159-8290.cd-24-0559","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0559","url":null,"abstract":"Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a whole genome CRISPRi screen and identified AR as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in AR also demonstrated increased tumor immunogenicity and promoted T cell mediated tumor-control. Notably, the increase in MHCI expression upon androgen receptor blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"93 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796939","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}
Cancer discoveryPub Date : 2024-12-06DOI: 10.1158/2159-8290.cd-24-0840
Anna E. Maciag, James P. Stice, Bin Wang, Alok K. Sharma, Albert H. Chan, Ken Lin, Devansh Singh, Marcin Dyba, Yue Yang, Saman Setoodeh, Brian P. Smith, Jin Hyun Ju, Stevan Jeknic, Dana Rabara, Zuhui Zhang, Erik K. Larsen, Dominic Esposito, John-Paul Denson, Michela Ranieri, Mary Meynardie, Sadaf Mehdizadeh, Patrick A. Alexander, Maria Abreu Blanco, David M. Turner, Rui Xu, Felice C. Lightstone, Kwok-Kin Wong, Andrew G. Stephen, Keshi Wang, Dhirendra K. Simanshu, Kerstin W. Sinkevicius, Dwight V. Nissley, Eli Wallace, Frank McCormick, Pedro J. Beltran
{"title":"Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C","authors":"Anna E. Maciag, James P. Stice, Bin Wang, Alok K. Sharma, Albert H. Chan, Ken Lin, Devansh Singh, Marcin Dyba, Yue Yang, Saman Setoodeh, Brian P. Smith, Jin Hyun Ju, Stevan Jeknic, Dana Rabara, Zuhui Zhang, Erik K. Larsen, Dominic Esposito, John-Paul Denson, Michela Ranieri, Mary Meynardie, Sadaf Mehdizadeh, Patrick A. Alexander, Maria Abreu Blanco, David M. Turner, Rui Xu, Felice C. Lightstone, Kwok-Kin Wong, Andrew G. Stephen, Keshi Wang, Dhirendra K. Simanshu, Kerstin W. Sinkevicius, Dwight V. Nissley, Eli Wallace, Frank McCormick, Pedro J. Beltran","doi":"10.1158/2159-8290.cd-24-0840","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0840","url":null,"abstract":"Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor activated states where current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in Phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer (NSCLC).","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"17 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788768","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}
Cancer discoveryPub Date : 2024-12-05DOI: 10.1158/2159-8290.CD-23-1480
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
{"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":"https://doi.org/10.1158/2159-8290.CD-23-1480","url":null,"abstract":"<p><p>Effective therapies for pancreatic ductal adenocarcinoma (PDAC) have been largely elusive. Here, we perform Multiplexed kinase Inhibitor Bead Mass Spectrometry on 102 patient derived xenografts derived from 14 unique primary PDAC to define the tumor-intrinsic kinome landscape. Our findings uncover three kinome subgroups making up two tumor-intrinsic kinome subtypes that we call kinotypes. The kinotypes show enrichment of different kinase classes and recapitulate previously described molecular subtypes, basal-like and classical. The kinotype characterizing basal-like tumors shows enrichment of receptor tyrosine kinases, whereas the kinotype characterizing classical tumors is enriched in understudied kinases involved in Wnt signaling and immune pathways. We validate our findings in two clinical trials and show that only patients with basal-like tumors derive significant benefit from EGFR inhibitors. Our results provide a comprehensive tumor-intrinsic kinome landscape of PDAC that strongly supports actionable kinotype specific kinase targets and provides a roadmap for kinase inhibitor therapy in PDAC.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer discoveryPub Date : 2024-12-02DOI: 10.1158/2159-8290.CD-24-0168
Dian Kortleve, Dora Hammerl, Mandy van Brakel, Rebecca Wijers, Daphne Roelofs, Kim Kroese, Mieke M Timmermans, Chen-Yi Liao, Shaozhuo Huang, Anita Trapman-Jansen, Renée Foekens, Justine Michaux, Monique T A de Beijer, Sonja I Buschow, Jeroen A A Demmers, Marleen Kok, Erik H J Danen, Michal Bassani-Sternberg, John W M Martens, Rachel J M Abbott, Reno Debets
{"title":"TCR-Engineered T Cells Directed against Ropporin-1 Constitute a Safe and Effective Treatment for Triple-Negative Breast Cancer.","authors":"Dian Kortleve, Dora Hammerl, Mandy van Brakel, Rebecca Wijers, Daphne Roelofs, Kim Kroese, Mieke M Timmermans, Chen-Yi Liao, Shaozhuo Huang, Anita Trapman-Jansen, Renée Foekens, Justine Michaux, Monique T A de Beijer, Sonja I Buschow, Jeroen A A Demmers, Marleen Kok, Erik H J Danen, Michal Bassani-Sternberg, John W M Martens, Rachel J M Abbott, Reno Debets","doi":"10.1158/2159-8290.CD-24-0168","DOIUrl":"10.1158/2159-8290.CD-24-0168","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) has an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. Human leukocyte antigen-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCR) from naïve repertoires. Following gene introduction into T cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize noncognate epitopes from alternative source proteins. Notably, this TCR-mediated killing of three-dimensional (3D) tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T cells as a treatment for the vast majority of patients with TNBC. Significance: Metastatic TNBC has a dismal prognosis. This study discovers Ropporin-1 as a target for T-cell therapy for most patients. The selected TCR is highly specific and sensitive in advanced models, and preclinical testing shows that the T-cell product expressing this TCR, manufactured according to good manufacturing practice, has favorable safety and potency.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2450-2470"},"PeriodicalIF":29.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016464","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}
Cancer discoveryPub Date : 2024-12-02DOI: 10.1158/2159-8290.CD-24-0190
Dhan Chand, David A Savitsky, Shanmugarajan Krishnan, Gabriel Mednick, Chloe Delepine, Pilar Garcia-Broncano, Kah Teong Soh, Wei Wu, Margaret K Wilkens, Olga Udartseva, Sylvia Vincent, Bishnu Joshi, Justin G Keith, Mariana Manrique, Marilyn Marques, Antoine Tanne, Daniel L Levey, Haiyong Han, Serina Ng, Jackson Ridpath, Olivia Huber, Benjamin Morin, Claire Galand, Sean Bourdelais, Randi B Gombos, Rebecca Ward, Yu Qin, Jeremy D Waight, Matthew R Costa, Alvaro Sebastian-Yague, Nils-Petter Rudqvist, Malgorzata Pupecka-Swider, Vignesh Venkatraman, Andrew Slee, Jaymin M Patel, Joseph E Grossman, Nicholas S Wilson, Daniel D Von Hoff, Justin Stebbing, Tyler J Curiel, Jennifer S Buell, Steven J O'Day, Robert B Stein
{"title":"Botensilimab, an Fc-Enhanced Anti-CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy.","authors":"Dhan Chand, David A Savitsky, Shanmugarajan Krishnan, Gabriel Mednick, Chloe Delepine, Pilar Garcia-Broncano, Kah Teong Soh, Wei Wu, Margaret K Wilkens, Olga Udartseva, Sylvia Vincent, Bishnu Joshi, Justin G Keith, Mariana Manrique, Marilyn Marques, Antoine Tanne, Daniel L Levey, Haiyong Han, Serina Ng, Jackson Ridpath, Olivia Huber, Benjamin Morin, Claire Galand, Sean Bourdelais, Randi B Gombos, Rebecca Ward, Yu Qin, Jeremy D Waight, Matthew R Costa, Alvaro Sebastian-Yague, Nils-Petter Rudqvist, Malgorzata Pupecka-Swider, Vignesh Venkatraman, Andrew Slee, Jaymin M Patel, Joseph E Grossman, Nicholas S Wilson, Daniel D Von Hoff, Justin Stebbing, Tyler J Curiel, Jennifer S Buell, Steven J O'Day, Robert B Stein","doi":"10.1158/2159-8290.CD-24-0190","DOIUrl":"10.1158/2159-8290.CD-24-0190","url":null,"abstract":"<p><strong>Significance: </strong>This study reveals that Fc-enhanced anti-CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti-CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"2407-2429"},"PeriodicalIF":29.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859120","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}
Cancer discoveryPub Date : 2024-12-02DOI: 10.1158/2159-8290.cd-24-1350
Samuel F. Bakhoum
{"title":"Targeting RNA and Protein Turnover in Aneuploid Cancers","authors":"Samuel F. Bakhoum","doi":"10.1158/2159-8290.cd-24-1350","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1350","url":null,"abstract":"Summary:Aneuploidy, an imbalance in chromosome number, is a hallmark of human cancers with chromosomal instability, and it remains a major therapeutic challenge. In this issue, Ippolito and colleagues identify RNA and protein turnover as targetable therapeutic vulnerabilities in aneuploid cancers.See related article by Ippolito et al., p. 2532","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"65 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760482","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}
Cancer discoveryPub Date : 2024-12-02DOI: 10.1158/2159-8290.cd-24-1476
Matteo Repetto, Nicole Fernandez, Alexander Drilon, Debyani Chakravarty
{"title":"Precision Oncology: 2024 in Review","authors":"Matteo Repetto, Nicole Fernandez, Alexander Drilon, Debyani Chakravarty","doi":"10.1158/2159-8290.cd-24-1476","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1476","url":null,"abstract":"Summary: This article discusses the specific advances made in precision oncology in 2024. We comment on the evolving nature of predictive molecular events used to select patients who will most benefit clinically from treatment. We also discuss advances in the development of strategic treatment regimens for combination therapies, rational drug design of small-molecule inhibitors, and structurally informed drug repurposing.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"73 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760483","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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