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Enhancing the Trajectories of Cancer Health Disparities Research: Improving Clinical Applications of Diversity, Equity, Inclusion, and Accessibility Cancer Discov. (IF 28.2) Pub Date : 2024-04-11 Rachel Martini, Endale Gebregzabher, Lisa Newman, Melissa B. Davis
Summary: In order to accurately detect and prevent racial disparities, self-reported race (SRR) and ethnicity remain valuable tools; however, inaccurate capture of patient identity and broad aggregation of minoritized race groups present challenges for data interpretation. Also, although SRR is a proxy for shared social/cultural experience, it is not an accurate representation of shared endogenous
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Epigenetic Control of Cancer Cell Dormancy and Awakening in Endocrine Therapy Resistance Cancer Discov. (IF 28.2) Pub Date : 2024-04-10 Arnau Llinas-Bertran, Meritxell Bellet-Ezquerra, Jose A. Seoane
Summary: Rosano, Sofyali, Dhiman, and colleagues show that epigenetic-related changes occur in endocrine therapy (ET)-induced dormancy in estrogen receptor positive (ER+) breast cancer, as well as in its reawakening. Targeting these epigenetic changes blocks the entrance to dormancy and reduces the persister cancer cell population, enhancing the cytotoxic effects of ET in vitro. See related article
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Artificial Intelligence in Oncology: Current Landscape, Challenges, and Future Directions Cancer Discov. (IF 28.2) Pub Date : 2024-04-10 William Lotter, Michael J. Hassett, Nikolaus Schultz, Kenneth L. Kehl, Eliezer M. Van Allen, Ethan Cerami
Artificial intelligence (AI) in oncology is advancing beyond algorithm development to integration into clinical practice. This review describes the current state of the field, with a specific focus on clinical integration. AI applications are structured according to cancer type and clinical domain, focusing on the four most common cancers and tasks of detection, diagnosis, and treatment. These applications
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ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-04-09 Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjostrom, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A. Johnson, Xiang Li, Xiaoling Li, Lauren A. Metang, Atreyi Mukherji, Quanhui Xu, Carla Rodriguez. Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B. Hanker, Ganesh V. Raj, Guanghui Zhu, Housheng Hansen. He, Zhao
Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide
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Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers Cancer Discov. (IF 28.2) Pub Date : 2024-04-09 Jingjing Jiang, Lingyan Jiang, Benjamin J. Maldonato, Yingyun Wang, Matthew Holderfield, Ida Aronchik, Ian P. Winters, Zeena Salman, Cristina Blaj, Marie Menard, Jens Brodbeck, Zhe Chen, Xing Wei, Michael J. Rosen, Yevgeniy Gindin, Bianca J. Lee, James W. Evans, Stephanie Chang, Zhican Wang, Kyle J. Seamon, Dylan Parsons, James Cregg, Abby Marquez, Aidan C.A. Tomlinson, Jason K. Yano, John E. Knox
RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations
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St. Jude Survivorship Portal: sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors Cancer Discov. (IF 28.2) Pub Date : 2024-04-09 Gavriel Y. Matt, Edgar Sioson, Kyla Shelton, Jian Wang, Congyu Lu, Airen Zaldivar Peraza, Karishma Gangwani, Robin Paul, Colleen Reilly, Aleksandar Acić, Qi Liu, Stephanie R. Sandor, Clay McLeod, Jaimin Patel, Fan Wang, Cindy Im, Zhaoming Wang, Yadav Sapkota, Carmen L. Wilson, Nickhill Bhakta, Kirsten K. Ness, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Jinghui Zhang, Yutaka Yasui,
Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. Over 1,600 phenotypic variables and
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Metabolic Signaling in Cancer Metastasis Cancer Discov. (IF 28.2) Pub Date : 2024-04-09 Sarah Krieg, Sara Isabel Fernandes, Constantinos Kolliopoulos, Ming Liu, Sarah-Maria Fendt
Metastases, which are the leading cause of death in patients with cancer, have metabolic vulnerabilities. Alterations in metabolism fuel the energy and biosynthetic needs of metastases but are also needed to activate cell state switches in cells leading to invasion, migration, colonization, and outgrowth in distant organs. Specifically, metabolites can activate protein kinases as well as receptors
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Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells. Cancer Discov. (IF 28.2) Pub Date : 2024-04-08 Gabriele Picco, Yanhua Rao, Angham Al Saedi, Yang Lee, Sara F. Vieira, Shriram Bhosle, Kieron May, Carmen Herranz-Ors, Samantha J. Walker, Raynold Shenje, Cansu Dincer, Freddy Gibson, Ruby Banerjee, Zoe Hewitson, Thilo Werner, Joshua E. Cottom, Yang Peng, Nanhua Deng, Philip Landis, Daniela Conticelli, Katrina McCarten, Jacob Bush, Mamta Sharma, Howard Lightfoot, David House, Emma Milford, Emma K.
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening
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Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-04-08 Rona Yaeger, Nataliya V. Uboha, Meredith S. Pelster, Tanios S. Bekaii-Saab, Minal Barve, Joel Saltzman, Joshua K. Sabari, Julio A. Peguero, Andrew Scott Paulson, Pasi A. Jänne, Marcia Cruz-Correa, Kenna Anderes, Karen Velastegui, Xiaohong Yan, Hirak Der-Torossian, Samuel J. Klempner, Scott E. Kopetz
Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective
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Insights and Opportunity Costs in Applying Spatial Biology to Study the Tumor Microenvironment Cancer Discov. (IF 28.2) Pub Date : 2024-04-08 Cameron R. Walker, Michael Angelo
Summary: The recent development of high-dimensional spatial omics tools has revealed the functional importance of the tumor microenvironment in driving tumor progression. Here, we discuss practical factors to consider when designing a spatial biology cohort and offer perspectives on the future of spatial biology research.
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The pan-RAF-MEK non degrading molecular glue NST-628 is a potent and brain penetrant inhibitor of the RAS-MAPK pathway with activity across diverse RAS- and RAF-driven cancers Cancer Discov. (IF 28.2) Pub Date : 2024-04-08 Meagan B. Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E. Cohen, Brooke M. Swalm, Chun Li, Aysegul Ozen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C. Dar, Yongxin Han, Klaus P. Hoeflich, Michael Hale, Margit Hagel
Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK
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Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity Cancer Discov. (IF 28.2) Pub Date : 2024-04-08 Isabella C. Glitza, Yongwoo David Seo, Christine N. Spencer, Jennifer R. Wortman, Elizabeth M. Burton, Farah A. Alayli, Christopher P. Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R. Cabanski, Matthew C. Wong, Christine B. Peterson, Brian Weiner, Nathan Hicks, John G. Auniņš, Christopher McChalicher, Emily Walsh, Michael T. Tetzlaff, Omid Hamid, Patrick A. Ott,
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutes-enriched spore formulation. Fecal microbiota
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CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma Cancer Discov. (IF 28.2) Pub Date : 2024-04-07 Sumanta K. Pal, Ben Tran, John B.A.G. Haanen, Michael E. Hurwitz, Adrian Sacher, Nizar M. Tannir, Lihua E. Budde, Simon J. Harrison, Sebastian Klobuch, Sagar S. Patel, Luis Meza, Mary-Lee Dequeant, Anna Ma, Qiuling Ally He, Leah M. Williams, Alissa Keegan, Ellen B. Gurary, Henia Dar, Sushant Karnik, Changan Guo, Heidi Heath, Rachel R. Yuen, Phuong K. Morrow, Neeraj Agarwal, Samer A. Srour
Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely
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Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-04-06 Katey S. S. Enfield, Emma Colliver, Claudia S Y. Lee, Alastair Magness, David A. Moore, Monica Sivakumar, Kristiana Grigoriadis, Oriol Pich, Takahiro Karasaki, Philip S. Hobson, Dina Levi, Selvaraju Veeriah, Clare Puttick, Emma L. Nye, Mary Green, Krijn K. Dijkstra, Masako Shimato, Ayse U. Akarca, Teresa Marafioti, Roberto Salgado, Allan Hackshaw, TRACERx Consortium, Mariam Jamal-Hanjani, Febe van
Understanding the role of the tumour microenvironment (TME) in lung cancer is critical to improving patient outcome. We identified four histology-independent archetype TMEs in treatment-naive early-stage lung cancer using imaging mass cytometry in the TRACERx study (n=81 patients/198 samples/2.3million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal
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A Molecular Voyage: Multiomics Insights into Circulating Tumor Cells Cancer Discov. (IF 28.2) Pub Date : 2024-04-06 Yu Wei Zhang, Ana Gvozdenovic, Nicola Aceto
Circulating tumor cells (CTCs) play a pivotal role in metastasis, the leading cause of cancer-associated death. Recent improvements of CTC isolation tools, coupled with a steady development of multiomics technologies at single-cell resolution, have enabled an extensive exploration of CTC biology, unlocking insights into their molecular profiles. A detailed molecular portrait requires CTC interrogation
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Cell States in Cancer: Drivers, Passengers, and Trailers Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Gaetano Gargiulo, Michela Serresi, Jean-Christophe Marine
Summary: Cancer is traditionally perceived through a genetic lens, with therapeutic strategies targeting oncogenic driver mutations. We advocate an overarching framework recognizing tumors as comprising driver, passenger, and trailer cell states: Tailoring therapies to simultaneously target driver genetics and cell states may enhance effectiveness and durability.
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Phase-Separated Biomolecular Condensation in Cancer: New Horizons and Next Frontiers Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Trever G. Bivona
Summary: Beyond lipid membrane compartments, cells including cancer cells utilize various membraneless compartments, often termed biomolecular condensates, to regulate or organize key cellular processes underlying physiologic or pathologic phenotypes. In this commentary, the emergence of biomolecular condensation in cancer biology is highlighted, with a focus on key unanswered questions and with implications
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From Base Pairs to City Squares: Comprehensive Precision Oncology for the Future Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Amy E. Leader, Christopher M. McNair, Jennifer M. Johnson
Summary: An increased understanding of the role of the social determinants of health in cancer prevention, cancer care, and outcomes can lead to their integration into genetics and genomics as well as informing interventions and clinical trials, creating a comprehensive precision oncology framework.
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Advancing Cancer Interception Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Susan M. Domchek, Robert H. Vonderheide
Summary: Rapid advances in technology and therapeutics, along with better methods to discern who is at risk for cancer by genetic testing and other means, has enabled the development of cancer interception. Targeted therapies and “immuno-interception” may eliminate premalignant lesions and require clinical trial and treatment paradigms altogether distinct from current approaches.
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Targeting Senescence for Next-Generation Cancer Treatments Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Eric Gilson, Pierre Soubeyran, Eric Solary
Summary: Cellular senescence has paradoxical effects on cancer emergence, progression, and therapeutic response. We herein identify four lessons that emerged from studying senescence interaction with cancer and emphasize four bottlenecks in the therapeutic manipulation of cellular senescence to prevent or cure cancer.
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Accelerating Drug Development Using Spatial Multi-omics Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Richard J.A. Goodwin, Stefan J. Platz, Jorge S. Reis-Filho, Simon T. Barry
Summary: Spatial biology approaches enabled by innovations in imaging biomarker platforms and artificial intelligence–enabled data integration and analysis provide an assessment of patient and disease heterogeneity at ever-increasing resolution. The utility of spatial biology data in accelerating drug programs, however, requires balancing exploratory discovery investigations against scalable and clinically
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Next Directions in the Neuroscience of Cancers Arising outside the CNS Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Moran Amit, Corina Anastasaki, Robert Dantzer, Ihsan Ekin Demir, Benjamin Deneen, Karen O. Dixon, Mikala Egeblad, Erin M. Gibson, Shawn L. Hervey-Jumper, Hubert Hondermarck, Claire Magnon, Michelle Monje, Shorook Na'ara, Yuan Pan, Elizabeth A. Repasky, Nicole N. Scheff, Erica K. Sloan, Sebastien Talbot, Kevin J. Tracey, Lloyd C. Trotman, Manuel Valiente, Linda Van Aelst, Varun Venkataramani, Humsa
Summary: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.
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Radical Collaboration: Reimagining Cancer Team Science Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Jesse S. Boehm, Tyler Jacks
Summary: Here, we define a future of cancer team science adopting “radical collaboration”—in which six “Hallmarks of Cancer Collaboration” are utilized to propel cancer teams to reach new levels of productivity and impact in the modern era. This commentary establishes a playbook for cancer team science that can be readily adopted by others.
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Pushing the Boundaries of Liquid Biopsies for Early Precision Intervention Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Valsamo Anagnostou, Victor E. Velculescu
Summary: Liquid biopsies are emerging as powerful minimally invasive approaches that have the potential to solve several long-standing problems spanning the continuum of cancer care: early detection of cancer, minimal residual disease tracking, and refinement of the heterogeneity of clinical responses together with therapeutic response monitoring in the metastatic setting. Existing challenges driven
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A Vision for Democratizing Next-Generation Oncology Clinical Trials Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Vivek Subbiah, Denis Horgan, Ishwaria M. Subbiah
Summary: Revolutionary advancements in oncology have transformed lives, but the clinical trials ecosystem encounters challenges, including restricted access to innovative therapies and a lack of diversity in participant representation. A vision emerges for democratized, globally accessible oncology trials, necessitating collaboration among researchers, clinicians, patients, and policymakers to shift
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Precision Endpoints for Contemporary Precision Oncology Trials Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Regina Hoo, Kevin L.M. Chua, Pankaj Kumar Panda, Anders J. Skanderup, Daniel S.W. Tan
Summary: Traditional endpoints such as progression-free survival and overall survival do not fully capture the pharmacologic and pharmacodynamic effects of a therapeutic intervention. Incorporating mechanism-driven biomarkers and validated surrogate proximal endpoints can provide orthogonal readouts of anti-tumor activity and delineate the relative contribution of treatment components on an individual
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The Virtual Child Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Richard J. Gilbertson, Sam Behjati, Anna-Lisa Böttcher, Marianne E. Bronner, Matthew Burridge, Henrick Clausing, Harry Clifford, Tracey Danaher, Laura K. Donovan, Jarno Drost, Alexander M.M. Eggermont, Chris Emerson, Mona G. Flores, Petra Hamerlik, Nada Jabado, Andrew Jones, Henrick Kaessmann, Claudia L. Kleinman, Marcel Kool, Lena M. Kutscher, Gavin Lindberg, Emily Linnane, John C. Marioni, John M
Summary: We are building the world's first Virtual Child–a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will “develop cancer” that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity
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Glioblastoma: Not Just Another Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Howard A. Fine
Summary: This commentary urges a paradigm shift in how we approach research and drug development for glioblastoma, reimagining it as an aberrant brain-like organ, distinct from other cancers, to inspire innovative treatment strategies and interdisciplinary collaboration, addressing the minimal progress in extending glioblastoma patient survival despite years of research and investment.
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The Cancer Spectrum Theory Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Hwa-Young Lee, Minkyo Song, Konrad H. Stopsack, Cheng Peng, Amanda I. Phipps, Molin Wang, Shuji Ogino, Naoko Sasamoto, Tomotaka Ugai
Summary: Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed
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Cancer and the Metaorganism Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Laurence Zitvogel, Guido Kroemer
Summary: Pathogenic shifts in the gut microbiota are part of the “ecological” alterations that accompany tumor progression and compromise immunosurveillance. The future management of health and disease including cancer will rely on the diagnosis of such shifts and their therapeutic correction by general or personalized strategies, hence restoring metaorganismal homeostasis.
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Using the National Cancer Plan to Drive Innovation in Cancer Research Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 W. Kimryn Rathmell
Summary: The NCI director presents her vision of the National Cancer Plan as an integrated framework that can help drive innovation in cancer research to speed progress toward ending cancer as we know it.
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The Biden Cancer Moonshot: American Progress, Global Commitment Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Catharine G. Young, Danielle M. Carnival
Summary: The Biden Cancer Moonshot is mobilizing efforts toward achieving two clear goals that President Joe Biden and First Lady Jill Biden set: prevent more than 4 million cancer deaths by 2047 and improve the experience of people who are touched by cancer. To achieve these ambitious but achievable goals, the Biden Cancer Moonshot is driving progress across the cancer journey utilizing all facets
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Tumor–Host Cometabolism Collaborates to Shape Cancer Immunity Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Yingcheng Wu, Qiang Zou, Peng Jiang, Qiang Gao
Summary: Nutrients are essential for supporting tumor growth and immune cell function in the tumor microenvironment, but emerging evidence reveals a paradoxical competition and collaboration between the metabolic demands of proliferating cancer cells and immune cell activation. Dietary interventions and metabolic immunoengineering offer promise to selectively modulate cancer and immune cell metabolism
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The Hallmarks of Precancer Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Mary M. Stangis, Zhengyi Chen, Jimin Min, Sarah E. Glass, Jordan O. Jackson, Megan D. Radyk, Xen Ping Hoi, W. Nathaniel Brennen, Ming Yu, Huy Q. Dinh, Robert J. Coffey, Martha J. Shrubsole, Keith S. Chan, William M. Grady, Srinivasan Yegnasubramanian, Costas A. Lyssiotis, Anirban Maitra, Richard B. Halberg, Neelendu Dey, Ken S. Lau
Summary: Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions
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Immunogenetic Diversity and Cancer Immunotherapy Disparities Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Noel F.C.C. de Miranda, Ferenc A. Scheeren
Summary: The success of checkpoint blockade cancer immunotherapies has unequivocally confirmed the critical role of T cells in cancer immunity and boosted the development of immunotherapeutic strategies targeting specific antigens on cancer cells. The vast immunogenetic diversity of human leukocyte antigen (HLA) class I alleles across populations is a key factor influencing the advancement of HLA class
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Somatic Mutations in Normal Tissues: Calm before the Storm Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Zahraa Rahal, Paul Scheet, Humam Kadara
Summary: We explore the phenomenon of somatic mutations, including those in cancer driver genes, that are present in healthy, normal-appearing tissues and their potential implications for cancer development. We also examine the landscape of these somatic mutations, discuss the role of clonal cell competition and external factors like inflammation in enhancing the fitness of mutant clones, and conclude
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Elucidating the Cell Surfaceome to Accelerate Cancer Drug Development Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Jacob B. Geri, William Pao
Summary: Cell surface proteins represent ideal therapeutic targets because of their accessibility to antibodies, T cell–directed therapies, and radiotherapies, but there are only 25 therapeutically relevant cell surface targets for which cancer therapies are approved in the United States or European Union. This commentary calls for intensified research into mapping the universe of cell surface proteins
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The 3D Revolution in Cancer Discovery Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Linghua Wang, Mingyao Li, Tae Hyun Hwang
Summary: The transition from 2D to 3D spatial profiling marks a revolutionary era in cancer research, offering unprecedented potential to enhance cancer diagnosis and treatment. This commentary outlines the experimental and computational advancements and challenges in 3D spatial molecular profiling, underscoring the innovation needed in imaging tools, software, artificial intelligence, and machine
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A Proposed Framework and Lexicon for Cancer Prevention Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Philip E. Castle, Jessica M. Faupel-Badger, Asad Umar, Timothy R. Rebbeck
Summary: Cancer prevention is central to efforts to control the burden of cancer. We propose a new terminology framework to help guide these efforts and promote a key equity principle: “equal care for equal risk.”
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Chemotherapy and the Extra-Tumor Immune Microenvironment: EXTRA-TIME Cancer Discov. (IF 28.2) Pub Date : 2024-04-04 Tri Giang Phan, Katherine N. Weilbaecher, Rebecca Aft, Peter I. Croucher, Christine L. Chaffer
Summary: Understandably, conventional therapeutic strategies have focused on controlling primary tumors. We ask whether the cost of such strategies is actually an increased likelihood of metastatic relapse.
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Lifileucel, an Autologous Tumor-infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non-small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors Cancer Discov. (IF 28.2) Pub Date : 2024-04-02 Adam J. Schoenfeld, Sylvia M. Lee, Bernard Doger de Speville, Scott N. Gettinger, Simon Hafliger, Ammar Sukari, Sophie Papa, Juan Francisco. Rodriguez-Moreno, Friedrich Graf Finckenstein, Rana Fiaz, Melissa Catlett, Guang Chen, Rongsu Qi, Emma L. Masteller, Viktoria Gontcharova, Kai He
In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1–6). Lifileucel was successfully manufactured
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IL-2 targeted to CD8+ T cells promotes robust effector T cell responses and potent antitumor immunity Cancer Discov. (IF 28.2) Pub Date : 2024-04-02 Kelly D. Moynihan, Manu P. Kumar, Hussein Sultan, Danielle C. Pappas, Terrence Park, S. Michael Chin, Paul Bessette, Ruth Y. Lan, Henry C. Nguyen, Nathan D. Mathewson, Irene Ni, Wei Chen, Yonghee Lee, Sindy Liao-Chan, Jessie Chen, Ton N.M. Schumacher, Robert D. Schreiber, Yik A. Yeung, Ivana M. Djuretic
IL-2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, while others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL-2 to CD8+ T cells, which are key anti-tumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, CD8 cis-targeted IL-2 that demonstrates
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Activating point mutations in the MET kinase domain represent a unique molecular subset of lung cancer and other malignancies targetable with MET inhibitors Cancer Discov. (IF 28.2) Pub Date : 2024-04-02 Federica Pecci, Seshiru Nakazawa, Biagio Ricciuti, Guilherme Harada, Jessica K. Lee, Joao V. Alessi, Adriana Barrichello, Victor R. Vaz, Giuseppe Lamberti, Alessandro Di Federico, Malini M. Gandhi, Dimitris Gazgalis, William W. Feng, Jie Jiang, Simon Baldacci, Marie-Anais Locquet, Felix H. Gottlieb, Monica F. Chen, Elinton Lee, Danielle Haradon, Anna Smokovich, Emma Voligny, Tom Nguyen, Vikas K. Goel
Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely
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CD8-targeted IL2 unleashes tumor-specific immunity in human cancer tissue by reviving the dysfunctional T cell pool Cancer Discov. (IF 28.2) Pub Date : 2024-04-02 Paulien Kaptein, Nadine Slingerland, Christina Metoikidou, Felix Prinz, Simone Brokamp, Mercedes Machuca-Ostos, Guido de Roo, Ton N.M. Schumacher, Yik A. Yeung, Kelly D. Moynihan, Ivana M. Djuretic, Daniela S. Thommen
Tumor-specific CD8+ T cells are key effectors of antitumor immunity but are often rendered dysfunctional in the tumor microenvironment. Immune checkpoint blockade can restore antitumor T cell function in some patients, however most do not respond to this therapy, often despite T cell infiltration in their tumors. We here explored a CD8-targeted IL2 fusion molecule (CD8-IL2) to selectively reactivate
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Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2 Cancer Discov. (IF 28.2) Pub Date : 2024-04-02 Lishu Chen, Qinghui Qi, Xiaoqing Jiang, Jin Wu, Yuanyuan Li, Zhaodan Liu, Yan Cai, Haowen Ran, Songyang Zhang, Cheng Zhang, Huiran Wu, Shuailiang Cao, Lanjuan Mi, Dake Xiao, Haohao Huang, Shuai Jiang, Jiaqi Wu, Bohan Li, Jiong Xie, Ji Qi, Fangye Li, Panpan Liang, Qiuying Han, Min Wu, Wenchao Zhou, Chenhui Wang, Weina Zhang, Xin Jiang, Kun Zhang, Huiyan Li, Xuemin Zhang, Ailing Li, Tao Zhou, Jianghong
Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells (GSCs) reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase (CKB), mediated by Zinc finger
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Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-03-29 Magdalena Matusiak, John W. Hickey, David G.P. van IJzendoorn, Guolan Lu, Lukasz Kidzinski, Shirley Zhu, Deana R.C. Colburg, Bogdan Luca, Darci J. Phillips, Sky W. Brubaker, Gregory W. Charville, Jeanne Shen, Kyle M. Loh, Derick K. Okwan-Duodu, Garry P. Nolan, Aaron M. Newman, Robert B. West, Matt van de Rijn
Tumor-associated macrophages are transcriptionally heterogeneous, but the spatial distribution and cell interactions that shape macrophage tissue roles remain poorly characterized. Here, we spatially resolve five distinct human macrophage populations in normal and malignant human breast and colon tissue and reveal their cellular associations. This spatial map reveals that distinct macrophage populations
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BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers Cancer Discov. (IF 28.2) Pub Date : 2024-03-29 Guang Lei, Chao Mao, Amber D. Horbath, Yuelong Yan, Shirong Cai, Jun Yao, Yan Jiang, Mingchuang Sun, Xiaoguang Liu, Jun Cheng, Zhihao Xu, Hyemin Lee, Qidong Li, Zhengze Lu, Li Zhuang, Mei-Kuang Chen, Anagha Alapati, Timothy A. Yap, Mien-Chie Hung, M. James You, Helen Piwnica-Worms, Boyi Gan
Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency
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Paradoxical activation of oncogenic signaling as a cancer treatment strategy Cancer Discov. (IF 28.2) Pub Date : 2024-03-27 Matheus Henrique. Dias, Anoek Friskes, Siying Wang, Joao M. Fernandes Neto, Frank van Gemert, Soufiane Mourragui, Chrysa Papagianni, Hendrik J. Kuiken, Sara Mainardi, Daniel Alvarez-Villanueva, Cor Lieftink, Ben Morris, Anna Dekker, Emma van Dijk, Lieke H.S. Wilms, Marcelo S. da Silva, Robin A. Jansen, Antonio Mulero-Sanchez, Elke Malzer, August Vidal, Cristina Santos, Ramon Salazar, Rosangela A.M
Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause
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Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues Cancer Discov. (IF 28.2) Pub Date : 2024-03-19 Mònica Sánchez-Guixé, Ferran Muiños, Morena Pinheiro-Santin, Víctor González-Huici, Carlos J. Rodriguez-Hernandez, Alexandra Avgustinova, Cinzia Lavarino, Abel González-Pérez, Jaume Mora, Núria López-Bigas
Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and, through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different
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Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations Cancer Discov. (IF 28.2) Pub Date : 2024-03-08 Azadeh C. Bashi, Elizabeth A. Coker, Krishna C. Bulusu, Patricia Jaaks, Claire Crafter, Howard Lightfoot, Marta Milo, Katrina McCarten, David F. Jenkins, Dieudonne van der Meer, James T. Lynch, Syd Barthorpe, Courtney L. Andersen, Simon T. Barry, Alexandra Beck, Justin Cidado, Jacob A. Gordon, Caitlin Hall, James Hall, Iman Mali, Tatiana Mironenko, Kevin Mongeon, James Morris, Laura Richardson, Paul
Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio
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Single-cell chromatin accessibility analysis reveals the epigenetic basis and signature transcription factors for the molecular subtypes of colorectal cancers Cancer Discov. (IF 28.2) Pub Date : 2024-03-06 Zhenyu Liu, Yuqiong Hu, Haoling Xie, Kexuan Chen, Lu Wen, Wei Fu, Xin Zhou, Fuchou Tang
Colorectal cancer (CRC) is a highly heterogeneous disease, with well-characterized subtypes based on genome, DNA methylome, and transcriptome signatures. To chart the epigenetic landscape of CRCs, we generated a high-quality single-cell chromatin accessibility atlas of epithelial cells for 29 patients. Abnormal chromatin states acquired in adenomas were largely retained in CRCs, which were tightly
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Introducing Five New Cancer Grand Challenges Teams Cancer Discov. (IF 28.2) Pub Date : 2024-03-06 David Scott, Dinah S. Singer
Summary: Cancer Grand Challenges is an international funding initiative that aims to unite the world’s best scientists to tackle some of cancer’s toughest problems by funding team science on a global scale. Here, we discuss the five newly funded teams and the challenges they will address over the coming years.
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Targeting the DHX9 RNA Helicase to Induce Antitumor Immunity in Small-Cell Lung Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-03-01 Katherine B. Chiappinelli
Summary: Murayama and colleagues establish DHX9 as an exciting new target to induce viral mimicry and downstream antitumor immunity. The potential for use in combination with existing immune therapies is especially exciting in SCLC, an immunologically cold and deadly disease. See related article by Murayama et al., p. 468 (10) .
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Combining TIGIT blockage with MDSC inhibition hinders breast cancer bone metastasis by activating anti-tumor immunity Cancer Discov. (IF 28.2) Pub Date : 2024-03-01 Lea Monteran, Nour Ershaid, Ye'ela Scharff, Yazeed Zoabi, Tamer Sanalla, Yunfeng Ding, Anna Pavlovsky, Yael Zait, Marva Langer, Tal Caller, Anat Eldar-Boock, Camila Avivi, Amir Sonnenblick, Ronit Satchi-Fainaro, Iris Barshack, Noam Shomron, Xiang H.-F. Zhang, Neta Erez
Bone is the most common site of breast cancer metastasis. Bone metastasis are incurable and are associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show
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Biodiversity Medicine: New Horizon and New Opportunity for Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-03-01 Jing Han Hong, Abner Herbert Lim, Khwanta Kaewnarin, Jason Yongsheng Chan, Cedric Chuan Young Ng, Bin Tean Teh
Summary: Accessibility to standard of care remains a challenge to patients in low- and middle-income countries (LMIC), hampering efforts to alleviate the burden of cancer and to improve overall health outcomes. In response to this pressing global health care issue, we propose here a new strategy to create affordable, easily accessible, and effective therapeutic solutions to address this inequity in
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Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene–Environment Interactions Cancer Discov. (IF 28.2) Pub Date : 2024-03-01 Cesar Cobaleda, Lucy A. Godley, Kim E. Nichols, Marcin W. Wlodarski, Isidro Sanchez-Garcia
Summary: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions
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A Highly Anticipated Selective Therapeutic Agent against CDK2: INX-315 Cancer Discov. (IF 28.2) Pub Date : 2024-03-01 Lotte P. Watts, Sabrina L. Spencer
Summary: In this issue, Dietrich, Trub, and colleagues describe and characterize a novel selective CDK2 inhibitor: INX-315. This agent shows promise in CCNE1-amplified cancers and in CDK4/6 inhibitor–resistant breast cancers. See related article by Dietrich et al., p. 446 (8).
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Glioblastoma-infiltrating CD8+ T cells are predominantly a clonally expanded GZMK+ effector population Cancer Discov. (IF 28.2) Pub Date : 2024-02-28 Anthony Z. Wang, Bryce L. Mashimo, Maximilian O. Schaettler, Ngima D. Sherpa, Lydia A. Leavitt, Alexandra J. Livingstone, Saad M. Khan, Mao Li, Markus I. Anzaldua-Campos, Joseph D. Bradley, Eric C. Leuthardt, Albert H. Kim, Joshua L. Dowling, Michael R. Chicoine, Pamela S. Jones, Bryan D. Choi, Daniel P. Cahill, Bob S. Carter, Allegra A. Petti, Tanner M. Johanns, Gavin P. Dunn
Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) with paired V(D)J sequencing, respectively, on TIL from
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Deep Learning Model for Tumor Type Prediction using Targeted Clinical Genomic Sequencing Data Cancer Discov. (IF 28.2) Pub Date : 2024-02-28 Madison Darmofal, Shalabh Suman, Gurnit Atwal, Michael Toomey, Jie-Fu Chen, Jason C. Chang, Efsevia Vakiani, Anna M. Varghese, Anoop Balakrishnan Rema, Aijazuddin Syed, Nikolaus Schultz, Michael F. Berger, Quaid Morris
Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole genome sequencing (WGS), or predicting across limited cancer types
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Early changes in tumor-naive cell-free methylomes and fragmentomes predict outcomes in pembrolizumab-treated solid tumors Cancer Discov. (IF 28.2) Pub Date : 2024-02-23 Eric Y. Stutheit-Zhao, Enrique Sanz-Garcia, Zhihui (Amy) Liu, Derek Wong, Kayla Marsh, Albiruni R. Abdul Razak, Anna Spreafico, Philippe L. Bedard, Aaron R. Hansen, Stephanie Lheureux, Dax Torti, Bernard Lam, Shih Yu Cindy Yang, Justin Burgener, Ping Luo, Yong Zeng, Nicholas Cheng, Philip Awadalla, Scott V. Bratman, Pamela S. Ohashi, Trevor J. Pugh, Lillian L. Siu
Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab, but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab