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Survivin promotes stem cell competence for skin cancer initiation Cancer Discov. (IF 29.7) Pub Date : 2024-11-11 Sara Canato, Rahul Sarate, Sofia Carvalho-Marques, Raquel Maia Soares, Yura Song, Sara Monteiro-Ferreira, Pauline Vieugué, Mélanie Liagre, Giancarlo Grossi, Erik Cardoso, Christine Dubois, Edward M. Conway, Silvia Schenone, Adriana Sanchez-Danes, Cedric Blanpain
Stem cells (SCs) and not progenitors (Ps) act as cells of origin of Basal Cell Carcinoma (BCC). The mechanisms promoting BCC formation in SCs or restricting tumour development in Ps are currently unknown. In this study, we transcriptionally profiled SCs and Ps and found that Survivin, a pleiotropic factor that promotes cell division and inhibits apoptosis was preferentially expressed in SCs. Using
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Sympathetic Neurons Promote Small Cell Lung Cancer Through the Beta-2 Adrenergic Receptor Cancer Discov. (IF 29.7) Pub Date : 2024-11-08 Tala FNU, Peiguo Shi, Wanwei Zhang, Sanny S.W. Chung, Christopher B. Damoci, Yinshan Fang, Qi-Yue Chen, Anjali Saqi, Yuefeng Huang, Xuebing Wu, Chao Lu, Dian Yang, Timothy C. Wang, Jianwen Que
The vagal nerve is linked to tumorigenesis in multiple tissues including small cell lung cancer (SCLC). However, the role of sympathetic neuron in SCLC development remains unknown. Here, we observed a significant reduction in tumor growth following chemical denervation of local sympathetic nerves in a mouse model of SCLC. Further study identified that β2-adrenergic receptor (ADRB2) on cancer cells
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Drugging p53: Barriers, Criteria, and Prospects Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Huaxin Song, Shujun Xiao, Jiaqi Wu, Min Lu
Summary: Pharmacologically targeting tumor suppressors necessitates an unprecedented strategy of restoring, rather than conventionally inhibiting, protein function, and p53, the most commonly mutated protein in cancer, has thus remained undruggable. In this study, we address long-standing misconceptions in the field and gaps in the scientific logic for a p53 function–restoration strategy, identify
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Immunogenicity and Efficacy of Personalized Adjuvant mRNA Cancer Vaccines Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Pedro Berraondo, Raquel Cuesta, Miguel F. Sanmamed, Ignacio Melero
Summary: In this issue, Gainor and colleagues report on the immunogenicity of personalized neoantigen-encoding mRNA vaccines that elicit measurable polyfunctional CD8+ and CD4+ T-cell responses in patients whose tumors have been resected. Reactivity is substantiated to 20% to 30% of the predicted MHC-I and MHC-II epitopes in four patients with NSCLC postsurgically treated with the vaccine alone and
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Redefining the Gastric Microbes in Promoting Gastric Tumorigenesis: The Rise of the Non–H. pylori Microbiome Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Chi Chun Wong, Jun Yu
Summary: Gastric cancer remains one of the top cancers in China compared with Western countries, mainly attributed to the high rates of Helicobacter pylori infection. However, recent discoveries on the non–H. pylori gastric microbiome have led to a paradigm shift in our understanding of microbial risk factors driving gastric cancer, which will impact future screening and prevention strategies.
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Building an Organ-Wide Macroscopic View of Cancer Hallmarks Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Suling Liu, Yuan Wang, Jiawen Feng, Zhihua Liu, Shengtao Zhou
Summary: Despite an increasingly detailed understanding of cancer hallmarks at molecular or atomic resolution, most studies, however, fall short of investigating the systemic interactions of cancer with the human body. We propose to investigate the hallmarks of cancer from an organ-wide macroscopic view, discuss the challenges in preclinical and clinical research to study the cross-organ regulation
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Early Cancer Detection Through Comprehensive Mapping of Dynamic Tumorigenesis Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Jiang Chang, Tongsen Zheng, Chen Wu
Summary: Current strategies for early cancer detection and diagnosis need updating to achieve greater precision, necessitating the creation of a comprehensive evolutionary map of tumorigenesis. This requires establishing high-quality prospective cohorts, systematically collecting samples for integrated spatiotemporal multiomics analyses, and efficiently translating laboratory findings into clinical
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Advancing Cancer Prevention through an AI-Based Integration of Traditional and Western Medicine Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Peng Zhang, Qian Zhang, Shao Li
Summary: Traditional Chinese medicine has accumulated a wealth of experiences in individualized cancer prevention and serves as a complement to Western medicine. We propose an artificial intelligence–based integration of traditional and Western medicine as a new paradigm for cancer prevention, encompassing cancer risk screening and preventive intervention, which will provide new solutions for cancer
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Exploring the Interplay of Diet, Obesity, Immune Function, and Cancer Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Yumin Fu, Xinyu Guo, Linmao Sun, Tianming Cui, Jiabei Wang, Yao Liu, Lianxin Liu
Summary: This commentary provides an in-depth exploration of the intricate relationships among diet, obesity, immune function, and cancer, highlighting the potential role of dietary interventions as complementary therapies in cancer treatment. Multiple analyses underscore the importance of personalized dietary strategies in cancer management and identify opportunities for further research in this evolving
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The Far Side of Resistance to RAS Inhibitors Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Michelangelo Marasco, Sandra Misale
Summary: In this issue, four articles highlight the critical role of nongenetic mechanisms and cell plasticity in mediating resistance to different classes of RAS inhibitors in pancreatic ductal adenocarcinoma and non–small cell lung cancer. See related article by Benitz et al., p. 2162 See related article by Dilly et al., p. 2135 See related article by Araujo et al., p. 2183 See related article by
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Beneath the Surface: Neoantigens beyond Chromosomal DNA Mutations Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Shicheng Su
Summary: The conventional wisdom is that the overwhelming majority of neoantigens arise from chromosomal DNA mutations; however, recent studies show that posttranscriptional and posttranslational events can also generate neoantigens. This commentary provides an overview of known and potential sources of nonchromosomal neoantigens, emerging technologies, and clinical trials that may move this field
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Combination Diagnostics: Adding Blood-Based ctDNA Screening to Low-Dose CT Imaging for Early Detection of Lung Cancer Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Daniel A. Haber, Steven J. Skates
Summary: Annual low-dose CT screening of individuals with a smoking history identifies early curable lung tumors and reduces cancer mortality by 20%, yet only a minority of eligible patients undergo such monitoring. Mazzone and colleagues apply a blood-based cfDNA fragmentomic assay as a high-sensitivity/low-specificity pre-screen to help stratify individuals who may benefit most from more definitive
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Targeting Noncoding cis-Regulatory Elements for Cancer Therapy in the Context of the 3D Genome Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Kailong Li, Gong-Hong Wei, Yuxin Yin, Jiawen Feng
Summary: Significant efforts have been made to identify and validate oncoproteins and ncRNAs as therapeutic targets for cancer therapy; however, emerging observations suggest that noncoding cis-regulatory elements, which orchestrate the 3D organization of the genome and thus the transcriptional landscape, are potential therapeutic targets as well. In this commentary, we envisage that further efforts
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A Call for Innovative Translational and Clinical Research to Address China’s Unique Cancer Landscape Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Chaoqi Zhang, Peng Wu, Dongyu Li, Xuanyu Gu, Chuqi Lin, Junhan Zhou, Dexin Shang, Jingjing Liu, Ruijie Ma, Bohui Zhao, Nan Sun, Jie He
Summary: The Chinese government has, in recent decades, implemented various administrative laws and regulatory policies to expedite cancer therapeutic development, boosting research and development pipelines for domestic pharmaceutical companies and clinical trials; however, China faces unique challenges given the high prevalence of certain cancer types and distinct disease burdens, some of which are
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Highly Multiplexed Tissue Imaging in Precision Oncology and Translational Cancer Research Cancer Discov. (IF 29.7) Pub Date : 2024-11-01 Alina Bollhagen, Bernd Bodenmiller
Precision oncology tailors treatment strategies to a patient’s molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling
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Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma Cancer Discov. (IF 29.7) Pub Date : 2024-10-30 Megan E. Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A. Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A. Behrmann, Katherine E. Vest, James Brugarolas, Pier Paolo Scaglioni, David R. Plas, Krushna C. Patra, Shuchi Gulati, Julio A. Landero
Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell
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CTR-FAPI PET enables precision management of medullary thyroid carcinoma Cancer Discov. (IF 29.7) Pub Date : 2024-10-29 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
Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. 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
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Cancer Prevalence across Vertebrates Cancer Discov. (IF 29.7) Pub Date : 2024-10-24 Zachary T. Compton, Walker Mellon, Valerie K. Harris, Shawn Rupp, Diego Mallo, Stefania E. Kapsetaki, Mallory Wilmot, Ryan Kennington, Kathleen Noble, Cristina Baciu, Lucia N. Ramirez, Ashley Peraza, Brian Martins, Sushil Sudhakar, Selin Aksoy, Gabriela Furukawa, Orsolya Vincze, Mathieu Giraudeau, Elizabeth G. Duke, Simon Spiro, Edmund Flach, Hannah Davidson, Christopher I. Li, Ashley Zehnder, Trevor
Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto’s paradox) and somatic mutation rate but decreases with gestation
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The Journey of Antibody–Drug Conjugates: Lessons Learned from 40 Years of Development Cancer Discov. (IF 29.7) Pub Date : 2024-10-23 Raffaele Colombo, Paolo Tarantino, Jamie R. Rich, Patricia M. LoRusso, Elisabeth G.E. de Vries
Antibody–drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into
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The Evolutionary Forest of Pancreatic Cancer Cancer Discov. (IF 29.7) Pub Date : 2024-10-08 Katelyn M. Mullen, Jungeui Hong, Marc A. Attiyeh, Akimasa Hayashi, Hitomi Sakamoto, Zachary A. Kohutek, Caitlin A. McIntyre, Haochen Zhang, Alvin P. Makohon-Moore, Amanda Zucker, Laura D. Wood, Matthew A. Myers, Brian J. Arnold, Simone Zaccaria, Joanne F. Chou, Marinela Capanu, Nicholas D. Socci, Benjamin J. Raphael, Christine A. Iacobuzio-Donahue
The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the genome landscapes, phylogenies and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or the evolutionary timing that each mutation
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Glioblastoma-cortical organoids recapitulate cell state heterogeneity and intercellular transfer Cancer Discov. (IF 29.7) Pub Date : 2024-10-07 Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O. Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L. Suva
Glioblastoma is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. Here, we model this ecosystem by growing glioblastoma into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA-seq analysis suggests that, compared to matched gliomasphere models, glioblastoma
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The Epigenetic Hallmarks of Cancer Cancer Discov. (IF 29.7) Pub Date : 2024-10-04 Manel Esteller, Mark A. Dawson, Cigall Kadoch, Feyruz V. Rassool, Peter A. Jones, Stephen B. Baylin
Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, “nonmutational epigenetic reprogramming” was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and
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Transforming Cancer Research through Informatics Cancer Discov. (IF 29.7) Pub Date : 2024-10-04 Juli D. Klemm, Dinah S. Singer, Jill P. Mesirov
Summary: For more than three decades, concurrent advances in laboratory technologies and computer science have driven the rise of cancer informatics. Today, software tools for cancer research are indispensable to the entire cancer research enterprise.
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A New Era of Data-Driven Cancer Research and Care: Opportunities and Challenges Cancer Discov. (IF 29.7) Pub Date : 2024-10-04 Felicia Gomez, Arpad M. Danos, Guilherme Del Fiol, Anant Madabhushi, Pallavi Tiwari, Joshua F. McMichael, Spyridon Bakas, Jiang Bian, Christos Davatzikos, Elana J. Fertig, Jayashree Kalpathy-Cramer, Johanna Kenney, Guergana K. Savova, Meliha Yetisgen, Eliezer M. Van Allen, Jeremy L. Warner, Fred Prior, Malachi Griffith, Obi L. Griffith
Summary: People diagnosed with cancer and their formal and informal caregivers are increasingly faced with a deluge of complex information, thanks to rapid advancements in the type and volume of diagnostic, prognostic, and treatment data. This commentary discusses the opportunities and challenges that the society faces as we integrate large volumes of data into regular cancer care.
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Can Ruxolitinib Crash TET2- and IDH2-Driven Clonal Hematopoiesis? Cancer Discov. (IF 29.7) Pub Date : 2024-10-04 Elmira Khabusheva, Margaret A. Goodell
Summary: In this issue, Waarts and colleagues developed an advanced ex vivo CRISPR screening platform to identify vulnerabilities in clonal hematopoiesis (CH). This unique system allowed the authors to identify a link between IDH2 and TET2 CH mutations, histone demethylases, and altered cytokine signaling, which enabled targeting by ruxolitinib leading to the elimination of CH clones, offering a possible
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Cancer Genomes Sometimes Take the Longest Evolutionary Road Cancer Discov. (IF 29.7) Pub Date : 2024-10-04 Alison M. Taylor
Summary: Baker and colleagues developed a new algorithm called “Gain Route Identification and Timing In Cancer” (GRITIC) to uncover the path of chromosomal evolution in a tumor, particularly in the context of whole-genome duplication. Their approach found that tumors with genome doubling frequently take an indirect path from one copy number state to another. In addition, the timing of genome doubling
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Ironing Out the Kinks: Arming Natural Killer Cells against Ovarian Cancer Cancer Discov. (IF 29.7) Pub Date : 2024-10-04 Hannah Noelle Bell, Weiping Zou
Summary: Ameliorating the tumor immune microenvironment is a key strategy to improve the therapeutic outcomes of patients with cancer. Sandoval and colleagues demonstrate that iron chelation enhances type I IFN production, promotes NK cell tumor trafficking and activation, and synergizes with chemotherapy drug cisplatin to reduce metastatic ovarian cancer progression in murine models. See related article
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TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells. Cancer Discov. (IF 29.7) Pub Date : 2024-10-02 Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias
Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion
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Combined KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model Cancer Discov. (IF 29.7) Pub Date : 2024-09-30 Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A. LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A. DePinho
Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor
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Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers Cancer Discov. (IF 29.7) Pub Date : 2024-09-30 Jamie E. Medina, Akshaya V. Annapragada, Pien Lof, Sarah Short, Adrianna L. Bartolomucci, Dimitrios Mathios, Shashikant Koul, Noushin Niknafs, Michael Noe, Zachariah H. Foda, Daniel C. Bruhm, Carolyn Hruban, Nicholas A. Vulpescu, Euihye Jung, Renu Dua, Jenna V. Canzoniero, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van den Broek, Lori J. Sokoll, Stephen B. Baylin, Michael F. Press, Dennis
Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer
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DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming Cancer Discov. (IF 29.7) Pub Date : 2024-09-26 Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M. Vaz, Giuseppe Tarantino, Tenna Holgersen. Bryde, Vindhya Vijay, Ashwin V. Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D. Gordan, Krushna C. Patra, Vanessa S. Silveira, Robert T. Manguso, Marc N. Wein, Christopher J. Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S. Gujral, Nabeel Bardeesy
Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived
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Advancing Global Health Equity in Oncology Clinical Trial Access. Cancer Discov. (IF 29.7) Pub Date : 2024-09-24 ,,,,,
Despite exponentially increased industry investment in oncology research and development with more than $80 billion spent annually, patient enrollment in clinical trials remains below 5% globally. Our multistakeholder international cancer coalition envisions ecosystem transformation with capacity building through a global "hub-and-spoke" network model to expand access to and accelerate clinical trials
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Trem2-expressing multinucleated giant macrophages are a biomarker of good prognosis in head and neck squamous cell carcinoma Cancer Discov. (IF 29.7) Pub Date : 2024-09-13 Gregoire Gessain, Ahmed-Amine Anzali, Marvin Lerousseau, Kevin Mulder, Mathilde Bied, Anne Auperin, Daniel Stockholm, Nicolas Signolle, Farah Sassi, Maria Eugenia Marques Da Costa, Antonin Marchais, Alexandre Sayadi, Daniela Weidner, Stefan Uderhardt, Quentin Blampey, Sumanth Reddy Nakkireddy, Sophie Broutin, Charles-Antoine Dutertre, Pierre Busson, Thomas Walter, Alix Marhic, Antoine Moya-Plana, Joanne
Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk-management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC) – a type of macrophages – in tumors from patients with HNSCC, which are associated with a favorable prognosis
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NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations Cancer Discov. (IF 29.7) Pub Date : 2024-09-13 Jessica J. Lin, Joshua C. Horan, Anupong Tangpeerachaikul, Aurélie Swalduz, Augusto Valdivia, Melissa L. Johnson, Benjamin Besse, D. Ross Camidge, Toshio Fujino, Satoshi Yoda, Linh Nguyen-Phuong, Hayato Mizuta, Ludovic Bigot, Catline Nobre, Jii Bum Lee, Mi Ra Yu, Scot Mente, Yuting Sun, Nancy E. Kohl, James R. Porter, Matthew D. Shair, Viola W. Zhu, Enriqueta Felip, Byoung Chul Cho, Luc Friboulet,
Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion–positive non–small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested.
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Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells Cancer Discov. (IF 29.7) Pub Date : 2024-09-09 Marica Rosaria. Ippolito, Johanna Zerbib, Yonatan Eliezer, Eli Reuveni, Sonia Vigano, Giuseppina De Feudis, Eldad D. Shulman, Anouk Savir Kadmon, Rachel Slutsky, Tiangen Chang, Emma M. Campagnolo, Silvia Taglietti, Simone Scorzoni, Sara Gianotti, Sara Martin, Julia Muenzner, Michael Mulleder, Nir Rozenblum, Carmela Rubolino, Tal Ben-Yishay, Kathrin Laue, Yael Cohen-Sharir, Ilaria Vigorito, Francesco
Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden
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Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers Cancer Discov. (IF 29.7) Pub Date : 2024-09-09 Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C. Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyova, Dirk Scharn, Mark A. Pearson, Johannes Popow, Anna C. Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L. Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V. Heymach
Mutations in HER2 occur in 2-4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2 mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively
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Tuning Responses to Polatuzumab Vedotin in B-cell Lymphoma Cancer Discov. (IF 29.7) Pub Date : 2024-09-04 Etienne Leveille, Shalin Kothari, Kadriye N. Cosgun, Coraline Mlynarczyk, Markus Müschen
Summary: Polatuzumab vedotin, an antibody–drug conjugate targeting CD79B, is the first new drug approved for first-line therapy of diffuse large B-cell lymphoma in more than two decades, although factors determining treatment responses to polatuzumab vedotin remain unknown. Two new studies identified central mechanisms of lower sensitivity, namely reduced accessibility of the CD79B epitope through
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Gene-Specific Machine Learning Models to Classify Driver Mutations in Clonal Hematopoiesis Cancer Discov. (IF 29.7) Pub Date : 2024-09-04 Christopher M. Arends, Siddhartha Jaiswal
Summary: There is no general consensus on the set of mutations capable of driving the age-related clonal expansions in hematopoietic stem cells known as clonal hematopoiesis, and current variant classifications typically rely on rules derived from expert knowledge. In this issue of Cancer Discovery, Damajo and colleagues trained and validated machine learning models without prior knowledge of clonal
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Correction: Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker. Cancer Discov. (IF 29.7) Pub Date : 2024-09-04
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Correction: Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis. Cancer Discov. (IF 29.7) Pub Date : 2024-09-04
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Insights on Future Directions in Cancer Research from the AACR NextGen Stars. Cancer Discov. (IF 29.7) Pub Date : 2024-09-04 Israel Cañadas,Gabriele Casirati,Kathleen E Houlahan,Kara N Maxwell,Arnav Mehta,Abhijit Parolia,Olivier Saulnier,Alison M Taylor,Claire E Thomas,Ignacio Vázquez-García
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If You Build It, Patients with Rare Cancers Will Come: A Successful Clinical Trial in Relapsed and Refractory JMML Cancer Discov. (IF 29.7) Pub Date : 2024-09-04 Nana Adjoa Ben-Crentsil, Eric Padron
Summary: Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and
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MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer Cancer Discov. (IF 29.7) Pub Date : 2024-08-28 Jitendra K. Meena, Jarey H. Wang, Nicholas J. Neill, Dianne Keough, Nagireddy Putluri, Panagiotis Katsonis, Amanda M. Koire, Hyemin Lee, Elizabeth A. Bowling, Siddhartha Tyagi, Mayra Orellana, Rocio Dominguez-Vidaña, Heyuan Li, Kenneth Eagle, Charles Danan, Hsiang-Ching Chung, Andrew D. Yang, William Wu, Sarah J. Kurley, Brian M. Ho, Joseph R. Zoeller, Calla M. Olson, Kristen L. Meerbrey, Olivier Lichtarge
Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism
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RNA shielding of P65 is required to potentiate oncogenic inflammation in TET2 mutated clonal hematopoiesis Cancer Discov. (IF 29.7) Pub Date : 2024-08-27 Nana Adjoa Ben-Crentsil, Wazim Mohammed Ismail, Maria E. Balasis, Hannah Newman, Ariel Quintana, Moritz Binder, Traci Kruer, Surendra Neupane, Meghan C. Ferrall-Fairbanks, Jenna Fernandez, Terra L. Lasho, Christy M. Finke, Mohammed L. Ibrahim, Kathy L. McGraw, Michael Wysota, Amy L. Aldrich, Christopher B. Ryder, Christopher T. Letson, Joshua Traina, Amy F. McLemore, Nathalie Droin, Aditi Shastri,
TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis (CH). These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of this inflammatory circuit is unknown. To address this, we performed
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Chromothripsis-mediated small cell lung carcinoma Cancer Discov. (IF 29.7) Pub Date : 2024-08-26 Natasha Rekhtman, Sam E. Tischfield, Christopher A. Febres-Aldana, Jake June-Koo. Lee, Jason C. Chang, Benjamin O. Herzberg, Pier Selenica, Hyung Jun Woo, Chad M. Vanderbilt, Soo-Ryum Yang, Fei Xu, Anita S. Bowman, Edaise M. da Silva, Anne Marie Noronha, Diana L. Mandelker, Miika Mehine, Semanti Mukherjee, Juan Blanco-Heredia, John J. Orgera, Gouri J. Nanjangud, Marina K. Baine, Rania G. Aly, Jennifer
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here we performed detailed clinicopathologic, genomic and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis
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TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer Cancer Discov. (IF 29.7) Pub Date : 2024-08-22 Dian Kortleve, Dora Hammerl, Mandy van Brakel, Rebecca Wijers, Daphne Roelofs, Kim Kroese, Mieke M. Timmermans, Chen-Yi Liao, Shaozhuo Huang, Anita Trapman-Jansen, Renee Foekens, Justine Michaux, Monique T.A. de Beijer, Sonja I. Buschow, Jeroen AA. Demmers, Marleen Kok, Erik HJ. Danen, Michal Bassani-Sternberg, John W.M. Martens, Rachel J.M. Abbott, Reno Debets
Triple-negative breast cancer (TNBC) shows 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. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naïve repertoires
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Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression. Cancer Discov. (IF 29.7) Pub Date : 2024-08-13 Hiroki Kobayashi, Tadashi Iida, Yosuke Ochiai, Ermanno Malagola, Xiaofei Zhi, Ruth A. White, Jin Qian, Feijing Wu, Quin T. Waterbury, Ruhong Tu, Biyun Zheng, Jonathan S. LaBella, Leah B. Zamechek, Atsushi Ogura, Susan L. Woods, Daniel L. Worthley, Atsushi Enomoto, Timothy C. Wang
Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn
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Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers Cancer Discov. (IF 29.7) Pub Date : 2024-08-09 Patrick Loi, Amy E. Schade, Carrie L. Rodriguez, Anjana Krishnan, Naiara Perurena, Van T.M. Nguyen, Yilin Xu, Marina Watanabe, Rachel A. Davis, Alycia Gardner, Natalie F. Pilla, Kaia Mattioli, Olesja Popow, Nuray Gunduz, Tamsin R.M. Lannagan, Samantha Fitzgerald, Ewa T. Sicinska, Jia-Ren Lin, William Tan, Lauren K. Brais, Kevin M. Haigis, Marios Giannakis, Kimmie Ng, Sandro Santagata, Kristian Helin
Current treatments for KRAS-mutant colorectal cancers (CRCs) are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in
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T Cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination With Pembrolizumab in the Phase 1 KEYNOTE-603 Study Cancer Discov. (IF 29.7) Pub Date : 2024-08-08 Justin F. Gainor, Manish R. Patel, Jeffrey S. Weber, Martin Gutierrez, Julie E. Bauman, Jeffrey M. Clarke, Ricklie Julian, Aaron J. Scott, Jessica L. Geiger, Kedar Kirtane, Celine Robert-Tissot, Brandon Coder, Moomal Tasneem, Jing Sun, Wei Zheng, Lauren Gerbereux, Andressa Laino, Filippos Porichis, Jack Russella Pollard, Peijie Hou, Vasudha Sehgal, Xing Chen, Manju Morrissey, Hikmat N. Daghestani,
mRNA-4157 (V940) is an individualized neoantigen therapy (INT) targeting up to 34 patient-specific tumor neoantigens to induce T cell responses and potentiate anti-tumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T cell responses to neoantigens from the first-in-human phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small
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Disparate pathways for extrachromosomal DNA biogenesis and genomic DNA repair Cancer Discov. (IF 29.7) Pub Date : 2024-08-07 John C. Rose, Julia A. Belk, Ivy Tsz-Lo. Wong, Jens Luebeck, Hudson T. Horn, Bence Daniel, Matthew G. Jones, Kathryn E. Yost, King L. Hung, Kevin S. Kolahi, Ellis J. Curtis, Calvin J. Kuo, Vineet Bafna, Paul S. Mischel, Howard Y. Chang
Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms is limited. Here, we couple a CRISPR-based method for ecDNA induction with extensive characterization of newly formed ecDNA to examine their biogenesis. We find that DNA circularization is efficient, irrespective of 3D genome context, with formation of 800kb, 1 Mb,
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The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics Cancer Discov. (IF 29.7) Pub Date : 2024-08-02 Jai Prakash, Yuval Shaked
The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies
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Iron: The Secret Ingredient Breaking PARPi Resistance Cancer Discov. (IF 29.7) Pub Date : 2024-08-02 Hamed Alborzinia, José Pedro Friedmann Angeli
Summary: PARP inhibitors (PARPi) are used as a first-line treatment option for cancers with BRCA1/2 mutations, yet a significant number of patients show a limited response to these agents. In the present study, Lei and colleagues demonstrate that PARPi promote increased ferroptosis sensitivity and this can be exploited therapeutically to improve the response to PARPi, marking an important therapeutic
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Lung Cancer Adoptive Cell Therapy: Inspiring TIL ACT Comes Center Stage Cancer Discov. (IF 29.7) Pub Date : 2024-08-02 Michael T. Lotze, Markus Maeurer, Sergio A. Quezada, George Coukos
Summary: Schoenfeld and colleagues report, in this issue, a measurable objective response rate in 6/28 (21.4%) of patients with advanced non–small cell lung cancer treated with lifileucel, a cell therapy product based on autologous tumor-infiltrating lymphocytes (TIL). Extending solid evidence in advanced melanoma that led to FDA approval of lifileucel, this new evidence bodes well for treating patients
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WRN Helicase: Is There More to MSI-H than Immunotherapy? Cancer Discov. (IF 29.7) Pub Date : 2024-08-02 Zev A. Wainberg
Summary: In this issue, Picco and colleagues provide further evidence that WRN inhibitors are synthetically lethal in microsatellite instability-high (MSI-H) cancers and function by blocking the helicase domain of select WRN residues. They demonstrate that WRN inhibitors may be even more effective in a subset of MSI-high tumors with (TA)n repeat expansions, which represents a possible strategy in clinical
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Identification and characterization of chemotherapy resistant high-risk neuroblastoma persister cells Cancer Discov. (IF 29.7) Pub Date : 2024-07-31 Liron D. Grossmann, Chia-Hui Chen, Yasin Uzun, Anusha Thadi, Adam J. Wolpaw, Kevin Louault, Yael Goldstein, Lea F. Surrey, Daniel Martinez, Matteo Calafatti, Mark Gerelus, Peng Gao, Lobin Lee, Khushbu Patel, Rebecca S. Kaufman, Guy Shani, Alvin Farrel, Sharon Moshitch-Moshkovitz, Paris Grimaldi, Matthew Shapiro, Nathan M. Kendsersky, Jarrett M. Lindsay, Colleen E. Casey, Kateryna Krytska, Laura Scolaro
Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. Here, we used single nucleus RNA sequencing and bulk whole genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched
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Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy Cancer Discov. (IF 29.7) Pub Date : 2024-07-31 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
Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate
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Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer Cancer Discov. (IF 29.7) Pub Date : 2024-07-29 Tito A. Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matias Marin Falco, Sung-Min Hwang, Eli Teran-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui-Hsuan Kuo, Jenna E. Moyer, M. Laura Martin, Jyothi Manohar, Kihwan Kim, Maria A. Sierra, Yusibeska Ramos, Chen Tan, Alexander Emmanuelli, Minkyung Song, Diana K. Morales, Dmitriy Zamarin, Melissa K. Frey, Evelyn Cantillo
Iron accumulation in tumors contributes to disease progression and chemoresistance. While targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone
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Pre-existing skin-resident CD8 and γδ T cell circuits mediate immune response in Merkel cell carcinoma and predict immunotherapy efficacy Cancer Discov. (IF 29.7) Pub Date : 2024-07-26 Zachary Z. Reinstein, Yue Zhang, Oscar E. Ospina, Matt D. Nichols, Victoria A. Chu, Alvaro de Mingo. Pulido, Karol Prieto, Jonathan V. Nguyen, Rui Yin, Carlos Moran Segura, Ahmed Usman, Brittney Sell, Spencer Ng, Janis V. de la Iglesia, Sunandana Chandra, Jeffrey A. Sosman, Raymond J. Cho, Jeffrey B. Cheng, Ellie Ivanova, Sergei B. Koralov, Robbert J.C. Slebos, Christine H. Chung, Nikhil I. Khushalani
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence
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MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer Cancer Discov. (IF 29.7) Pub Date : 2024-07-26 Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C. Panepinto, Francesca Minicozzi, Joseph R. Merrill, Amanda M. Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E. Demerdash, Tse-Luen Wee, David L. Spector, Scott K. Lyons, David A. Tuveson, Paolo Cifani, Christopher R. Vakoc
The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation
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A targetable secreted neural protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention Cancer Discov. (IF 29.7) Pub Date : 2024-07-19 Norihiro Yamaguchi, Y Gloria Wu, Ethan Ravetch, Mai Takahashi, Abdul G. Khan, Akimasa Hayashi, Wenbin Mei, Dennis Hsu, Shigeaki Umeda, Elisa de Stanchina, Ivo C. Lorenz, Christine A. Iacobuzio-Donahue, Sohail F. Tavazoie
Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer secreted protein that becomes over-expressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig like domain 2 (AMIGO2) as its receptor