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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
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Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC paralogs Cancer Discov. (IF 28.2) Pub Date : 2024-02-22 Shreoshi Pal Choudhuri, Luc Girard, Jun Yi Stanley Lim, Jillian F. Wise, Braeden Freitas, Di Yang, Edmond Wong, Seth Hamilton, Victor D. Chien, Yoon Jung Kim, Collin Gilbreath, Jun Zhong, Sarah Phat, David T. Myers, Camilla L. Christensen, Hanieh Mazloom-Farsibaf, Marcello Stanzione, Kwok-Kin Wong, Yin P. Hung, Anna F. Farago, Catherine B. Meador, Nicholas J. Dyson, Michael S. Lawrence, Sihan Wu, Benjamin
Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a pre-clinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo
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Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma Cancer Discov. (IF 28.2) Pub Date : 2024-02-22 Toni K. Choueiri, Amber C. Donahue, David A. Braun, Brian I. Rini, Thomas Powles, John B.A.G. Haanen, James Larkin, Xinmeng Jasmine Mu, Jie Pu, Rosemary E. Teresi, Alessandra di Pietro, Paul B. Robbins, Robert J. Motzer
The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and
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Co-Clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts Cancer Discov. (IF 28.2) Pub Date : 2024-02-15 Timothy P. DiPeri, Kurt W. Evans, Bailiang Wang, Ming Zhao, Argun Akcakanat, Maria Gabriela Raso, Yasmeen Q. Rizvi, Xiaofeng Zheng, Anil Korkut, Kaushik Varadarajan, Burak Uzunparmak, Ecaterina E. Dumbrava, Shubham Pant, Jaffer A. Ajani, Paula R. Pohlmann, V. Behrana Jensen, Milind Javle, Jordi Rodon, Funda Meric-Bernstam
Zanidatamab is a bispecific HER2-targeted antibody which has demonstrated antitumor activity in a broad range of HER2 amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pre-treatment or post-progression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models
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Precision Targeting of Mutant PI3Kα Cancer Discov. (IF 28.2) Pub Date : 2024-02-08 Grace Q. Gong, Bart Vanhaesebroeck
Summary: PIK3CA, which encodes the p110α catalytic subunit of PI 3-kinase alpha (PI3Kα), is one of the most frequently genetically activated kinases in solid tumors. In two back-to-back papers, Varkaris and colleagues report on the development of a novel allosteric PI3Kα-mutant–selective inhibitor and early clinical experience with this compound. See related article by Varkaris et al., p. 227 (6)
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“RIPping” off Pancreas Cancer's Blockage of Immune Surveillance Cancer Discov. (IF 28.2) Pub Date : 2024-02-08 Xiuting Liu, Blake E. Sells, David G. DeNardo
Summary: MHC-I downregulation is correlated with immunotherapy resistance in PDAC, but efficient strategies to increase cell-surface MHC-I are still lacking. This study by Sang, Zhou, Chen, Yu, and colleagues identified inhibition of tumor-intrinsic RIPK2 as a pharmacologic target to block the degradation of MHC-I on tumor cells and improved PDAC responses to anti–PD-1 immunotherapy. See related article
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Mutant p53 Gain-of-Function in the Spotlight: Are We Suffering a GOF Delusion? Cancer Discov. (IF 28.2) Pub Date : 2024-02-08 David P. Lane
Summary: Mutant p53 proteins are often highly expressed in human cancers and have been thought to have oncogenic driver gain-of-function (GOF) properties. Wang and colleagues show, surprisingly, that this is not the case because removing the TP53-mutant gene from human and mouse cancer cells using CRISPR technology has no effect on cancer cell growth in vitro or in vivo. See related article by Wang
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Early immune remodeling steers clinical response to frontline chemoimmunotherapy in advanced gastric cancer Cancer Discov. (IF 28.2) Pub Date : 2024-02-06 Minae An, Arnav Mehta, Byung Hoon Min, You Jeong Heo, Samuel J. Wright, Milan Parikh, Lynn Bi, Hyuk Lee, Tae Jun Kim, Song-Yi Lee, Jeonghyeon Moon, Ryan J. Park, Matthew R. Strickland, Woong-Yang Park, Won Ki Kang, Kyoung-Mee Kim, Seung Tae Kim, Samuel J. Klempner, Jeeyun Lee
Adding anti-PD1 to 5-FU/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy we conducted a phase II frontline trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab
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Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy Cancer Discov. (IF 28.2) Pub Date : 2024-02-05 Yaniv Kazansky, Daniel Cameron, Helen S. Mueller, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Yasumichi Kuwahara, Romel Somwar, Marc Ladanyi, Rui Qu, Elisa de Stanchina, Filemon S. Dela Cruz, Andrew L. Kung, Mrinal M. Gounder, Alex Kentsis
Epigenetic dependencies have become evident in many cancers. Based on antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics and diverse experimental models,
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Pan-cancer comparative and integrative analyses of driver alterations using Japanese and international genomic databases Cancer Discov. (IF 28.2) Pub Date : 2024-01-26 Sara Horie, Yuki Saito, Yasunori Kogure, Kota Mizuno, Yuta Ito, Mariko Tabata, Takanori Kanai, Koichi Murakami, Junji Koya, Keisuke Kataoka
Using 48,627 samples from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), we present a pan-cancer landscape of driver alterations and their clinical actionability in Japanese patients. Comparison with Whites in Genomics Evidence Neoplasia Information Exchange (GENIE) demonstrates high TP53 mutation frequencies in Asians across multiple cancer types. Integration of C-CAT, GENIE, and
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EGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth Cancer Discov. (IF 28.2) Pub Date : 2024-01-19 Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Ramya S. Kuna, Kacie A. Traina, Camila Robles-Oteiza, Deborah Ayeni, Elizabeth M. Kwong, Stellar Levy, Anna-Maria Globig, Matthew M. Nobari, George Z. Cheng, Sandra L. Leibel, Robert J. Homer, Reuben J. Shaw, Christian M. Metallo, Katerina Politi, Susan M. Kaech
The limited efficacy of currently approved immunotherapies in EGFR-driven lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophage (TA-AM) proliferation which supports tumor growth by rewiring
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Cancer mutations converge on a collection of protein assemblies to predict resistance to replication stress Cancer Discov. (IF 28.2) Pub Date : 2024-01-18 Xiaoyu Zhao, Akshat Singhal, Sungjoon Park, JungHo Kong, Robin Bachelder, Trey Ideker
Rapid proliferation is a hallmark of cancer, associated with sensitivity to therapeutics that cause DNA replication stress (RS). Many tumors exhibit drug resistance, however, via molecular pathways that are incompletely understood. Here, we develop an ensemble of predictive models that elucidate how cancer mutations impact the response to common RS-inducing (RSi) agents. The models implement recent
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Sotorasib is a pan-RASG12C inhibitor capable of driving clinical response in NRASG12C cancers Cancer Discov. (IF 28.2) Pub Date : 2024-01-18 Douglas A. Rubinson, Noritaka Tanaka, Ferran Fece de la Cruz, Kevin S. Kapner, Michael H. Rosenthal, Bryanna L. Norden, Haley Barnes, Sara Ehnstrom, Alvin A. Morales-Giron, Lauren K. Brais, Christopher T. Lemke, Andrew J. Aguirre, Ryan B. Corcoran
KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Since amino acid sequences of the three main RAS isoforms—KRAS, NRAS and HRAS—are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common
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Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms Cancer Discov. (IF 28.2) Pub Date : 2024-01-17 Andrew J. Dunbar, Robert L. Bowman, Young C. Park, Kavi O'Connor, Franco Izzo, Robert M. Myers, Abdul Karzai, Zach Zaroogian, Won Jun Kim, Ines Fernandez-Maestre, Michael R. Waarts, Abbas Nazir, Wenbin Xiao, Tamara Codilupi, Max Brodsky, Mirko Farina, Louise Cai, Sheng F. Cai, Benjamin Wang, Wenbin An, Julie L. Yang, Shoron Mowla, Shira E. Eisman, Amritha Varshini Hanasoge Somasundara, Jacob L. Glass
Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPNs), most commonly JAK2V617F. While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors
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TREX1 inactivation unleashes cancer cell STING-interferon signaling and promotes anti-tumor immunity Cancer Discov. (IF 28.2) Pub Date : 2024-01-16 Tetsuo Tani, Haritha Mathsyaraja, Marco Campisi, Ze-Hua Li, Koji Haratani, Caroline G. Fahey, Keiichi Ota, Navin R. Mahadevan, Yingxiao Shi, Shin Saito, Kei Mizuno, Tran C. Thai, Nobunari Sasaki, Mizuki Homme, Choudhury Fabliha B. Yusuf, Adam Kashishian, Jipsa Panchal, Min Wang, Benjamin J. Wolf, Thanh U. Barbie, Cloud P. Paweletz, Prafulla C. Gokhale, David Liu, Ravindra Uppaluri, Shunsuke Kitajima
A substantial fraction of cancers evade immune detection by silencing STING (Stimulator of Interferon Genes)-interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic or DNA damaging therapies can restore anti-tumor immunity in multiple pre-clinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic
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Mobilizing China and the Global Community to Confront the Treatment Desert for Pediatric Solid Tumors Cancer Discov. (IF 28.2) Pub Date : 2024-01-12 Shuhang Wang, Yale Jiang, Rongshou Zheng, Yue Yu, Wenqiang Wei, Ning Li
Summary: Pediatric solid tumors are distinct clinical entities that impose heavy socioeconomic burden and while their incidence has increased in recent years, treatment options are often limited, with only 27 drugs approved for pediatric solid tumors in the United States, and fewer still, 13, in China. The scale of the unmet medical need is immense and new efforts are urgently needed to develop efficient
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Is It Time to Incorporate Liquid Biopsy into High-Risk Cancer Surveillance Protocols in Li–Fraumeni Syndrome? Cancer Discov. (IF 28.2) Pub Date : 2024-01-12 Alicia Latham, Suzanne P. MacFarland, Michael F. Walsh, Kara N. Maxwell, Zsofia K. Stadler
Summary: In the first prospective study evaluating circulating tumor DNA (ctDNA) for early cancer detection, Wong, Luo, and colleauges demonstrate the feasibility of liquid biopsy as an augmentation to current surveillance protocols for patients with Li–Fraumeni syndrome, an inherited cancer predisposition associated with high cancer risk in both pediatric and adult populations. Though additional clinical
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Measuring Progress in Precision Oncology Cancer Discov. (IF 28.2) Pub Date : 2024-01-12 Peter Horak, Stefan Fröhling
Summary: In this issue of Cancer Discovery, Suehnholz and colleagues describe their efforts to quantify the gradual yet steady progress of precision oncology by surveying the regulatory approvals of targeted cancer therapies, and thus the actionability of corresponding molecular alterations in clinical practice, over more than 20 years. Their work also suggests a relationship between the discovery
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UNCAN.eu: Toward a European Federated Cancer Research Data Hub Cancer Discov. (IF 28.2) Pub Date : 2024-01-12 Michael Boutros, Michael Baumann, Anna Bigas, Linda Chaabane, Julien Guérin, Jens K. Habermann, Aurélien Jobard, Pier Giuseppe Pelicci, Oliver Stegle, Giovanni Tonon, Alfonso Valencia, Eva C. Winkler, Patricia Blanc, Ruggero De Maria, Rene H. Medema, Peter Nagy, Josep Tabernero, Eric Solary
Summary: To enable a collective effort that generates a new level of UNderstanding CANcer (UNCAN.eu) [Cancer Discov (2022) 12 (11): OF1], the European Union supports the creation of a sustainable platform that connects cancer research across Member States. A workshop hosted in Heidelberg gathered European cancer experts to identify ongoing initiatives that may contribute to building this platform and
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Bispecific T-cell Engagers in Metastatic Castration-Resistant Prostate Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-01-12 Chadi Hage Chehade, Georges Gebrael, Neeraj Agarwal
Summary: To date, immune targeting agents have provided limited benefits in patients with metastatic prostate cancer. Bispecific T-cell engagers, especially targeting STEAP1, have shown encouraging results in preclinical and phase I studies and thus represent a novel and promising treatment option in this setting. See related article by Nolan-Stevaux et al., p. 90 (7). See related article by Kelly
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Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation Cancer Discov. (IF 28.2) Pub Date : 2024-01-11 Gian Marco Franceschini, Orsetta Quaini, Kei Mizuno, Francesco Orlando, Yari Ciani, Sheng-Yu Ku, Michael Sigouros, Emily Rothmann, Alicia Alonso, Matteo Benelli, Caterina Nardella, Joonghoon Auh, Dory Freeman, Brian Hanratty, Mohamed Adil, Olivier Elemento, Scott T. Tagawa, Felix Y. Feng, Orazio Caffo, Consuelo Buttigliero, Umberto Basso, Peter S. Nelson, Eva Corey, Michael C. Haffner, Gerhardt Attard
Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on
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Micronuclei and Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-01-10 Melody Di Bona, Samuel F. Bakhoum
Chromosome-containing micronuclei are a feature of human cancer. Micronuclei arise from chromosome mis-segregation and characterize tumors with elevated rates of chromosomal instability. Although their association with cancer has been long recognized, only recently have we broadened our understanding of the mechanisms that govern micronuclei formation and their role in tumor progression. In this review
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Passenger gene co-amplifications create collateral therapeutic vulnerabilities in cancer Cancer Discov. (IF 28.2) Pub Date : 2024-01-10 Yi Bei, Luca Brame, Marieluise Kirchner, Raphaela Fritsche-Guenther, Severine Kunz, Animesh Bhattacharya, Mara-Camelia Rusu, Dennis Gurgen, Frank P.B. Dubois, Julia K.C. Koppke, Jutta Proba, Nadine Wittstruck, Olga Alexandra. Sidorova, Rocío Chamorro Gonzalez, Heathcliff Dorado Garcia, Lotte Bruckner, Robin Xu, Madalina Giurgiu, Elias Rodriguez-Fos, Qinghao Yu, Bastiaan Spanjaard, Richard P. Koche
DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger co-amplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger co-amplifications are accompanied by distinct dependency
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Targeting DHX9 triggers tumor-intrinsic interferon response and replication stress in Small Cell Lung Cancer Cancer Discov. (IF 28.2) Pub Date : 2024-01-08 Takahiko Murayama, Jun Nakayama, Xinpei Jiang, Kenichi Miyata, Alexander D. Morris, Kathy Q. Cai, Rahul M. Prasad, Xueying Ma, Andrey Efimov, Neel Belani, Emily R. Gerstein, Yinfei Tan, Yan Zhou, William Kim, Reo Maruyama, Kerry S. Campbell, Lu Chen, Yibin Yang, Siddharth Balachandran, Israel Canadas
Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry”, has emerged as an effective strategy to convert immunologically “cold” tumors into “hot”. Through a curated CRISPR-based screen of RNA Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers
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AI Differentiates Two Similar Blood Cancers Cancer Discov. (IF 28.2) Pub Date : 2023-12-18
A new artificial intelligence tool can distinguish prefibrotic myelofibrosis from essential thrombocythemia, which are often confused by pathologists, by analyzing digitized slides of bone marrow biopsies. The tool made the right call 92% of the time. Researchers are still trying to determine how the AI tool makes its decisions.
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Toward Ablative SBRT for Nonmetastatic PDAC Cancer Discov. (IF 28.2) Pub Date : 2023-12-14
Combining a superoxide dismutase mimetic, avasopasem manganese, with stereotactic body radiation therapy may enable safe delivery of higher than standard radiation doses for patients with nonmetastatic, inoperable pancreatic adenocarcinoma. The phase Ib/II findings also suggest improved outcomes with avasopasem's addition, although the trial wasn't designed to compare arms and a larger study is needed
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Menin Inhibitors Trigger Leukemia Remissions Cancer Discov. (IF 28.2) Pub Date : 2023-12-14
Menin inhibitors have proven effective in patients with acute leukemias. A phase II study of revumenib yielded a response rate of 63% in patients with relapsed or refractory disease and KMT2A rearrangements; a phase I trial combining the drug with three chemotherapies also yielded complete remissions in patients with acute myeloid leukemia. A phase I study of a different menin inhibitor detected responses
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Auto-HCT May Be Best after Chemo in DLBCL Cancer Discov. (IF 28.2) Pub Date : 2023-12-13
Some patients with diffuse large B-cell lymphoma eligible for chimeric antigen receptor T-cell therapy end up receiving chemotherapy due to a lack of timely access to treatment. In this situation, those who achieve a complete remission with bridging chemotherapy may do better with autologous hematopoietic cell transplantation, a registry analysis suggests.
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Re-“Formate” T-cell Antitumor Responses Cancer Discov. (IF 28.2) Pub Date : 2023-12-12 Mei-Chun Lin, Sofie Hedlund Moller, Ping-Chih Ho
Summary: Rowe and colleagues discover that one-carbon (1C) metabolism rewiring occurs upon T-cell activation to support proliferation and cytolytic activity in CD8+ T cells and that supplementation of 1C donor formate rescues the dysfunctional T cells and their responsiveness to anti–PD-1 in selective tumor-infiltrated T-cell subsets. This finding represents an attractive strategy to overcome a metabolic
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Precision Oncology: 2023 in Review Cancer Discov. (IF 28.2) Pub Date : 2023-12-12 Yonina R. Murciano-Goroff, Sarah P. Suehnholz, Alexander Drilon, Debyani Chakravarty
Summary: This article presents a review of recent major advances in precision oncology and the future implications of these advances, specifying the iterative progress achieved from the end of 2022 through 2023. We discuss the different classes of precision oncology drugs and associated biomarkers as well as the improvements in clinical trial design that have enabled the efficient testing of these
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Gelling Bodies: Understanding the Mechanisms Underlying Arsenic Trioxide Action Cancer Discov. (IF 28.2) Pub Date : 2023-12-12 Paolo Salomoni
Summary: The study by Bercier and colleagues investigates the mechanisms of action of arsenic trioxide (ATO). The authors find that ATO promotes transition of PML nuclear bodies to a gel-like state via the PML trimerization domain and a critical cysteine residue. Overall, this work sheds new light onto how PML–RARα, the oncogene of APL, is targeted by ATO for disease eradication. See related article
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Highlights of FDA Oncology Approvals in 2023: Bispecific T-cell Engagers, Pediatric Indications, and Inclusive Drug Development Cancer Discov. (IF 28.2) Pub Date : 2023-12-12 Joshua M. Donaldson, Marjilla Seddiq, Michael J. Fusco, Shyamli Singla, Gulsum E. Pamuk, Rosa J. Lee-Alonso, Bronwyn D. Mixter, Kirsten B. Goldberg, Laleh Amiri-Kordestani, R. Angelo de Claro, Nicole Drezner, Nicole J. Gormley, Bindu Kanapuru, Steven J. Lemery, Lola A. Fashoyin-Aje, Nicholas C. Richardson, Harpreet Singh, Daniel L. Suzman, Marc R. Theoret, Paul G. Kluetz, Richard Pazdur
Summary: Cancer drug development remained robust in 2023. Highlights of U.S. drug approvals this year include new immunotherapies and targeted drug development in adult and pediatric patients as well as patients with rare diseases.
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Noninvasive and Multicancer Biomarkers: The Promise of LINE-1 Retrotransposons Cancer Discov. (IF 28.2) Pub Date : 2023-12-12 Aurelien J. Doucet, Gael Cristofari
Summary: LINE-1 retrotransposons are frequently active in epithelial tumors. In a new study, Taylor, Wu and colleagues now describe that one of the proteins encoded by LINE-1 elements, ORF1p, is detected in the bloodstream of patients with cancer, and can be used as a noninvasive and multicancer biomarker for diagnosis or treatment monitoring. See related article by Taylor, Wu et al., p. 2532 (7).
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Oral Arsenic Regimen for APL Deemed “Revolutionary” Cancer Discov. (IF 28.2) Pub Date : 2023-12-12
Patients with newly diagnosed acute promyelocytic leukemia have excellent responses and survival outcomes with an entirely oral arsenic-based regimen—arsenic trioxide, all-trans retinoic acid, and ascorbic acid—that could also ease the treatment burden on their lives.
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Artificial Intelligence Identifies Novel Disease Pathways Cancer Discov. (IF 28.2) Pub Date : 2023-12-11
Artificial intelligence (AI) can be trained to recognize a hallmark of invasive lobular carcinoma—inactivation of the CDH1 gene—and identify tumor features that may be missed with genomic sequencing. In the future, AI could help identify new targets for treatment in invasive lobular carcinoma and other malignancies.
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ImmunoGen Takeover Caps Year of Record ADC Investments Cancer Discov. (IF 28.2) Pub Date : 2023-12-11
AbbVie's $10.1 billion acquisition of ImmunoGen caps off a year of industry deals around antibody–drug conjugates, an area in which companies are continuing to explore new targets, linker technologies, and diverse warheads, emphasizing a commitment to refining the technology and improving treatment options for patients.
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Homing In on RNA Fusions in Breast Cancer Cancer Discov. (IF 28.2) Pub Date : 2023-12-11
Researchers pinpointed specific RNA fusions in ESR1 in some metastatic breast cancers, an aberration that can prevent endocrine therapies from binding their target. New treatments are needed to overcome resistance to existing therapies and improve how patients fare.
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Cancer Evolution: A Multifaceted Affair Cancer Discov. (IF 28.2) Pub Date : 2023-12-04 Giovanni Ciriello, Luca Magnani, Sarah J. Aitken, Leila Akkari, Sam Behjati, Douglas Hanahan, Dan A. Landau, Nuria Lopez-Bigas, Darío G. Lupiáñez, Jean-Christophe Marine, Ana Martin-Villalba, Gioacchino Natoli, Anna C. Obenauf, Elisa Oricchio, Paola Scaffidi, Andrea Sottoriva, Alexander Swarbrick, Giovanni Tonon, Sakari Vanharanta, Johannes Zuber
Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes
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INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors Cancer Discov. (IF 28.2) Pub Date : 2023-12-04 Catherine Dietrich, Alec Trub, Antonio Ahn, Michael Taylor, Krutika Ambani, Keefe T. Chan, Kun-Hui Lu, Christabella A. Mahendra, Catherine Blyth, Rhiannon Coulson, Susanne Ramm, April C. Watt, Sunil Kumar Matsa, John Bisi, Jay Strum, Patrick Roberts, Shom Goel
Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacological inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent
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A Single-Cell CRISPR Screen Reveals Intratumoral CD8+ T-cell Fate Regulomes. Cancer Discov. (IF 28.2) Pub Date : 2023-12-01
IKAROS, ETS1, and RBPJ were identified as key checkpoints of cytotoxic T lymphocyte differentiation.
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The Extracellular Matrix Dictates Regional Differences in Tumor Initiation. Cancer Discov. (IF 28.2) Pub Date : 2023-12-01
Epidermal cells in different body regions are not equally sensitive to oncogenic transformation.
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Lineage Switching Occurs Upon Relapse in Pediatric Acute Myeloid Leukemia. Cancer Discov. (IF 28.2) Pub Date : 2023-12-01
Relapsed tumors in pediatric AML are enriched in primitive cells and lose myeloid transcriptional programs.
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Additivity Predicts the Clinical Efficacy of Approved Combination Therapies. Cancer Discov. (IF 28.2) Pub Date : 2023-12-01
A drug additivity model accurately matches the clinical efficacy of most approved drug combinations.
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FDA Investigating CAR-Related T-cell Malignancies Cancer Discov. (IF 28.2) Pub Date : 2023-11-30
The FDA is investigating reports that BCMA- and CD19-directed autologous chimeric antigen receptor T-cell immunotherapies, which are used to treat a variety of blood cancers, may be causing secondary malignancies. However, the agency and hematologists say the potential benefits of the agents, which have saved thousands of lives, outweigh this risk.
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Short-Read Sequencing Detects Large Structural Variants in Cancer Genomes. Cancer Discov. (IF 28.2) Pub Date : 2023-11-22
Most large structural variants (SV) can be detected by short-read sequencing (SRS) of cancer genomes.
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Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer. Cancer Discov. (IF 28.2) Pub Date : 2023-11-22
Pantothetic acid is required for metabolic activity that supports MYC-driven breast tumor growth.
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Tertiary Lymphoid Structures Validated as Biomarker Cancer Discov. (IF 28.2) Pub Date : 2023-11-22
New trial data confirm the potential of tertiary lymphoid structures to serve as a predictive biomarker of responsiveness to an immune checkpoint inhibitor–based drug regimen. According to study results presented at the Society for Immunotherapy of Cancer Annual Meeting, treatment with a PD-L1–targeted agent plus a multikinase inhibitor with anti-angiogenic activity yielded clinical responses in patients
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Kidney Cancer Researcher Tapped as NCI Director Cancer Discov. (IF 28.2) Pub Date : 2023-11-21
Vanderbilt University Medical Center's W. Kimryn Rathmell, MD, PhD, MMHC, will serve as the 17th director of the NCI, bringing her extensive research experience, clinical proficiency, institutional leadership, and a commitment to mentorship to the position.
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ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer Cancer Discov. (IF 28.2) Pub Date : 2023-11-20 Belinda Kingston, Alex Pearson, Maria Teresa Herrera-Abreu, Li-Xuan Sim, Rosalind J. Cutts, Heena Shah, Laura Moretti, Lucy S. Kilburn, Hannah Johnson, Iain R. Macpherson, Alistair Ring, Judith M. Bliss, Yingwei Hou, Weiyi Toy, John A. Katzenellenbogen, Sarat Chandarlapaty, Nicholas C. Turner
Fulvestrant is used to treat patients with hormone receptor positive advanced breast cancer but acquired resistance is poorly understood. PlasmaMATCH Cohort A (NCT03182634) investigated the activity of fulvestrant in patients with activating ESR1 mutations in circulating tumor DNA (ctDNA). Baseline ESR1 mutations Y537S associated with poor, and Y537C with good outcome. Sequencing of baseline and EOT
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Claudin-6 CAR T Cells Are Safe and Have Potential Clinical Activity. Cancer Discov. (IF 28.2) Pub Date : 2023-11-17
The safety profile of claudin-6 (CLDN6)-specific CAR T cells was manageable with and without CARVac.