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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

  •   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.

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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,

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   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

  •   The SCRUM-MONSTAR Cancer-Omics Ecosystem: Striving for a Quantum Leap in Precision Medicine
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-18
    Tadayoshi Hashimoto, Yoshiaki Nakamura, Takao Fujisawa, Mitsuho Imai, Taro Shibuki, Naoko Iida, Hiroshi Ozaki, Norio Nonomura, Chigusa Morizane, Hiroji Iwata, Susumu Okano, Wataru Yamagami, Naoya Yamazaki, Shigenori Kadowaki, Hiroya Taniguchi, Makoto Ueno, Shogen Boku, Eiji Oki, Yoshito Komatsu, Satoshi Yuki, Akitaka Makiyama, Tomoyuki Otsuka, Hiroki Hara, Naohiro Okano, Tomohiro Nishina, Yasutoshi

    The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence–driven multi-omics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease–based precision medicine for resectable solid tumors, including

  •   Rational protein engineering to enhance MHC-independent T cell receptors
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-09
    Ju-Fang Chang, Jack H. Landmann, Tien-Ching Chang, Mehmet Emrah. Selli, Yangdon Tenzin, John M. Warrington, Julie Ritchey, Yu-Sung Hsu, Michael Slade, Deepesh Kumar. Gupta, John F. DiPersio, Alex S. Holehouse, Nathan Singh

    Chimeric antigen receptor (CAR)-based therapies have pioneered synthetic cellular immunity but remain limited in their long-term efficacy. Emerging data suggest that dysregulated CAR-driven T cell activation causes T cell dysfunction and therapeutic failure. To re-engage the precision of the endogenous T cell response, we designed MHC-independent T cell receptors (miTCRs) by linking antibody variable

  •   Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant NSCLC
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-08
    Haniel A. Araujo, Ximo Pechuan-Jorge, Teng Zhou, Minh Truong Do, Xin Hu, Frank R. Rojas Alvarez, Maria E. Salvatierra, Heladio P. Ibarguen, Richard Lee, Rashi Raghulan, Harshit Shah, Mariela A. Moreno Ayala, Kevin Chen, Nataliya Tovbis Shifrin, Shuhong Wu, Luisa M. Solis Soto, Marcelo V. Negrao, Don L. Gibbons, David S. Hong, Jack A. Roth, John V. Heymach, Jianjun Zhang, Jingjing Jiang, Mallika Singh

    Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with

  •   Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-08
    Julien Dilly, Megan T. Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D. Parent, Connor J. Hennessey, Alexander C. Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A. Uribe, Annan Yang, Kevin S. Kapner, Felix P. Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E. Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M. Lopez, Christopher A. Bristow, Michael

    KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133

  •   ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-08
    Simone Benitz, Alec Steep, Malak M. Nasser, Jonathan Preall, Ujjwal Mukund. Mahajan, Holly McQuithey, Ian Loveless, Erick T. Davis, Hui-Ju Wen, Daniel W. Long, Thomas Metzler, Samuel Zwernik, Michaela Louw, Donald Rempinski, Daniel J. Salas-Escabillas, Sydney M. Brender, Linghao Song, Ling Huang, Brian K. Theisen, Zhenyu Zhang, Nina G. Steele, Ivonne Regel, Filip Bednar, Howard C. Crawford

    Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained

  •   A classical epithelial state drives acute resistance to KRAS inhibition in pancreas cancer
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-08
    Anupriya Singhal, Hannah C. Styers, Jonathan Rub, Zhuxuan Li, Stefan R. Torborg, Jung Yun Kim, Olivera Grbovic-Huezo, Huijin Feng, Zeynep Cagla. Tarcan, Hulya Sahin Ozkan, Jill Hallin, Olca Basturk, Rona Yaeger, James G. Christensen, Doron Betel, Yan Yan, Iok In Christine Chio, Elisa de Stanchina, Tuomas Tammela

    Intra-tumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials but efficacy is limited by acquired resistance. Using genetically

  •   Clonal Lineage Tracing with Somatic Delivery of Recordable Barcodes Reveals Migration Histories of Metastatic Prostate Cancer
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-06
    Ryan N. Serio, Armin Scheben, Billy Lu, Domenic V. Gargiulo, Lucrezia Patruno, Caroline L. Buckholtz, Ryan J. Chaffee, Megan C. Jibilian, Steven G. Persaud, Stephen J. Staklinski, Rebecca Hassett, Lise M. Brault, Daniele Ramazzotti, Christopher E. Barbieri, Adam C. Siepel, Dawid G. Nowak

    The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer (PCa) using a novel injection-based mouse model — EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we

  •   Single cell view of tumor microenvironment gradients in pleural mesothelioma
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-03
    Bruno Giotti, Komal Dolasia, William Zhao, Peiwen Cai, Robert Sweeney, Elliot Merritt, Evgeny Kiner, Grace S. Kim, Atharva Bhagwat, Thinh Nguyen, Samarth Hegde, Bailey G. Fitzgerald, Sanjana Shroff, Travis Dawson, Monica Garcia-Barros, Jamshid Abdul-Ghafar, Rachel Chen, Sacha Gnjatic, Alan Soto, Rachel Brody, Seunghee Kim-Schulze, Zhihong Chen, Kristin G. Beaumont, Miriam Merad, Raja M. Flores, Robert

    Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME

  •   Oncogenic KRAS-dependent stromal interleukin-33 directs the pancreatic microenvironment to promote tumor growth
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-03
    Katelyn L. Donahue, Hannah R. Watkoske, Padma Kadiyala, Wenting Du, Kristee Brown, Michael K. Scales, Ahmed M. Elhossiny, Carlos E. Espinoza, Emily L. Lasse Opsahl, Brian D. Griffith, Yukang Wen, Lei Sun, Ashley Velez-Delgado, Nur M. Renollet, Jacqueline Morales, Nicholas M. Nedzesky, Rachael K. Baliira, Rosa E. Menjivar, Paola I. Medina-Cabrera, Arvind Rao, Benjamin Allen, Jiaqi Shi, Timothy L. Frankel

    Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer associated fibroblasts (CAFs). The mechanisms underlying this conversion, including regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to target CAFs therapeutically have so far failed. Here

  •   Expression of Concern: Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma.
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-01
    Aayoung Hong,Gatien Moriceau,Lu Sun,Shirley Lomeli,Marco Piva,Robert Damoiseaux,Sheri L Holmen,Norman E Sharpless,Willy Hugo,Roger S Lo

  •   Tumor Promoters and Opportunities for Molecular Cancer Prevention.
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-01
    William Hill,Clare E Weeden,Charles Swanton

    Environmental carcinogens increase cancer incidence via both mutagenic and non-mutagenic mechanisms. There are over 500 known or suspected carcinogens classified by the International Agency for Research on Cancer. Sequencing of both cancerous and histologically non-cancerous tissue has been instrumental in improving our understanding of how environmental carcinogens cause cancer. Understanding how

  •   Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally.
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-01
    Javier Carmona,Elena Chavarria,Kate Donoghue,Christina von Gertten,Petra Oberrauch,Emma Pailler,Giovanni Scoazec,Ruud Weijer,Judith Balmaña,Irene Brana,Cinzia Brunelli,Suzette Delaloge,Marc Deloger,Pierre Delpy,Ingemar Ernberg,Rebecca C Fitzgerald,Elena Garralda,Martin Lablans,Janne Lëhtio,Carlos Lopez,Maialen Fernández,Rosalba Miceli,Paolo Nuciforo,Raquel Perez-Lopez,Elena Provenzano,Marjanka K Schmidt

    Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.

  •   Targeted Bias: The Next Swing at IL2 Therapy
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-01
    Kayla R. Kulhanek, Anusha Kalbasi

    Summary: Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte therapy. In back-to-back articles, Moynihan and Kaptein introduce a new fusion protein that delivers a biased IL2 mutein to CD8 T cells. See related article by Moynihan et al., p. 1206 (6). See related article by Kaptein et al.,

  •   Pan-RAF:MEK Molecular Glues Take Center Stage
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-01
    Matthew J. Hangauer, Jorge Silvio Gutkind, Fleur M. Ferguson

    Summary: In this issue, Ryan and colleagues describe the preclinical development of a pan-RAF:MEK molecular glue with superior efficacy, brain penetrance, and tolerability in xenograft models of Ras/Raf/MAPK pathway–driven tumors. See related article by Ryan et al., p. 1190 (1).

  •   Precision Targeting of the Gut Microbiome for Cancer Immunotherapy
    Cancer Discov. (IF 29.7) Pub Date : 2024-07-01
    Pasquale Lombardi, David J. Pinato

    Summary: Transforming gut microbial status from a prognostic trait to a therapeutic target is a key goal to understand and reverse resistance to anticancer immunotherapy. Glitza and colleagues propose selective manipulation of the gut microbiome with SER401 following antibiotic preconditioning and highlight multiple challenges in delivering microbiome manipulation to the clinic. See related article

  •   The history of chromosomal instability in genome doubled tumors
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-29
    Toby M. Baker, Siqi Lai, Andrew R. Lynch, Tom Lesluyes, Haixi Yan, Huw A. Ogilvie, Annelien Verfaillie, Stefan Dentro, Amy L. Bowes, Nischalan Pillay, Adrienne M. Flanagan, Charles Swanton, Paul T. Spellman, Maxime Tarabichi, Peter Van Loo

    Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states

  •   The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-26
    Shiyan Wang, Yong Zeng, Lin Zhu, Min Zhang, Lei Zhou, Weixiong Yang, Weishan Luo, Lina Wang, Yanming Liu, Helen Zhu, Xin Xu, Peiran Su, Xinyue Zhang, Musaddeque Ahmed, Wei Chen, Moliang Chen, Sujun Chen, Mykhaylo Slobodyanyuk, Zhongpeng Xie, Jiansheng Guan, Wen Zhang, Aafaque A. Khan, Shingo Sakashita, Ni Liu, Nhu-An Pham, Paul C. Boutros, Zunfu Ke, Michael F. Moran, Zongwei Cai, Chao Cheng, Jun Yu

    Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptome, proteome and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through

  •   Biologic and clinical analysis of childhood gamma delta T-ALL identifies LMO2/STAG2 rearrangements as extremely high-risk
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-25
    Shunsuke Kimura, Chun Shik Park, Lindsey E. Montefiori, Ilaria Iacobucci, Petri Polonen, Qingsong Gao, Elizabeth D. Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J. Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R. Crews, Hester A. de Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah Elisa. Muhle, Sarah Elitzur, Gabriele

    Acute lymphoblastic leukemia expressing the gamma delta T cell receptor (yo T-ALL) is a poorly understood disease. We studied 200 children with yo T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. yo T-ALL diagnosed in children under three years of age was extremely high-risk

  •   CD28 costimulation augments CAR signaling in NK cells via the LCK/CD3Z/ZAP70 signaling axis
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-20
    Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P. Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun Hee Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana Karen. Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J. Montalvo, Sophia L. Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran

    Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity

  •   Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers.
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-14
    Raghuvaran Shanmugam,Prativa Majee,Wei Shi,Mert Burak Ozturk,Thamil Selvan Vaiyapuri,Khaireen Idzham,Anandhkumar Raju,Seung Hee Shin,Kerem Fidan,Joo-Leng Low,Joelle Yi Heng Chua,Yap Choon Kong,Ong Yue Qi,Emile Tan,Aik Yong Chok,Isaac Seow-En,Ian Wee,Dominique Camat Macalinao,Dawn Qingqing Chong,Hong Yun Chang,Fiona Lee,Wei Qiang Leow,Maki Murata-Hori,Zhang Xiaoqian,Chia Shumei,Chris Soon Heng Tan,Ramanuj

    Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant

  •   Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children's Oncology Group.
    Cancer Discov. (IF 29.7) Pub Date : 2024-09-04
    Elliot Stieglitz,Alex G Lee,Steven P Angus,Christopher Davis,Donald A Barkauskas,David Hall,Scott C Kogan,Julia Meyer,Steven D Rhodes,Sarah K Tasian,Xiaoling Xuei,Kevin Shannon,Mignon L Loh,Elizabeth Fox,Brenda J Weigel

    Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor

  •   Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-03
    Peter J Mazzone,Peter B Bach,Jacob Carey,Caitlin A Schonewolf,Katalin Bognar,Manmeet S Ahluwalia,Marcia Cruz-Correa,David Gierada,Sonali Kotagiri,Kathryn Lloyd,Fabien Maldonado,Jesse D Ortendahl,Lecia V Sequist,Gerard A Silvestri,Nichole Tanner,Jeffrey C Thompson,Anil Vachani,Kwok-Kin Wong,Ali H Zaidi,Joseph Catallini,Ariel Gershman,Keith Lumbard,Laurel K Millberg,Jeff Nawrocki,Carter Portwood,Aakanksha

    Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic

  •   The Cell Cycle: a Key to Unlock EZH2-targeted Therapy Resistance.
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-03
    Rachel L Paolini,George P Souroullas

    In this issue, a study by Kazansky and colleagues explored resistance mechanisms after EZH2 inhibition in malignant rhabdoid tumors (MRT) and epithelioid sarcomas (ES). The study identified genetic alterations in EZH2 itself, along with alterations that converge on RB1-E2F-mediated cell-cycle control, and demonstrated that inhibition of cell-cycle kinases, such as Aurora Kinase B (AURKB) could bypass

  •   Optimus-Era Dose Finding for Rare Cancers.
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-03
    Yonina R Murciano-Goroff,Sean M Devlin,Alexia Iasonos,Alexander Drilon

    Advances in cancer biology and diagnostics have led to the recognition of a multitude of rare cancer subtypes, emphasizing the pressing need for strategies to accelerate drug development for patients with these cancers. This paper addresses the unique challenges of dose finding in trials that accrue small numbers of patients with rare cancers; strategies for dose optimization are proposed, in line

  •   When Lightning Strikes Twice: Routes to Second Malignancies in Young Patients.
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-03
    Clarissa N Pacyna,Jyoti Nangalia

    Given the rarity of cancer in childhood, it should be even more uncommon for pediatric cancer survivors to develop a second, independent malignancy, yet they incur a greatly elevated risk after initial remission. In this issue of Cancer Discovery, Sánchez-Guixé and colleagues unpick the origins of second tumours in four children, and the potential role platinum-based chemotherapy may play in subsequent

  •   A Deep Learning Model for Cancer Type Prediction Sets a New Standard.
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-03
    Salil Garg

    Classifying tumor types using machine learning approaches is not always trivial, particularly for challenging cases such as cancers of unknown primary. In this issue of Cancer Discovery, Darmofal and colleagues describe a new tool that uses information from a clinical sequencing panel to diagnose tumor type, and show that the model is particularly robust. See related article by Darmofal et al., p.

  •   Unlocking the Next Frontier in Precision Oncology: Addressing Drug-Tolerant Residual Disease.
    Cancer Discov. (IF 29.7) Pub Date : 2024-06-03
    Jessica J Lin,Justin F Gainor,Vincent K Lam,Christine M Lovly

    Drug-tolerant residual disease (DTRD) after the initial maximal response to a systemic therapy can serve as a tumor reservoir for the development of acquired drug resistance and represents a major clinical challenge across various cancers and types of therapies. To unlock the next frontier in precision oncology, we propose a fundamental paradigm shift in the treatment of metastatic cancers with a sharpened

  •   CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype Specific Vulnerability in IDH2- and TET2-Mutant Cells
    Cancer Discov. (IF 29.7) Pub Date : 2024-05-31
    Michael R. Waarts, Shoron Mowla, Meaghan Boileau, Anthony R. Martinez Benitez, Junya Sango, Maya Bagish, Ines Fernandez-Maestre, Yufan Shan, Shira E. Eisman, Young C. Park, Matthew Wereski, Isabelle Csete, Kavi O'Connor, Angelica C. Romero-Vega, Linde A. Miles, Wenbin Xiao, Xiaodi Wu, Richard P. Koche, Scott A. Armstrong, Alan H. Shih, Eirini P. Papapetrou, Jason M. Butler, Sheng F. Cai, Robert L.

    Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial

  •   Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium
    Cancer Discov. (IF 29.7) Pub Date : 2024-05-24
    Anagha Inguva. Sheth, Mark J. Althoff, Hunter Tolison, Krysta Engel, Maria L. Amaya, Anna E. Krug, Tracy N. Young, Mohammad Minhajuddin, Shanshan Pei, Sweta B. Patel, Amanda Winters, Regan Miller, Ian T. Shelton, Jonathan St-Germain, Tianyi Ling, Courtney L. Jones, Brian Raught, Austin E. Gillen, Monica Ransom, Sarah Staggs, Clayton A. Smith, Daniel A. Pollyea, Brett M. Stevens, Craig T. Jordan

    Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. While venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study

  •   CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma
    Cancer Discov. (IF 29.7) Pub Date : 2024-05-20
    Xu Zhang, Shoufu Duan, Panagiota E. Apostolou, Xiaoping Wu, Jun Watanabe, Matthew Gallitto, Tara Barron, Kathryn R. Taylor, Pamelyn J. Woo, Xu Hua, Hui Zhou, Hong-Jian Wei, Nicholas McQuillan, Kyung-Don Kang, Gregory K. Friedman, Peter D. Canoll, Kenneth Chang, Cheng-Chia Wu, Rintaro Hashizume, Christopher R. Vakoc, Michelle Monje, Guy M. McKhann, Joseph A. Gogos, Zhiguo Zhang

    High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone

  •   A functional survey of the regulatory landscape of estrogen-receptor-positive breast cancer evolution
    Cancer Discov. (IF 29.7) Pub Date : 2024-05-16
    Iros Barozzi, Neil Slaven, Eleonora Canale, Rui Lopes, Ines Amorim Monteiro Barbosa, Melusine Bleu, Diana Ivanoiu, Claudia Pacini, Emanuela Mensa, Alfie Chambers, Sara Bravaccini, Sara Ravaioli, Balazs Gyorffy, Maria Vittoria Dieci, Giancarlo Pruneri, Giorgio G. Galli, Luca Magnani

    Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer (HDBC), potentially explaining ~40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing

  •   Perivascular NOTCH3+ stem cells drive meningioma tumorigenesis and resistance to radiotherapy
    Cancer Discov. (IF 29.7) Pub Date : 2024-05-14
    Abrar Choudhury, Martha A. Cady, Calixto-Hope G. Lucas, Hinda Najem, Joanna J. Phillips, Brisa Palikuqi, Naomi Zakimi, Tara Joseph, Janeth Ochoa. Birrueta, William C. Chen, Nancy Ann Oberheim Bush, Shawn L. Hervey-Jumper, Ophir D. Klein, Christine M. Toedebusch, Craig M. Horbinski, Stephen T. Magill, Aparna Bhaduri, Arie Perry, Peter J. Dickinson, Amy B. Heimberger, Alan Ashworth, Elizabeth E. Crouch

    Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood

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