Article
Cell Biology
Camilla Calandrini, Sander R. van Hooff, Irene Paassen, Dilara Ayyildiz, Sepide Derakhshan, M. Emmy M. Dolman, Karin P. S. Langenberg, Marieke van de Ven, Cecilia de Heus, Nalan Liv, Marcel Kool, Ronald R. de Krijger, Godelieve A. M. Tytgat, Marry M. Van den Heuvel-Eibrink, Jan J. Molenaar, Jarno Drost
Summary: This study demonstrates that drug screening using organoids can identify therapeutic vulnerabilities in MRT and proposes neddylation inhibition as a potential treatment strategy. Mechanistic studies and in vivo experiments confirm the therapeutic efficacy of MLN4924 for MRT, suggesting a new direction for targeted therapy in this aggressive childhood malignancy.
Article
Multidisciplinary Sciences
Salima Benbarche, Cecile K. Lopez, Eralda Salataj, Zakia Aid, Cecile Thirant, Marie-Charlotte Laiguillon, Severine Lecourt, Yannis Belloucif, Camille Vaganay, Marion Antonini, Jiang Hu, Alexandra da Silva Babinet, Delphine Ndiaye-Lobry, Bryann Pardieu, Arnaud Petit, Alexandre Puissant, Julie Chaumeil, Thomas Mercher, Camille Lobry
Summary: This study reveals that fusion oncogenes like ETO2-GLIS2 can induce the activation of Super Enhancers (SEs) that regulate essential gene modules synergizing for leukemia progression, promoting the growth and survival of leukemia cells.
Article
Oncology
Yukitomo Ishi, Yongzhan Zhang, Ali Zhang, Takahiro Sasaki, Andrea Piunti, Amreena Suri, Jun Watanabe, Kouki Abe, Xingyao He, Hiroaki Katagi, Pankaj Bhalla, Manabu Natsumeda, Lihua Zou, Ali Shilatifard, Rintaro Hashizume
Summary: Targeted inhibition of EZH2 and BRD4 activities is an effective approach for treating AT/RT, reducing cell proliferation and invasiveness. The combination of EZH2 and BRD4 inhibition shows increased therapeutic benefit in vitro and in vivo.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Oncology
Katherine E. Miller, Gregory Wheeler, Stephanie LaHaye, Kathleen M. Schieffer, Sydney Cearlock, Lakshmi Prakruthi Rao Venkata, Alejandro Otero Bravo, Olivia E. Grischow, Benjamin J. Kelly, Peter White, Christopher R. Pierson, Daniel R. Boue, Selene C. Koo, Darren Klawinski, Mark A. Ranalli, Ammar Shaikhouni, Ralph Salloum, Margaret Shatara, Jeffrey R. Leonard, Richard K. Wilson, Catherine E. Cottrell, Elaine R. Mardis, Daniel C. Koboldt
Summary: This study analyzed seven rhabdoid tumors from three pediatric patients using a multimodal molecular approach. The findings revealed SMARCB1 germline alterations in all patients and tumors, as well as different subgroups of rhabdoid tumors. The study also showed non-clonal origin of synchronous brain and kidney tumors, and suggested the likely origin of lung and abdominal metastasis. Other genetic events were identified in tumors but did not offer prognostic or therapeutic potential for rhabdoid tumors.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Hsin-Wei Wu, Chia-Hung Wu, Shih-Chieh Lin, Chih-Chun Wu, Hsin-Hung Chen, Yi-Wei Chen, Yi-Yen Lee, Feng-Chi Chang
Summary: This study aimed to differentiate atypical teratoid rhabdoid tumor (AT/RT) from medulloblastoma based on clinical and MRI features. MRI findings, including lower ADC value, more peritumoral invasion, and absence of the tumor central vein sign, may be helpful in distinguishing AT/RT from medulloblastoma.
Article
Oncology
Julian Kolorz, Salih Demir, Adrian Gottschlich, Iris Beirith, Matthias Ilmer, Daniel Luethy, Christoph Walz, Mario M. Dorostkar, Thomas Magg, Fabian Hauck, Dietrich von Schweinitz, Sebastian Kobold, Roland Kappler, Michael Berger
Summary: This study found that neurokinin-1 receptor is highly expressed in Rhabdoid tumors and demonstrated that the neurokinin-1 receptor antagonist aprepitant can serve as a novel therapeutic approach in treating Rhabdoid tumors.
Review
Pharmacology & Pharmacy
Zhongyan Zhang, Hailiang Wang, Qian Yan, Jinwei Cui, Yubin Chen, Shiye Ruan, Jiayu Yang, Zelong Wu, Mingqian Han, Shanzhou Huang, Qi Zhou, Chuanzhao Zhang, Baohua Hou
Summary: Genome-wide CRISPR/Cas9 screening is an important method for identifying drug resistance-associated genes. It has been widely used in the treatment of malignancies with drug resistance, and has significant implications for further treatment.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Oncology
Andrew J. Bellantoni, Lars M. Wagner
Summary: Precision oncology offers a more effective treatment option for pediatric solid tumors, particularly those driven by kinase fusions. However, the efficacy of these treatments is limited for tumors without genetic alterations due to the lack of predictive biomarkers.
Article
Biochemistry & Molecular Biology
Sama Shamloo, Andreas Kloetgen, Stavroula Petroulia, Kathryn Hockemeyer, Sonja Sievers, Aristotelis Tsirigos, Ioannis Aifantis, Jochen Imig
Summary: The incidence of melanoma, a commonly occurring cancer, has been increasing. Advanced-stage melanoma patients have poor prognoses compared to earlier stages. Targeted therapies for advanced-stage melanomas have been effective, but patients develop BRAF-inhibitor resistance. This resistance is mainly driven by mutations in the MAPK pathway, but other factors such as lncRNAs are still poorly understood. A comprehensive study on lncRNA expression and screening for BRAF inhibitor resistance can provide valuable insights for potential combinatorial treatment approaches.
Article
Clinical Neurology
Pascal D. Johann, Lea Altendorf, Emma-Maria Efremova, Till Holsten, Mona Steinbuegl, Karolina Nemes, Alicia Eckhardt, Catena Kresbach, Michael Bockmayr, Arend Koch, Christine Haberler, Manila Antonelli, John DeSisto, Martin U. Schuhmann, Peter Hauser, Reiner Siebert, Susanne Bens, Marcel Kool, Adam L. Green, Martin Hasselblatt, Michael C. Fruehwald, Ulrich Schueller
Summary: This study investigated the molecular characteristics of recurrent AT/RT tumors compared to their matched primary tumors. It found that there were subtle molecular changes, with chromosome 1q gain and chromosome 10 loss being the most common alterations in recurrences. These findings may help identify novel therapeutic targets for AT/RT recurrences.
ACTA NEUROPATHOLOGICA
(2023)
Article
Pharmacology & Pharmacy
Maria Krchniakova, Silvia Paukovcekova, Petr Chlapek, Jakub Neradil, Jan Skoda, Renata Veselska
Summary: This study analyzed the effects of combining three TKIs and two iron-chelating agents in the treatment of pediatric solid tumors. The results showed that the combination of these drugs had synergistic and/or additive effects, inhibiting cell signaling and inducing apoptosis. The combination of lapatinib with the iron-chelating agents had the most significant effects. These findings provide a rationale for the novel strategy of combining iron-chelating agents with TKIs in the therapy of pediatric solid tumors.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biology
Laura Schubert, Anh T. Le, Trista K. Hinz, Andre C. Navarro, Sarah K. Nelson-Taylor, Raphael A. Nemenoff, Lynn E. Heasley, Robert C. Doebele
Summary: CRISPR/Cas9 gene editing is a powerful tool in cancer biology, and this article introduces a novel method of validating sgRNAs that successfully target their intended loci and generate oncogenic gene rearrangements, using IL3-independence in Ba/F3 cells.
Article
Oncology
Katrina M. Morgan, Vei Shaun Siow, Stephen Strotmeyer, Kenneth W. Gow, Marcus M. Malek
Summary: Pediatric non-CNS MRTs are rare and aggressive malignancies. Age <1 year and presence of metastasis are negative prognostic indicators, while surgical intervention can improve survival rates. However, the presence of residual disease may lead to worse outcomes.
ANNALS OF SURGICAL ONCOLOGY
(2021)
Editorial Material
Clinical Neurology
Rohan Rao, Abigail Koehler, Yehudit Rothman, Brandi Turner, Jamie Denlinger, Melissa Erickson, Matthew Hagen, Timothy S. Braverman, Abdelkader Mahammedi, Karl Golnik, Mario Zuccarello, Yair M. Gozal, E. Randolph Broun, Susan N. Chi, Soma Sengupta
Summary: This case reports a rare 43-year-old female patient with ATRT who responded well to a slightly modified treatment plan.
Article
Oncology
Xiaojing Lu, Yuzhi Pang, Hui Cao, Xiaoxiao Liu, Lin Tu, Yanying Shen, Xiaona Jia, Jen-Chieh Lee, Yuexiang Wang
Summary: CDK1 is highly expressed in advanced GIST and essential for GIST proliferation. Inhibition of CDK1 with RO-3306 showed promising results in reducing tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models, suggesting CDK1 as a potential therapeutic target for advanced GIST patients.
Article
Oncology
Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh Dharia, Luca Mariani, Noha A. M. Shendy, Stephanie Nance, Anand G. Patel, Ying Shao, Maya Mundada, Lily Maxham, Paul M. C. Park, Logan H. Sigua, Ken Morita, Amy Saur Conway, Amanda L. Robichaud, Antonio R. Perez-Atayde, Melissa J. Bikowitz, Taylor R. Quinn, Olaf Wiest, John Easton, Ernst Schonbrunn, Martha L. Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi
Summary: Gene expression is regulated by histone modifications, and EP300 plays a significant role in high-risk neuroblastoma. The compound JQAD1, which targets EP300, effectively induces cell apoptosis in neuroblastoma cells with limited toxicity to normal cells.
Article
Biochemistry & Molecular Biology
Joshua Pan, Jason J. Kwon, Jessica A. Talamas, Ashir A. Borah, Francisca Vazquez, Jesse S. Boehm, Aviad Tsherniak, Marinka Zitnik, James M. McFarland, William C. Hahn
Summary: In high-throughput functional genomic screens, single gene perturbations can induce multiple cascading functional outcomes, known as pleiotropy. Our approach successfully recovered pleiotropic functions, untangled signaling pathways, and predicted unknown protein complex subunit stoichiometry using fitness screen data alone.
Meeting Abstract
Oncology
Lisa D. Cervia, Tsukasa Shibue, Benjamin Gaeta, Ashir A. Borah, Lisa Leung, Naomi Li, Nancy Dumont, Alfredo Gonzalez, Nolan Bick, Mariya Kazachkova, Joshua M. Dempster, John M. Krill-Burger, Federica Piccioni, Namrata D. Udeshi, Meagan E. Olive, Steven A. Carr, David E. Root, James M. McFarland, Francisca Vazquez, William C. Hahn
Article
Cell Biology
Taku Harada, Yaser Heshmati, Jeremie Kalfon, Monika W. Perez, Juliana Xavier Ferrucio, Jazmin Ewers, Benjamin Hubbell Engler, Andrew Kossenkov, Jana M. Ellegast, Joanna S. Yi, Allyson Bowker, Qian Zhu, Kenneth Eagle, Tianxin Liu, Yan Kai, Joshua M. Dempster, Guillaume Kugener, Jayamanna Wickramasinghe, Zachary T. Herbert, Charles H. Li, Jost Vrabic Koren, David M. Weinstock, Vikram R. Paralkar, Behnam Nabet, Charles Y. Lin, Neekesh Dharia, Kimberly Stegmaier, Stuart H. Orkin, Maxim Pimkin
Summary: In this study, MEF2D and IRF8 were identified as selective transcriptional dependencies of KMT2A-rearranged AML, forming a distinct core regulatory module that directly controls the expression of key oncogenes. This mechanism of context-specific transcriptional addiction highlights the importance of specialized regulatory circuits in specific AML subtypes.
GENES & DEVELOPMENT
(2022)
Article
Oncology
Jana M. Ellegast, Gabriela Alexe, Amanda Hamze, Shan Lin, Hannah J. Uckelmann, Philipp J. Rauch, Maxim Pimkin, Linda S. Ross, Neekesh Dharia, Amanda L. Robichaud, Amy Saur Conway, Delan Khalid, Jennifer A. Perry, Mark Wunderlich, Lina Benajiba, Yana Pikman, Behnam Nabet, Nathanael S. Gray, Stuart H. Orkin, Kimberly Stegmaier
Summary: This study identified IRF2BP2 as a selective AML dependency, revealing the importance of cell-intrinsic inflammatory signaling for leukemic cell death, and established IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.
Article
Medicine, General & Internal
Martin Jadersten, Ingrid Lilienthal, Nikolaos Tsesmetzis, Magda Lourda, Sofia Bengtzen, Anna Bohlin, Cornelia Arnroth, Tom Erkers, Brinton Seashore-Ludlow, Geraldine Giraud, Giti S. Barkhordar, Sijia Tao, Linda Fogelstrand, Leonie Saft, Paivi Ostling, Raymond F. Schinazi, Baek Kim, Torsten Schaller, Gunnar Juliusson, Stefan Deneberg, Soren Lehmann, Georgios Z. Rassidakis, Martin Hoglund, Jan-Inge Henter, Nikolas Herold
Summary: The addition of hydroxyurea to standard chemotherapy in newly diagnosed AML patients appears to be safe and effective, resulting in high rates of complete remission and reduced measurable residual disease. Targeted inhibition of SAMHD1 by hydroxyurea enhances the efficacy of cytarabine treatment.
JOURNAL OF INTERNAL MEDICINE
(2022)
Article
Oncology
Eshini Panditharatna, Joana G. Marques, Tingjian Wang, Maria C. Trissal, Ilon Liu, Li Jiang, Alexander Beck, Andrew Groves, Neekesh Dharia, Deyao Li, Samantha E. Hoffman, Guillaume Kugener, McKenzie L. Shaw, Hafsa M. Mire, Olivia A. Hack, Joshua M. Dempster, Caleb Lareau, Lingling Dai, Logan H. Sigua, Michael A. Quezada, Ann-Catherine J. Stanton, Meghan Wyatt, Zohra Kalani, Amy Goodale, Francisca Vazquez, Federica Piccioni, John G. Doench, David E. Root, Jamie N. Anastas, Kristen L. Jones, Amy Saur Conway, Sylwia Stopka, Michael S. Regan, Yu Liang, Hyuk-Soo Seo, Kijun Song, Puspalata Bashyal, William P. Jerome, Nathan D. Mathewson, Sirano Dhe-Paganon, Mario L. Suva, Angel M. Carcaboso, Cinzia Lavarino, Jaume Mora, Quang-De Nguyen, Keith L. Ligon, Yang Shi, Sameer Agnihotri, Nathalie Y. R. Agar, Kimberly Stegmaier, Charles D. Stiles, Michelle Monje, Todd R. Golub, Jun Qi, Mariella G. Filbin
Summary: This article introduces a new treatment strategy for H3K27M gliomas by inhibiting the BAF complex, which promotes differentiation and improves survival in patients.
Meeting Abstract
Hematology
Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh Dharia, Ashleigh Meyer, Delan Khalid, Sebastian Scheich, Bjoern Haeupl, Louis M. Staudt, Thomas Oellerich, Kimberly Stegmaier
Article
Cell Biology
Diana Y. Y. Lu, Jana M. Ellegast, Kenneth N. Ross, Clare F. Malone, Shan Lin, Nathaniel W. Mabe, Neekesh V. Dharia, Ashleigh Meyer, Amy Conway, Angela H. H. Su, Julia Selich-Anderson, Cenny Taslim, Andrea K. Byrum, Bo Kyung A. Seong, Biniam Adane, Nathanael S. Gray, Miguel N. Rivera, Stephen L. Lessnick, Kimberly Stegmaier
Summary: Transcription factors (TFs) are often mutated in cancer, but pediatric cancers exhibit few genome-wide mutations yet frequently have sentinel mutations affecting TFs. This study describes an alternative, central transcriptional mechanism in Ewing sarcoma wherein the constraint of the fusion TF EWS-FLI's activity supports cancer growth. ETV6 is identified as a crucial TF in this disease, repressing the transcriptional output of EWS-FLI.
NATURE CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Bennett K. Wolf, Yanding Zhao, Andrew McCray, William H. Hawk, Luke T. Deary, Nicholas W. Sugiarto, Ian S. LaCroix, Scott A. Gerber, Chao Cheng, Xiaofeng Wang
Summary: In this study, a multi-omics approach was used to investigate the dynamic targeting mechanism of SWI/SNF. The AP-1 family members were identified as critical interacting partners for SWI/SNF complexes. It was demonstrated that AP-1 and SWI/SNF cooperate in chromatin targeting and restructuring of the three-dimensional promoter-enhancer architecture. The interaction between AP-1 and SWI/SNF was found to be important for the chromatin localization mediated by SWI/SNF.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Oncology
Lisa D. Cervia, Tsukasa Shibue, Ashir A. Borah, Benjamin Gaeta, Linh He, Lisa Leung, Naomi Li, Sydney M. Moyer, Brian H. Shim, Nancy Dumont, Alfredo Gonzalez, Nolan R. Bick, Mariya Kazachkova, Joshua M. Dempster, John Michael Krill-Burger, Federica Piccioni, Namrata D. Udeshi, Meagan E. Olive, Steven A. Carr, David E. Root, James M. McFarland, Francisca Vazquez, William C. Hahn
Summary: By measuring gene essentiality in 1,086 cancer cell lines, we identified a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 that is crucial for the survival of a subset of epithelial tumors with high aneuploidy. Inhibiting BIRC6 in cell lines dependent on this complex significantly reduced cell fitness in vitro and resulted in tumor regression in vivo. Mechanistically, BIRC6 suppression activated the integrated stress response (ISR) by stabilizing the heme-regulated inhibitor, which is a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. This discovery provides insights into the regulation of ISR and offers a potential therapeutic strategy.
Article
Oncology
Ricardo de Matos Simoes, Ryosuke Shirasaki, Sondra L. Downey-Kopyscinski, Geoffrey M. Matthews, Benjamin G. Barwick, Vikas A. Gupta, Daphne Dupere-Richer, Shizuka Yamano, Yiguo Hu, Michal Sheffer, Eugen Dhimolea, Olga Dashevsky, Sara Gandolfi, Kazuya Ishiguro, Robin M. Meyers, Jordan G. Bryan, Neekesh V. Dharia, Paul J. Hengeveld, Johanna B. Bruggenthies, Huihui Tang, Andrew J. Aguirre, Quinlan L. Sievers, Benjamin L. Ebert, Brian J. Glassner, Christopher J. Ott, James E. Bradner, Nicholas P. Kwiatkowski, Daniel Auclair, Joan Levy, Jonathan J. Keats, Richard W. J. Groen, Nathanael S. Gray, Aedin C. Culhane, James M. McFarland, Joshua M. Dempster, Jonathan D. Licht, Lawrence H. Boise, William C. Hahn, Francisca Vazquez, Aviad Tsherniak, Constantine S. Mitsiades
Summary: Clinical progress in multiple myeloma has been limited due to the lack of therapies targeting specific oncogenic mutations. However, a study using CRISPR technology identified 116 genes that significantly affect the fitness of MM cells compared to other malignancies. These genes encode various factors critical for MM cell biology and provide new therapeutic targets not easily identifiable by standard genomic analysis.
Meeting Abstract
Oncology
Jimmy A. Guo, Jennifer Su, Ananya Jambhale, Julien Dilly, Connor J. Hennessey, Carina Shiau, Patrick Yu, Steven Wang, Junning Wang, Laleh Abbassi, James Neiswender, Tate Bertea, Annan Yang, Qijia Yu, Peter Westcott, Jason Schenkel, Daniel Y. Kim, Hannah I. Hoffman, Grissel Cervantes Jaramillo, Giselle A. Uribe, Westley W. Wu, Arnav Mehta, David Ting, Julian A. Pacheco, Amy Deik, Clary Clish, Francisca Vazquez, Brian Wolpin, Aviv Regev, William A. Freed-Pastor, Joseph D. Mancias, Tyler Jacks, William L. Hwang, Andrew J. Aguirre
Article
Biochemical Research Methods
Niklas Sandstroem, Valentina Carannante, Karl Olofsson, Patrick A. Sandoz, Elisabeth L. Moussaud-Lamodiere, Brinton Seashore-Ludlow, Hanna Van Ooijen, Quentin Verron, Thomas Frisk, Madoka Takai, Martin Wiklund, Paeivi Ostling, Bjorn Onfelt
Summary: In this study, a methodology based on a multichambered microwell chip is presented, which allows for direct assessment of drug or immune cell cytotoxic efficacy. The methodology enables long-term cell culture, efficient screening, and high-quality imaging. The feasibility of this methodology is demonstrated through drug cytotoxicity screening and cellular cytotoxicity screening experiments.
CELL REPORTS METHODS
(2022)
Article
Oncology
Daniel P. Bondeson, Brenton R. Paolella, Adhana Asfaw, Michael Rothberg, Thomas A. Skipper, Carly Langan, Gabriel Mesa, Alfredo Gonzalez, Lauren E. Surface, Kentaro Ito, Mariya Kazachkova, William N. Colgan, Allison Warren, Joshua M. Dempster, John M. Krill-Burger, Maria Ericsson, Andrew A. Tang, Iris Fung, Emily S. Chambers, Mai Abdusamad, Nancy Dumont, John G. Doench, Federica Piccioni, David E. Root, Jesse Boehm, William C. Hahn, Michael Mannstadt, James M. McFarland, Francisca Vazquez, Todd R. Golub
Summary: Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers remain bleak. In this study, the authors identified a correlation between overexpression of the phosphate importer SLC34A2 and sensitivity to the phosphate exporter XPR1 in cancer cell lines. They also observed this correlation in patient-derived tumor samples. Inhibition of phosphate efflux led to intracellular phosphate accumulation and reduced tumor cell viability.