journal
https://read.qxmd.com/read/38230747/jak2v617f-reversible-activation-shows-its-essential-requirement-in-myeloproliferative-neoplasms
#21
JOURNAL ARTICLE
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, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R Martinez Benitez, Aaron D Viny, Richard P Koche, Sara C Meyer, Dan A Landau, Ross L Levine
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 to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined, Dre-rox/Cre-lox dual recombinase system...
January 12, 2024: Cancer Discovery
https://read.qxmd.com/read/38227896/trex1-inactivation-unleashes-cancer-cell-sting-interferon-signaling-and-promotes-anti-tumor-immunity
#22
JOURNAL ARTICLE
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, Jennifer Cain, David A Barbie
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 acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification...
January 10, 2024: Cancer Discovery
https://read.qxmd.com/read/38197697/passenger-gene-co-amplifications-create-collateral-therapeutic-vulnerabilities-in-cancer
#23
JOURNAL ARTICLE
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, Clemens A Schmitt, Johannes H Schulte, Angelika Eggert, Kerstin Haase, Jennifer Kirwan, Anja Ih Hagemann, Philipp Mertins, Jan R Dorr, Anton G Henssen
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 profiles. In a proof-of-principle study, we demonstrate that co-amplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency to the mTOR pathway...
January 10, 2024: Cancer Discovery
https://read.qxmd.com/read/38197680/non-invasive-detection-of-neuroendocrine-prostate-cancer-through-targeted-cell-free-dna-methylation
#24
JOURNAL ARTICLE
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, Ana Aparicio, Francesca Demichelis, Himisha Beltran
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 metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA)...
January 10, 2024: Cancer Discovery
https://read.qxmd.com/read/38197599/micronuclei-and-cancer
#25
JOURNAL ARTICLE
Melody Di Bona, Samuel F Bakhoum
UNLABELLED: 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, we provide a brief historical account of micronuclei, depict the mechanisms underpinning their creation, and illuminate their capacity to propel tumor evolution through genetic, epigenetic, and transcriptional transformations...
January 10, 2024: Cancer Discovery
https://read.qxmd.com/read/38189443/targeting-dhx9-triggers-tumor-intrinsic-interferon-response-and-replication-stress-in-small-cell-lung-cancer
#26
JOURNAL ARTICLE
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 (SCLCs). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity...
January 8, 2024: Cancer Discovery
https://read.qxmd.com/read/38426560/insights-into-the-molecular-mechanisms-of-genetic-predisposition-to-hematopoietic-malignancies-the-importance-of-gene-environment-interactions
#27
JOURNAL ARTICLE
Cesar Cobaleda, Lucy A Godley, Kim E Nichols, Marcin W Wlodarski, Isidro Sanchez-Garcia
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 and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways...
March 1, 2024: Cancer Discovery
https://read.qxmd.com/read/38426559/targeting-the-dhx9-rna-helicase-to-induce-antitumor-immunity-in-small-cell-lung-cancer
#28
JOURNAL ARTICLE
Katherine B Chiappinelli
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) .
March 1, 2024: Cancer Discovery
https://read.qxmd.com/read/38426558/a-highly-anticipated-selective-therapeutic-agent-against-cdk2-inx-315
#29
JOURNAL ARTICLE
Lotte P Watts, Sabrina L Spencer
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).
March 1, 2024: Cancer Discovery
https://read.qxmd.com/read/38426557/biodiversity-medicine-new-horizon-and-new-opportunity-for-cancer
#30
JOURNAL ARTICLE
Jing Han Hong, Abner Herbert Lim, Khwanta Kaewnarin, Jason Yongsheng Chan, Cedric Chuan Young Ng, Bin Tean Teh
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 cancer treatment: the use of science-based biodiversity medicine as an alternative to modern drug therapy, in which we will leverage and combine high-throughput omics technologies with artificial intelligence, to study local biodiversity, their potential anticancer properties, and short- and long-term clinical response and outcomes...
March 1, 2024: Cancer Discovery
https://read.qxmd.com/read/38327193/precision-targeting-of-mutant-pi3k%C3%AE
#31
JOURNAL ARTICLE
Grace Q Gong, Bart Vanhaesebroeck
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) . See related article by Varkaris et al., p. 240 (5) .
February 8, 2024: Cancer Discovery
https://read.qxmd.com/read/38327192/-ripping-off-pancreas-cancer-s-blockage-of-immune-surveillance
#32
JOURNAL ARTICLE
Xiuting Liu, Blake E Sells, David G DeNardo
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 by Sang et al., p. 326 (1) .
February 8, 2024: Cancer Discovery
https://read.qxmd.com/read/38327191/mutant-p53-gain-of-function-in-the-spotlight-are-we-suffering-a-gof-delusion
#33
JOURNAL ARTICLE
David P Lane
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 et al., p. 362 (10) .
February 8, 2024: Cancer Discovery
https://read.qxmd.com/read/37931288/alveolar-differentiation-drives-resistance-to-kras-inhibition-in-lung-adenocarcinoma
#34
JOURNAL ARTICLE
Zhuxuan Li, Xueqian Zhuang, Chun-Hao Pan, Yan Yan, Rohit Thummalapalli, Jill Hallin, Stefan Torborg, Anupriya Singhal, Jason C Chang, Eusebio Manchado, Lukas E Dow, Rona Yaeger, James G Christensen, Scott W Lowe, Charles M Rudin, Simon Joost, Tuomas Tammela
UNLABELLED: Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors...
February 8, 2024: Cancer Discovery
https://read.qxmd.com/read/37916956/discovery-and-clinical-proof-of-concept-of-rly-2608-a-first-in-class-mutant-selective-allosteric-pi3k%C3%AE-inhibitor-that-decouples-antitumor-activity-from-hyperinsulinemia
#35
JOURNAL ARTICLE
Andreas Varkaris, Ermira Pazolli, Hakan Gunaydin, Qi Wang, Levi Pierce, Alessandro A Boezio, Artemisa Bulku, Lucian DiPietro, Cary Fridrich, Adam Frost, Fabrizio Giordanetto, Erika P Hamilton, Katherine Harris, Michael Holliday, Tamieka L Hunter, Amanda Iskandar, Yongli Ji, Alexandre Larivée, Jonathan R LaRochelle, André Lescarbeau, Fabien Llambi, Brenda Lormil, Mary M Mader, Brenton G Mar, Iain Martin, Thomas H McLean, Klaus Michelsen, Yakov Pechersky, Erika Puente-Poushnejad, Kevin Raynor, Dipali Rogala, Ramin Samadani, Alison M Schram, Kelley Shortsleeves, Sweta Swaminathan, Shahein Tajmir, Gege Tan, Yong Tang, Roberto Valverde, Bryan Wehrenberg, Jeremy Wilbur, Bret R Williams, Hongtao Zeng, Hanmo Zhang, W Patrick Walters, Beni B Wolf, David E Shaw, Donald A Bergstrom, James Watters, James S Fraser, Pascal D Fortin, D Randal Kipp
UNLABELLED: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation...
February 8, 2024: Cancer Discovery
https://read.qxmd.com/read/37791898/nkg2a-is-a-therapeutic-vulnerability-in-immunotherapy-resistant-mhc-i-heterogeneous-triple-negative-breast-cancer
#36
JOURNAL ARTICLE
Brandie C Taylor, Xiaopeng Sun, Paula I Gonzalez-Ericsson, Violeta Sanchez, Melinda E Sanders, Elizabeth C Wescott, Susan R Opalenik, Ann Hanna, Shu-Ting Chou, Luc Van Kaer, Henry Gomez, Claudine Isaacs, Tarah J Ballinger, Cesar A Santa-Maria, Payal D Shah, Elizabeth C Dees, Brian D Lehmann, Vandana G Abramson, Jennifer A Pietenpol, Justin M Balko
UNLABELLED: Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner...
February 8, 2024: Cancer Discovery
https://read.qxmd.com/read/38213299/bispecific-t-cell-engagers-in-metastatic-castration-resistant-prostate-cancer
#37
EDITORIAL
Chadi Hage Chehade, Georges Gebrael, Neeraj Agarwal
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 et al., p. 76 (8).
January 12, 2024: Cancer Discovery
https://read.qxmd.com/read/38213298/is-it-time-to-incorporate-liquid-biopsy-into-high-risk-cancer-surveillance-protocols-in-li-fraumeni-syndrome
#38
EDITORIAL
Alicia Latham, Suzanne P MacFarland, Michael F Walsh, Kara N Maxwell, Zsofia K Stadler
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 validation in larger cohorts is needed, this research highlights that a multimodal approach is likely necessary to improve the sensitivity of liquid biopsy assays for early cancer detection...
January 12, 2024: Cancer Discovery
https://read.qxmd.com/read/38213297/measuring-progress-in-precision-oncology
#39
EDITORIAL
Peter Horak, Stefan Fröhling
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 of candidate therapeutic targets through comprehensive tumor profiling and molecularly guided cancer drug development. See related article by Suehnholz et al...
January 12, 2024: Cancer Discovery
https://read.qxmd.com/read/38213296/uncan-eu-toward-a-european-federated-cancer-research-data-hub
#40
JOURNAL ARTICLE
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
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 discuss the governance and long-term evolution of a European Federated Cancer Data Hub.
January 12, 2024: Cancer Discovery
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