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JOURNAL ARTICLE
Rona Yaeger, Meredith A McKean, Rizwan Haq, J Thaddeus Beck, Matthew H Taylor, Jonathan Eliezer Cohen, Daniel W Bowles, Shirish M Gadgeel, Catalin Mihalcioiu, Kyriakos P Papadopoulos, Eli L Diamond, Keren B Sturtz, Gang Feng, Stefanie K Drescher, Micaela B Reddy, Bhaswati Sengupta, Arnab K Maity, Suzy A Brown, Anurag Singh, Eric N Brown, Brian R Baer, Jim Wong, Tung-Chung Mou, Wen-I Wu, Dean R Kahn, Sunyana Gadal, Neal Rosen, John J Gaudino, Patrice A Lee, Dylan P Hartley, S Michael Rothenberg
RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling...
April 30, 2024: Cancer Discovery
#2
JOURNAL ARTICLE
Jad I Belle, Devashish Sen, John M Baer, Xiuting Liu, Varintra E Lander, Jiayu Ye, Blake E Sells, Brett L Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C Fields, Li Ding, Hyun Kim, Paolo P Provenzano, Sheila A Stewart, David G DeNardo
UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression...
April 29, 2024: Cancer Discovery
#3
JOURNAL ARTICLE
Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart
The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast cancer associated fibroblasts (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth...
April 29, 2024: Cancer Discovery
#4
JOURNAL ARTICLE
Jad I Belle, Devashish Sen, John M Baer, Xiuting Liu, Varintra E Lander, Jiayu Ye, Blake E Sells, Brett L Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C Fields, Li Ding, Hyun Kim, Paolo P Provenzano, Sheila A Stewart, David G DeNardo
PDAC therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression...
April 29, 2024: Cancer Discovery
#5
JOURNAL ARTICLE
Sean R Corcoran, James D Phelan, Jaewoo Choi, Galina Shevchenko, Rachel E Fenner, Xin Yu, Sebastian Scheich, Tony Hsiao, Vivian M Morris, Evangelia K Papachristou, Kamal Kishore, Clive S D'Santos, Yanlong Ji, Stefania Pittaluga, George W Wright, Henning Urlaub, Kuan-Ting Pan, Thomas Oellerich, Jagan Muppidi, Daniel J Hodson, Louis M Staudt
Polatuzumab Vedotin (Pola-V) is an antibody-drug conjugate directed to the CD79B subunit of the B cell receptor (BCR). When combined with conventional immunochemotherapy, Pola-V improves outcomes in DLBCL. To identify determinants of Pola-V sensitivity, we used CRISPR-Cas9 screening for genes that modulated Pola-V toxicity for lymphomas or the surface expression of its target, CD79B. Our results reveal the striking impact of CD79B glycosylation on Pola-V epitope availability on the lymphoma cell surface and on Pola-V toxicity...
April 25, 2024: Cancer Discovery
#6
JOURNAL ARTICLE
Yiman Liu, Qinglan Li, Lele Song, Chujie Gong, Sylvia Tang, Krista A Budinich, Ashley Vanderbeck, Kaeli M Mathias, Gerald B Wertheim, Son C Nguyen, Riley Outen, Eric F Joyce, Ivan Maillard, Liling Wan
Gain-of-function mutations in the histone acetylation 'reader' ENL, found in AML and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications...
April 24, 2024: Cancer Discovery
#7
JOURNAL ARTICLE
Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart
UNLABELLED: The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth...
April 17, 2024: Cancer Discovery
#8
JOURNAL ARTICLE
Arnau Llinas-Bertran, Meritxell Bellet-Ezquerra, Jose A Seoane
Rosano, Sofyali, Dhiman, and colleagues show that epigenetic-related changes occur in endocrine therapy (ET)-induced dormancy in estrogen receptor positive (ER+) breast cancer, as well as in its reawakening. Targeting these epigenetic changes blocks the entrance to dormancy and reduces the persister cancer cell population, enhancing the cytotoxic effects of ET in vitro. See related article by Rosano et al. (9).
April 10, 2024: Cancer Discovery
#9
JOURNAL ARTICLE
Jingjing Jiang, Lingyan Jiang, Benjamin J Maldonato, Yingyun Wang, Matthew Holderfield, Ida Aronchik, Ian P Winters, Zeena Salman, Cristina Blaj, Marie Menard, Jens Brodbeck, Zhe Chen, Xing Wei, Michael J Rosen, Yevgeniy Gindin, Bianca J Lee, James W Evans, Stephanie Chang, Zhican Wang, Kyle J Seamon, Dylan Parsons, James Cregg, Abby Marquez, Aidan C A Tomlinson, Jason K Yano, John E Knox, Elsa Quintana, Andrew J Aguirre, Kathryn C Arbour, Abby Reed, W Clay Gustafson, Adrian L Gill, Elena S Koltun, David Wildes, Jacqueline A M Smith, Zhengping Wang, Mallika Singh
UNLABELLED: RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models...
April 9, 2024: Cancer Discovery
#10
JOURNAL ARTICLE
Gavriel Y Matt, Edgar Sioson, Kyla Shelton, Jian Wang, Congyu Lu, Airen Zaldivar Peraza, Karishma Gangwani, Robin Paul, Colleen Reilly, Aleksandar Acić, Qi Liu, Stephanie R Sandor, Clay McLeod, Jaimin Patel, Fan Wang, Cindy Im, Zhaoming Wang, Yadav Sapkota, Carmen L Wilson, Nickhill Bhakta, Kirsten K Ness, Gregory T Armstrong, Melissa M Hudson, Leslie L Robison, Jinghui Zhang, Yutaka Yasui, Xin Zhou
Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. Over 1,600 phenotypic variables and 400 million genetic variants from over 7,700 childhood cancer survivors can be explored on this free, open-access portal...
April 9, 2024: Cancer Discovery
#11
JOURNAL ARTICLE
Gabriele Picco, Yanhua Rao, Angham Al Saedi, Yang Lee, Sara F Vieira, Shriram Bhosle, Kieron May, Carmen Herranz-Ors, Samantha J Walker, Raynold Shenje, Cansu Dincer, Freddy Gibson, Ruby Banerjee, Zoe Hewitson, Thilo Werner, Joshua E Cottom, Yang Peng, Nanhua Deng, Philip Landis, Daniela Conticelli, Katrina McCarten, Jacob Bush, Mamta Sharma, Howard Lightfoot, David House, Emma Milford, Emma K Grant, Michal P Glogowski, Craig D Wagner, Marcus Bantscheff, Anna Rutkowska-Klute, Cell Model Network Uk Group, Francesca Zappacosta, Jonathan Pettinger, Syd Barthorpe, H Christian Eberl, Brian T Jones, Jessica L Schneck, Dennis J Murphy, Emile E Voest, Joshua P Taygerly, Michael P DeMartino, Matthew A Coelho, Jonathan Houseley, Geeta Sharma, Benjamin J Schwartz, Mathew J Garnett
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage...
April 9, 2024: Cancer Discovery
#12
JOURNAL ARTICLE
Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjostrom, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A Johnson, Xiang Li, Xiaoling Li, Lauren A Metang, Atreyi Mukherji, Quanhui Xu, Carla Rodriguez Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B Hanker, Ganesh V Raj, Guanghui Zhu, Housheng Hansen He, Zhao Wang, Carlos L Arteaga, Han Liang, Felix Y Feng, Yunguan Wang, Tao Wang, Ping Mu
Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage...
April 8, 2024: Cancer Discovery
#13
JOURNAL ARTICLE
Meagan B Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E Cohen, Brooke M Swalm, Chun Li, Aysegul Ozen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C Dar, Yongxin Han, Klaus P Hoeflich, Michael Hale, Margit Hagel
Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors...
April 8, 2024: Cancer Discovery
#14
JOURNAL ARTICLE
Rona Yaeger, Nataliya V Uboha, Meredith S Pelster, Tanios S Bekaii-Saab, Minal Barve, Joel Saltzman, Joshua K Sabari, Julio A Peguero, Andrew Scott Paulson, Pasi A Jänne, Marcia Cruz-Correa, Kenna Anderes, Karen Velastegui, Xiaohong Yan, Hirak Der-Torossian, Samuel J Klempner, Scott E Kopetz
UNLABELLED: Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab...
April 8, 2024: Cancer Discovery
#15
JOURNAL ARTICLE
Katey S S Enfield, Emma Colliver, Claudia S Y Lee, Alastair Magness, David A Moore, Monica Sivakumar, Kristiana Grigoriadis, Oriol Pich, Takahiro Karasaki, Philip S Hobson, Dina Levi, Selvaraju Veeriah, Clare Puttick, Emma L Nye, Mary Green, Krijn K Dijkstra, Masako Shimato, Ayse U Akarca, Teresa Marafioti, Roberto Salgado, Allan Hackshaw, TRACERx Consortium, Mariam Jamal-Hanjani, Febe van Maldegem, Nicholas McGranahan, Benjamin Glass, Hanna Pulaski, Eric Walk, James L Reading, Sergio A Quezada, Crispin T Hiley, Julian Downward, Erik Sahai, Charles Swanton, Mihaela Angelova
Understanding the role of the tumour microenvironment (TME) in lung cancer is critical to improving patient outcome. We identified four histology-independent archetype TMEs in treatment-naive early-stage lung cancer using imaging mass cytometry in the TRACERx study (n=81 patients/198 samples/2.3million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC)...
April 6, 2024: Cancer Discovery
#16
JOURNAL ARTICLE
Sumanta K Pal, Ben Tran, John B A G Haanen, Michael E Hurwitz, Adrian Sacher, Nizar M Tannir, Lihua E Budde, Simon J Harrison, Sebastian Klobuch, Sagar S Patel, Luis Meza, Mary-Lee Dequeant, Anna Ma, Qiuling Ally He, Leah M Williams, Alissa Keegan, Ellen B Gurary, Henia Dar, Sushant Karnik, Changan Guo, Heidi Heath, Rachel R Yuen, Phuong K Morrow, Neeraj Agarwal, Samer A Srour
UNLABELLED: Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial...
April 5, 2024: Cancer Discovery
#17
JOURNAL ARTICLE
Yu Wei Zhang, Ana Gvozdenovic, Nicola Aceto
UNLABELLED: Circulating tumor cells (CTCs) play a pivotal role in metastasis, the leading cause of cancer-associated death. Recent improvements of CTC isolation tools, coupled with a steady development of multiomics technologies at single-cell resolution, have enabled an extensive exploration of CTC biology, unlocking insights into their molecular profiles. A detailed molecular portrait requires CTC interrogation across various levels encompassing genomic, epigenetic, transcriptomic, proteomic and metabolic features...
April 5, 2024: Cancer Discovery
#18
JOURNAL ARTICLE
Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Farah A Alayli, Christopher P Loo, Shikha Gautam, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John G Auniņš, Christopher McChalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa LaVallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo
UNLABELLED: Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutes-enriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]...
April 4, 2024: Cancer Discovery
#19
JOURNAL ARTICLE
Cameron R Walker, Michael Angelo
The recent development of high-dimensional spatial omics tools has revealed the functional importance of the tumor microenvironment in driving tumor progression. Here, we discuss practical factors to consider when designing a spatial biology cohort and offer perspectives on the future of spatial biology research.
April 3, 2024: Cancer Discovery
#20
JOURNAL ARTICLE
Federica Pecci, Seshiru Nakazawa, Biagio Ricciuti, Guilherme Harada, Jessica K Lee, Joao V Alessi, Adriana Barrichello, Victor R Vaz, Giuseppe Lamberti, Alessandro Di Federico, Malini M Gandhi, Dimitris Gazgalis, William W Feng, Jie Jiang, Simon Baldacci, Marie-Anais Locquet, Felix H Gottlieb, Monica F Chen, Elinton Lee, Danielle Haradon, Anna Smokovich, Emma Voligny, Tom Nguyen, Vikas K Goel, Zachary Zimmerman, Sumandeep Atwal, Xinan Wang, Magda Bahcall, Rebecca S Heist, Sumaiya Iqbal, Nishant Gandhi, Andrew Elliott, Ari M Vanderwalde, Patrick C Ma, Balazs Halmos, Stephen V Liu, Jianwei Che, Alexa B Schrock, Alexander Drilon, Pasi A Janne, Mark M Awad
Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others...
April 3, 2024: Cancer Discovery
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