Major advances in our understanding of cancer pathogenesis and therapy have come from efforts to catalog genomic alterations in cancer. A growing number of large-scale genomic studies have uncovered mutations that drive cancer by perturbing cotranscriptional and post-transcriptional regulation of gene expression. These include alterations that affect each phase of RNA processing, including splicing, transport, editing, and decay of messenger RNA. The discovery of these events illuminates a number...
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Mixed-lineage leukemia (MLL) complexes bound in only one mode to nucleosomes with ubiquitinated H2B.
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Research on breast cancer is rapidly progressing, leading to new therapies and treatment approaches, yet in men with the disease it continues to lag. Recently, the FDA released a draft guidance to address this disparity, outlining strategies to improve drug development for men such as including them in clinical trials and using nontraditional data sources.
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A Chinese study of patients with HER2-positive metastatic breast cancer shows that the HER2 inhibitor pyrotinib increases progression-free survival and objective response rates over lapatinib. Pyrotinib did increase the incidence of side effects such as diarrhea and hand–foot syndrome. However, about 54% of trial participants had previously taken trastuzumab, so the study's results may not hold true in the United States, where most patients receive it.
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In mouse models of melanoma, lower intratumoral heterogeneity (ITH) correlated with lower tumor growth.
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A recent U.S. Preventive Services Task Force statement reiterates the importance of screening women for BRCA1/2 mutations and recommends that more women undergo risk-assessment screening, including those with a personal history of certain cancers and those with certain ancestries. Experts consider the recommendations a positive, if incremental, step that will likely have the biggest impact on community practices.
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Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSC). Here, we show that GSCs, differentiated glioblastoma cells (DGC), and nonmalignant brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell-cycle arrest and apoptosis. Chromatin immunoprecipitation revealed that BMAL1 preferentially...
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Ptpn2 deletion increased the ratio of TIM3+ terminally exhausted to SLAMF6+ progenitor CD8+ T cells.
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Restoration of p53 led to an accumulation of αKG in mouse pancreatic cancer cells.
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Hematopoietic stem cell–engineered invariant NK T (HSC-iNKT) cells have preclinical antitumor activity.
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Pegilodecakin plus anti–PD-1 showed tolerability and efficacy in some advanced solid tumors.
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Dimeric BRAF kinase domains bound to dimeric scaffold protein 14-3-3 had active-site asymmetry.
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Summary:T-cell transfer into lymphodepleted recipients results not only in homeostatic activation of the infused cells but also in T-cell inhibition due to upregulation of immune checkpoint receptors including PD-1 and CTLA4, thereby mitigating T-cell efficacy. Dual checkpoint blockade of PD-1 and CTLA4 in conjunction with lymphodepletion—an "immunotransplant"—uncouples the T-cell inhibition from activation and amplifies the T-cell antitumor immune response. See related article by Marshall et al.,...
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T-cell transfer into lymphodepleted recipients induces homeostatic activation and potentiates antitumor efficacy. In contrast to canonical T-cell receptor–induced activation, homeostatic activation yields a distinct phenotype and memory state whose regulatory mechanisms are poorly understood. Here, we show in patients and murine models that, following transfer into lymphodepleted bone marrow transplant (BMT) recipients, CD8+ T cells undergo activation but also simultaneous homeostatic inhibition...
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The kinase LKB1 is a critical tumor suppressor in sporadic and familial human cancers, yet the mechanisms by which it suppresses tumor growth remain poorly understood. To investigate the tumor-suppressive capacity of four canonical families of LKB1 substrates in vivo, we used CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic KRAS-driven lung adenocarcinoma. We demonstrate that members of the SIK family are critical for constraining tumor development. Histologic and gene-expression...
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CRISPR-based target validation of 10 anticancer drugs suggests many therapies don't work as thought. The findings call into question some of the common techniques used for demonstrating a drug's on-target mechanism of action.
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The FDA recently released a final guidance that outlines the specific situations in which placebos can be used in oncology clinical trials—and in which patients and investigators should be unblinded. Oncologists consider the guidance useful, but note that it largely aligns with how oncology trials are already conducted.
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The Genomics of Drug Sensitivity in Cancer project recently added 4 years of additional data to a large-scale database designed to identify predictive biomarkers for cancer therapies. Freely available online, these data are driving research on the relationship between genomic features and drug responses to better tailor treatment to individual patients.
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Asciminib with ponatinib was more effective than either alone in chronic myeloid leukemia (CML).
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In a regulatory first, the FDA has collaboratively reviewed a new cancer treatment with drug agencies in Canada and Australia, allowing for simultaneous approval of lenvatinib in combination with pembrolizumab for the treatment of recurrent endometrial carcinomas.
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The histone modification H3K36me2 recruits DNMT3A, a DNA methyltransferase associated with cancer.
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Cancer cells in the brain can form synaptic connections with neighboring neuronal cells, according to a trio of recently published studies. When activated, these synapses promote tumor proliferation, survival, and invasiveness. Disrupting the communication channels between neurons and cancer cells could help blunt the growth of deadly gliomas and brain metastases.
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-Secretase inhibitors with BCMA CAR-T therapy improved survival in a multiple myeloma mouse model.
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Investigators in the LIBRETTO-001 phase I/II trial presented new data on the experimental RET inhibitor selpercatinib at the 2019 World Conference on Lung Cancer. The agent produced robust responses in patients with RET-altered non–small cell lung cancer who had already received multiple therapies, raising hopes that it will soon receive FDA approval.
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Summary:GRM4, a GWAS-suspected tumor suppressor, is tested in a mouse model of osteosarcomagenesis as well as the putative oncogene it suppresses, IL23. Both are expressed in and exert the bulk of their influence among tumor-infiltrating myeloid-derived antigen-presenting cells, rather than osteosarcoma cells. See related article by Kansara et al., p. 1511.
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Between 1980 and 2018, novel cancer drug approvals as a percentage share of all novel FDA drug approvals increased from 4.5% to 26.7%.
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Summary:In this issue of Cancer Discovery, Rasool and colleagues show that TF11H/CDK7 phosphorylates the MED1 component of the Mediator complex, which enhances its interaction with androgen receptor (AR), and that this phosphorylation is increased in prostate cancer that is resistant to castration and enzalutamide. A covalent CDK7-specific inhibitor (THZ1) impairs AR-mediated MED1 recruitment to chromatin, and can suppress enzalutamide resistance in vitro and induce tumor regression in a castration-resistant...
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The glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4–/– gene–targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1+/– mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related...
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The Albert and Mary Lasker Foundation bestowed two awards on five scientists for their groundbreaking research. Max D. Cooper, MD, of the Emory University School of Medicine in Atlanta, GA, and Jacques Miller, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia, received the 2019 Albert Lasker Basic Medical Research Award for identifying the two classes of lymphocytes, B cells and T cells. H. Michael Shepard, PhD, formerly of Genentech; Dennis J. Slamon, MD, of...
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Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional...
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Lymphoma cells were more likely to take hold in gliotic central nervous systems (CNS) in mice.
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Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1...
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Liquid biopsy outperforms single-lesion tumor biopsy in detecting heterogeneous resistance alterations.
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Mutations in the LKB1 (also known as STK11) tumor suppressor are the third most frequent genetic alteration in non–small cell lung cancer (NSCLC). LKB1 encodes a serine/threonine kinase that directly phosphorylates and activates 14 AMPK family kinases ("AMPKRs"). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Here, we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models,...
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The folate transporter SLC19A1 ferries charged cyclic dinucleotides (CDN) into human cells.
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