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Δευτέρα 1 Ιουλίου 2019


Anti-BCMA CAR T-cell Therapy Reins in Myeloma [News in Brief]
Autologous immune cells genetically engineered to target B-cell maturation antigen can help patients with relapsed or refractory multiple myeloma achieve deep molecular remissions with minimal neurotoxicity, according to initial data from a phase I trial.
Cancer Discovery current issue
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Lymphoma Chemotherapy: Hungry Macrophages Strike the Final Blow [In the Spotlight]
Summary:Macrophages modulate tumor response to chemotherapy; in this issue, Lossos and colleagues show that high-dose alkylating agents instigate a synthetic lethal program in lymphoma cells that is independent of DNA damage and involves recruitment and priming of macrophages for antibody-mediated tumor phagocytosis. These findings implicate chemotherapy-elicited macrophages as critical effectors of lymphoma clearance during biological therapy. See related article by Lossos et al., p. 944.
Cancer Discovery current issue
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Study Verifies Value of Real-World Evidence [News in Brief]
To demonstrate the potential of real-world evidence generated from real-world data, Foundation Medicine and Flatiron Health teamed up to create a large-scale clinico-genomic database. The database, which links clinical and genomic data gathered from patients with non-small cell lung cancer treated in community practices, was validated in a recent study.
Cancer Discovery current issue
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Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy [Research Articles]
Previous studies have described that tumor organoids can capture the diversity of defined human carcinoma types. Here, we describe conditions for long-term culture of human mucosal organoids. Using this protocol, a panel of 31 head and neck squamous cell carcinoma (HNSCC)–derived organoid lines was established. This panel recapitulates genetic and molecular characteristics previously described for HNSCC. Organoids retain their tumorigenic potential upon xenotransplantation. We observe differential...
Cancer Discovery current issue
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Scientists See Human Cancer in Zebrafish [News in Brief]
Researchers have developed an immune-deficient adult zebrafish model that engrafts a variety of human cancers, allowing them to visualize tumor growth at single-cell resolution and track responses to drug therapy. Using the model, they identified a possible treatment for rhabdomyosarcoma.
Cancer Discovery current issue
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Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment [Research Articles]
The BCL2 family plays important roles in acute myeloid leukemia (AML). Venetoclax, a selective BCL2 inhibitor, has received FDA approval for the treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to venetoclax. Genes involved in mitochondrial organization and function were significantly...
Cancer Discovery current issue
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Noted [News in Brief]
A collection of recently published news items.
Cancer Discovery current issue
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Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor [Research Articles]
Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. In this study, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFRL858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an...
Cancer Discovery current issue
10:05
Understanding Hyperprogression in Cancer [News in Depth]
During the American Association for Cancer Research Annual Meeting 2019, a panel of experts convened to discuss the concept of hyperprogressive disease (HPD), including key criteria, hypotheses as to the underlying biology, and what needs to be done to better understand and assess patients' risk of HPD.
Cancer Discovery current issue
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A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 [Research Articles]
Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic...
Cancer Discovery current issue
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Microbiota Manipulated to Enhance Immunity [News in Depth]
Oncologists are testing fecal transplants and other microbiome-based products in combination with checkpoint inhibitors in an effort to increase and enhance responses. However, questions remain about how the microbes affect host immunity and which preparations of bacteria are optimal.
Cancer Discovery current issue
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Correction: ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma [Corrections]
Cancer Discovery current issue
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Gaussian Mixture Models for Probabilistic Classification of Breast Cancer
In the era of omics-driven research, it remains a common dilemma to stratify individual patients based on the molecular characteristics of their tumors. To improve molecular stratification of patients with breast cancer, we developed the Gaussian mixture model (GMM)–based classifier. This probabilistic classifier was built on mRNA expression data from more than 300 clinical samples of breast cancer and healthy tissue and was validated on datasets of ESR1, PGR, and ERBB2, which encode standard clinical...
Cancer Research current issue
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The Tumor Metabolic Microenvironment: Lessons from Lactate
The extracellular milieu of tumors is generally assumed to be immunosuppressive due in part to metabolic factors. Here, we review methods for probing the tumor metabolic microenvironment. In parallel, we consider the resulting available evidence, with a focus on lactate, which is the most strongly increased metabolite in bulk tumors. Limited microenvironment concentration measurements suggest depletion of glucose and modest accumulation of lactate (less than 2-fold). Isotope tracer measurements show...
Cancer Research current issue
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Anti-CD24 Antibody-Nitric Oxide Conȷugate Selectively and Potently Suppresses Hepatic Carcinoma
Nitric oxide (NO) has a wide range of potential applications in tumor therapy. However, a targeted delivery system for NO donors has remained elusive, creating a bottleneck that limits its druggability. The antibody–drug conjugate (ADC) is a targeted drug delivery system composed of an antibody linked to an active cytotoxic drug. This design may compensate for the weak targeting ability and various biological functions of the NO donor. In this study, we designed the NO donor HL-2, which had a targeted,...
Cancer Research current issue
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Detection of NTRK Fusions: Merits and Limitations of Current Diagnostic Platforms
Oncogenic fusions involving NTRK1, NTRK2, and NTRK3 with various partners are diagnostic of infantile fibrosarcoma and secretory carcinoma yet also occur in lower frequencies across many types of malignancies. Recently, targeted small molecular inhibitor therapy has been shown to induce a durable response in a high percentage of patients with NTRK fusion–positive cancers, which has made the detection of NTRK fusions critical. Several techniques for NTRK fusion diagnosis exist, including pan-Trk IHC,...
Cancer Research current issue
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Epigenetic Regulation of NAMPT by NAMPT-AS Drives Metastatic Progression in Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show...
Cancer Research current issue
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The AURORA of a New Way to Value Myeloid Immunosuppression in Cancer
Inhibiting myeloid-derived suppressor cells (MDSC) might be the ultimate barrier to break down tumor defenses and recover the preexisting T-cell immunity required to respond to immunotherapy. However, selectively intercepting MDSCs to prove their etiologic role in cancer progression is not an easy task. In this issue of Cancer Research, Yin and colleagues demonstrate unequivocally that the Aurora A kinase inhibitor, alisertib, specifically neutralizes MDSCs and triggers the rapid accrual of cytotoxic...
Cancer Research current issue
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DFMO and 5-Azacytidine Increase M1 Macrophages in the Tumor Microenvironment of Murine Ovarian Cancer
Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumor microenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further...
Cancer Research current issue
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Poly Combs the Immune System: PRC2 Loss in Malignant Peripheral Nerve Sheath Tumors Can Dampen Immune Responses
Epigenetic modifications including altered DNA methylation and histone posttranslational modifications (PTM) are central to the biology of several cancers. These modifications can regulate DNA accessibility and consequently, gene expression. In this issue, Wojcik and colleagues explore epigenetic drivers of malignant peripheral nerve sheath tumors (MPNST) harboring loss-of-function polycomb-repressive complex 2 mutations. They demonstrate alterations in specific histone PTMs and a global increase...
Cancer Research current issue
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Highlights from Recent Cancer Literature
Cancer Research current issue
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First Strike-Second Strike Strategies in Metastatic Cancer: Lessons from the Evolutionary Dynamics of Extinction
While clinical cancer research has produced many highly effective drugs, the diversity and evolutionary capacity of most cancer populations remain insurmountable barriers to cure. Here, we propose that curative outcomes may, nevertheless, be achieved by sequencing therapies that are individually effective but noncurative. Basic principles for such an approach are derived from the eco-evolutionary dynamics of background extinctions in which a “first strike” reduces the size and heterogeneity of the...
Cancer Research current issue
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A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a high-risk disease with a poor prognosis, particularly in elderly patients. Because current AML treatment relies primarily on untargeted therapies with severe side effects that limit patient eligibility, identification of novel therapeutic AML targets is highly desired. We recently described AT1413, an antibody produced by donor B cells of a patient with AML cured after allogeneic hematopoietic stem cell transplantation. AT1413 binds CD43s, a unique sialylated epitope...
Cancer Research current issue
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Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth In Vivo
mTOR is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. Here we assessed mLST8 loss in a panel of normal and cancer cells and observed little to no impact on assembly or activity of mTORC1. However, mLST8 loss blocked mTOR association with mTORC2 cofactors...
Cancer Research current issue
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Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion
Pancreatic ductal adenocarcinoma (PDAC) is associated with robust activity of the coagulation system. To determine mechanisms by which clotting factors influence PDAC tumor progression, we generated and characterized C57Bl/6-derived KPC (KRasG12D, TRP53R172H) cell lines. Tissue factor (TF) and protease-activated receptor-1 (PAR-1) were highly expressed in primary KPC pancreatic lesions and KPC cell lines similar to expression profiles observed in biopsies of patients with PDAC. In allograft studies,...
Cancer Research current issue
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Targeting the High-Mobility Group Box 3 Protein Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin
Chemotherapeutic regimens for ovarian cancer often include the use of DNA interstrand crosslink–inducing agents (e.g., platinum drugs) or DNA double-strand break–inducing agents. Unfortunately, the majority of patients fail to maintain a durable response to treatment, in part, due to drug resistance, contributing to a poor survival rate. In this study, we report that cisplatin sensitivity can be restored in cisplatin-resistant ovarian cancer cells by targeting the chromatin-associated high-mobility...
Cancer Research current issue
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A Multigene Assay Determines Risk of Recurrence in Patients with Triple-Negative Breast Cancer
Approximately 40% of patients with stage I–III triple-negative breast cancer (TNBC) recur after standard treatment, whereas the remaining 60% experience long-term disease-free survival (DFS). There are currently no clinical tests to assess the risk of recurrence in TNBC patients. We previously determined that TNBC patients with MHC class II (MHCII) pathway expression in their tumors experienced significantly longer DFS. To translate this discovery into a clinical test, we developed an MHCII Immune...
Cancer Research current issue
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Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants
Genome-wide association study–identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project,...
Cancer Research current issue
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RNA Sequencing of the NCI-60: Integration into CellMiner and CellMiner CDB
CellMiner (http://discover.nci.nih.gov/cellminer) and CellMinerCDB (https://discover.nci.nih.gov/cellminercdb/) are web-based applications for mining publicly available genomic, molecular, and pharmacologic datasets of human cancer cell lines including the NCI-60, Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, Cancer Therapeutics Response Portal, NCI/DTP small cell lung cancer, and NCI Almanac cell line sets. Here, we introduce our RNA sequencing (RNA-seq) data for the NCI-60...
Cancer Research current issue
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Epigenomic Reordering Induced by Polycomb Loss Drives Oncogenesis but Leads to Therapeutic Vulnerabilities in Malignant Peripheral Nerve Sheath Tumors
Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with recurrent loss-of-function alterations in polycomb-repressive complex 2 (PRC2), a histone-modifying complex involved in transcriptional silencing. To understand the role of PRC2 loss in pathogenesis and identify therapeutic targets, we conducted parallel global epigenomic and proteomic analysis of archival formalin-fixed, paraffin-embedded (FFPE) human MPNST with and without PRC2 loss (MPNSTLOSS vs. MPNSTRET). Loss of PRC2...
Cancer Research current issue
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TTPAL Promotes Colorectal Tumorigenesis by Stabilizing TRIP6 to Activate Wnt/{beta}-Catenin Signaling
Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal cancer from a Chinese cohort (n = 102), which was further validated by a The Cancer Genome Atlas (TCGA) cohort (n = 376). High expression of TTPAL was significantly associated with shortened...
Cancer Research current issue
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LncRNA SNHG10 Facilitates Hepatocarcinogenesis and Metastasis by Modulating Its Homolog SCARNA13 via a Positive Feedback Loop
Understanding the roles of noncoding RNAs (ncRNA) in tumorigenesis and metastasis would establish novel avenues to identify diagnostic and therapeutic targets. Here, we aimed to identify hepatocellular carcinoma (HCC)–specific ncRNA and to investigate their roles in hepatocarcinogenesis and metastasis. RNA-seq of xenografts generated by lung metastasis identified long noncoding RNA small nucleolar RNA host gene 10 (SNHG10) and its homolog SCARNA13 as novel drivers for the development and metastasis...
Cancer Research current issue
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Inflammatory Breast Cancer Promotes Development of M2 Tumor-Associated Macrophages and Cancer Mesenchymal Cells through a Complex Chemokine Network
Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer that displays profound cancer stem cell (CSC) and mesenchymal features that promote rapid metastasis. Another hallmark of IBC is high infiltration of M2 tumor-associated (immune-suppressing) macrophages. The molecular mechanism that drives these IBC phenotypes is not well understood. Using patient breast tumor specimens, breast cancer cell lines, and a patient-derived xenograft model of IBC, we demonstrate that IBC strongly...
Cancer Research current issue
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Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells
Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted...
Cancer Research current issue
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MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation
Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1/CD133–associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1/CD133 and enhanced tumorigenicity of GBM cells...
Cancer Research current issue
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LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma
In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated the biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic...
Cancer Research current issue
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Contact-Dependent Killing by Cytotoxic T Lymphocytes Is Insufficient for EL4 Tumor Regression In Vivo
Immunotherapies are an emerging strategy for treatment of solid tumors. Improved understanding of the mechanisms employed by cytotoxic T lymphocytes (CTL) to control tumors will aid in the development of immunotherapies. CTLs can directly kill tumor cells in a contact-dependent manner or may exert indirect effects on tumor cells via secretion of cytokines. Here, we aim to quantify the importance of these mechanisms in murine thymoma EL4/EG7 cells. We developed an agent-based model (ABM) and an ordinary...
Cancer Research current issue
10:05
PGC1{alpha} Inhibits Polyamine Synthesis to Suppress Prostate Cancer Aggressiveness
Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer. Here, we show that PGC1α represses the metastatic properties of prostate cancer cells via modulation...
Cancer Research current issue
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Aurora A Inhibition Eliminates Myeloid Cell-Mediated Immunosuppression and Enhances the Efficacy of Anti-PD-L1 Therapy in Breast Cancer
The Aurora A inhibitor alisertib shows encouraging activities in clinical trials against advanced breast cancer. However, it remains unclear whether and how the inflammatory microenvironment is involved in its efficacy. Here, we demonstrated that inhibition of Aurora A directly reshaped the immune microenvironment through removal of tumor-promoting myeloid cells and enrichment of anticancer T lymphocytes, which established a tumor-suppressive microenvironment and significantly contributed to the...
Cancer Research current issue
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