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  • Distinct Tumor-Immune Microenvironments Occur at Different Tumor Sites
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-01
    American Association for Cancer Research

    Tumor regression was linked to immune infiltration in a patient with chemotherapy-treated ovarian cancer.

    更新日期:2017-09-23
  • Local Delivery of IFNα Has Antitumor Activity in Bladder Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-01
    American Association for Cancer Research

    Intravesical delivery of rAd-IFNα/Syn3 is safe and achieves durable responses in high-grade NMIBC.

    更新日期:2017-09-22
  • Ascorbate Depletion Reduces TET2 Activity to Accelerate Leukemogenesis
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-01
    American Association for Cancer Research

    Elevated ascorbate levels maintain TET2 activity in HSCs and decline with differentiation.

    更新日期:2017-09-22
  • EWS–FLI1 Retargets BAF Chromatin Remodeling Complexes in Ewing Sarcoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-01
    American Association for Cancer Research

    BAF recruitment to GGAA microsatellites activates the Ewing sarcoma transcriptional program.

    更新日期:2017-09-22
  • TERT Promoter Mutations Promote Immortalization and Genomic Instability
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-25
    American Association for Cancer Research

    TERT promoter mutations may induce early and late tumorigenesis by separate mechanisms.

    更新日期:2017-09-22
  • CMTM6 Regulates PD-L1 Expression and Antitumor Immunity
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-25
    American Association for Cancer Research

    CMTM6 binds to PD-L1 on the plasma membrane to promote its stability and inhibitory activity.

    更新日期:2017-09-22
  • First-Line Abemaciclib Effective in ER+ Breast Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-22
    American Association for Cancer Research

    Interim data from the MONARCH3 study indicate that abemaciclib is an effective first-line therapy for advanced ER-positive, HER2-negative breast cancer. Adding the investigational CDK4/6 inhibitor to letrozole significantly improved patients' progression-free survival, compared with those given a placebo alongside endocrine therapy.

    更新日期:2017-09-22
  • GPC2 May Be an Immunotherapeutic Target in High-Risk Neuroblastoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-22
    American Association for Cancer Research

    A GPC2-targeting antibody–drug conjugate promotes tumor regression in a high-risk neuroblastoma PDX.

    更新日期:2017-09-22
  • Talimogene Laherparepvec Enhances the Efficacy of PD-1 Blockade
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-22
    American Association for Cancer Research

    Talimogene laherparepvec plus pembrolizumab achieved response in 62% of patients with melanoma.

    更新日期:2017-09-22
  • First-Line Dabrafenib plus Trametinib Has Activity in BRAFV600E NSCLC
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-22
    American Association for Cancer Research

    Dabrafenib plus trametinib achieves responses in 64% of patients with metastatic BRAFV600E NSCLC.

    更新日期:2017-09-22
  • Gammaproteobacteria Metabolize Gemcitabine to Promote Chemoresistance
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-22
    American Association for Cancer Research

    Most human PDACs harbor intratumor Gammaproteobacteria that may promote gemcitabine resistance.

    更新日期:2017-09-22
  • WNT and SHH Drive the Tumorigenesis of a Rare Embryonal Brain Tumor
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-22
    American Association for Cancer Research

    Coexpression of Wnt and Shh in Sox2+/Pax6+ apical radial glia in the VZ drives ETMR formation in vivo.

    更新日期:2017-09-22
  • How Ribosomes Translate Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-18
    Sergey O. Sulima; Isabel J.F. Hofman; Kim De Keersmaecker; Jonathan D. Dinman

    A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis—from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on “onco-ribosomes” as an Achilles' heel of cancer cells and a promising target for further therapeutic intervention. Significance: The recent discovery of somatic mutations in ribosomal proteins in several cancers has strengthened the link between ribosome defects and cancer progression, while also raising the question of which cellular mechanisms such defects exploit. Here, we discuss the emerging molecular mechanisms by which ribosomes support oncogenesis, and how this understanding is driving the design of novel therapeutic strategies. Cancer Discov; 7(10); 1–19. ©2017 AACR.

    更新日期:2017-09-21
  • Vitamin C Restores TET2 Activity in TET2-Deficient Leukemia
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-25
    American Association for Cancer Research

    TET2 restoration promotes DNA demethylation and differentiation to suppress leukemic progression.

    更新日期:2017-09-21
  • MAGE-A3–Targeted Autologous CD4+ T Cells May Target Metastatic Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-25
    American Association for Cancer Research

    Adoptive transfer of MAGE-A3–targeted CD4+ T cells is safe and achieves responses in several tumor types.

    更新日期:2017-09-21
  • Neural Precursors Drive Glioma Invasion of the Subventricular Zone
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-25
    American Association for Cancer Research

    A NPC-derived pleiotrophin promotes glioma invasion into the subventricular zone.

    更新日期:2017-09-21
  • Crizotinib Has Antitumor Activity in ALK-Positive ALCL and IMT
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-18
    American Association for Cancer Research

    Crizotinib has an overall response rate of 90% in ALCL and 86% in IMT at the recommended phase II dose.

    更新日期:2017-09-21
  • Anti-CTLA4 and Anti–PD-1 Act on Distinct T-cell Populations
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-18
    American Association for Cancer Research

    Both anti–PD-1 and anti-CTLA4 target subpopulations of exhausted-like CD8+ T cells.

    更新日期:2017-09-21
  • TMPRSS2–ERG Alters the cis-Regulatory Landscape and Activates NOTCH
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-18
    American Association for Cancer Research

    In TMPRSS2–ERG-positive prostate tumors, ERG establishes new clusters of regulatory elements (CORE).

    更新日期:2017-09-21
  • PON2 Promotes Glucose Uptake to Support PDAC Growth and Metastasis
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-18
    American Association for Cancer Research

    PON2 promotes GLUT1-mediated glucose transport, is upregulated in PDAC, and is required for PDAC growth.

    更新日期:2017-09-21
  • Epigenetic Repression of LINE-1 Elements Protects Drug-Resistant Cells
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-11
    American Association for Cancer Research

    H3K9me3–dependent heterochromatin formation maintains drug-tolerant persister (DTP) cell viability.

    更新日期:2017-09-21
  • The 1q42.1 Risk Allele Promotes Melanoma via PARP1 Upregulation
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-11
    American Association for Cancer Research

    An intronic indel variant enhances RECQL binding to upregulate PARP1 in melanocytic cells.

    更新日期:2017-09-21
  • HR Intermediates Can Induce Chromosomal Translocations
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-11
    American Association for Cancer Research

    Multi-invasions (MI) are HR intermediates formed when a ssDNA invades two dsDNA.

    更新日期:2017-09-21
  • Error-Prone DNA Repair Targets the H3K36me3 Chromatin of Active Genes
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-11
    American Association for Cancer Research

    Carcinogen-associated error-prone DNA repair increases the mutation rate of active genes in cancer.

    更新日期:2017-09-21
  • Inactivating BRAF Mutations Modulate RAS–MAPK Signaling
    Cancer Discov. (IF 20.011) Pub Date : 2017-08-11
    American Association for Cancer Research

    Hypoactive BRAF mutants bind more tightly to active RAS and amplify ERK signaling.

    更新日期:2017-09-21
  • Anticancer Sulfonamides Induce Splicing Factor RBM39 Degradation
    Cancer Discov. (IF 20.011) Pub Date : 2017-05-12
    American Association for Cancer Research

    Anticancer sulfonamides produce aberrant splicing by inducing degradation of the splicing factor RBM39.

    更新日期:2017-09-21
  • IFNγ Acts on Endothelial Cells to Promote Tumor Regression
    Cancer Discov. (IF 20.011) Pub Date : 2017-05-05
    American Association for Cancer Research

    IFNγ induces vascular regression and tumor ischemia to initiate tumor regression.

    更新日期:2017-09-21
  • Melanoma Drugs Effective as Adjuvants
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-20
    American Association for Cancer Research

    BRAF-targeted strategies and PD-1–blocking immunotherapy are more effective adjuvant therapies than currently approved options for patients with high-risk resectable melanoma. However, choosing the best agent for patients with BRAF-mutated disease remains a challenge.

    更新日期:2017-09-20
  • Gemtuzumab Ozogamicin Makes a Comeback
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-20
    American Association for Cancer Research

    After being pulled from the market 7 years ago, gemtuzumab ozogamicin has been reapproved by the FDA, this time for adults newly diagnosed with acute myeloid leukemia, as well as patients 2 years of age and older with relapsed/refractory disease. The CD33-targeting antibody–drug conjugate can be given as a single agent or in combination with chemotherapy.

    更新日期:2017-09-20
  • Blimp1 induces transient metastatic heterogeneity in pancreatic cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Shin-Heng Chiou; Viviana I. Risca; Gordon X. Wang; Dian Yang; Barbara M. Grüner; Arwa S. Kathiria; Rosanna K. Ma; Dedeepya Vaka; Pauline Chu; Margaret Kozak; Laura Castellini; Edward E. Graves; Grace E. Kim; Philippe Mourrain; Albert C. Koong; Amato J. Giaccia; Monte M. Winslow

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes, and hypoxia-mediated induction of BLIMP1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which upregulation of BLIMP1 links microenvironmental cues to a metastatic stem cell character. SIGNIFICANCE: PDAC is an almost uniformly lethal cancer, largely due to its tendency for metastasis. We define a highly metastatic subpopulation of cancer cells, uncover a key transcriptional regulator of metastatic ability, and define hypoxia as an important factor within the tumor microenvironment that increases metastatic proclivity. Cancer Discov; 7(10); 1–16. ©2017 AACR. See related commentary by Vakoc and Tuveson, p. 1067.

    更新日期:2017-09-20
  • Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Carlos R Gil Del Alcazar; Sung Jin Huh; Muhammad B Ekram; Anne Trinh; Lin L Liu; Francisco Beca; Xiaoyuan Zi; Minsuk Kwak; Helga Bergholtz; Ying Su; Lina Ding; Hege G Russnes; Andrea L. Richardson; Kirsten Babski; Elizabeth Min Hui Kim; Charles McDonnell; Jon Wagner; Ron Rowberry; Gordon J. Freeman; Deborah Dillon; Therese Sorlie; Lisa M. Coussens; Judy E. Garber; Rong Fan; Kristie Bobolis; D Craig Allred; Joon Jeong; So Yeon Park; Franziska Michor; Kornelia Polyak

    To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression. SIGNIFICANCE: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1–18. ©2017 AACR. See related commentary by Speiser and Verdeil, p. 1062.

    更新日期:2017-09-19
  • Loss of MutL Disrupts Chk2-dependent Cell Cycle Control Through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Svasti Haricharan; Nindo Punturi; Purba Singh; Kimberly R. Holloway; Meenakshi Anurag; Jacob Schmelz; Cheryl Schmidt; Jonathan T. Lei; Vera Suman; Kelly Hunt; John A. Olson; Jeremy Hoog; Shunqiang Li; Shixia Huang; Dean P. Edwards; Shyam M. Kavuri; Matthew N. Bainbridge; Cynthia X. Ma; Matthew J. Ellis

    Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. SIGNIFICANCE: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1–16. ©2017 AACR.

    更新日期:2017-09-19
  • Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Marco Ruella; Michael Klichinsky; Saad S Kenderian; Olga Shestova; Amy Ziober; Daniel O Kraft; Michael Feldman; Mariusz A Wasik; Carl H. June; Saar Gill

    Patients with otherwise treatment-resistant Hodgkin lymphoma could benefit from chimeric antigen receptor T-cell (CART) therapy. However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in Hodgkin lymphoma, CART should target both malignant cells and the TME. We demonstrated CD123 on both Hodgkin lymphoma cells and TME, including tumor-associated macrophages (TAM). In vitro, Hodgkin lymphoma cells convert macrophages toward immunosuppressive TAMs that inhibit T-cell proliferation. In contrast, anti-CD123 CART recognized and killed TAMs, thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicated Hodgkin lymphoma and established long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu. SIGNIFICANCE: Anti-CD123 chimeric antigen receptor T cells target both the malignant cells and TAMs in Hodgkin lymphoma, thereby eliminating an important immunosuppressive component of the tumor microenvironment. Cancer Discov; 7(10); 1–14. ©2017 AACR.

    更新日期:2017-09-19
  • Exploiting drug addiction mechanisms to select against MAPKi-resistant melanoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Aayoung Hong; Gatien Moriceau; Lu Sun; Shirley Lomeli; Marco Piva; Robert Damoiseaux; Sheri L. Holmen; Norman E. Sharpless; Willy Hugo; Roger S. Lo

    Melanoma resistant to MAPK inhibitor(s) (MAPKi) displays loss-of-fitness upon experimental MAPKi withdrawal and, clinically, may be re-sensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi-addiction in MAPKi-resistant MUTBRAF or MUTNRAS melanoma. MAPKi-addiction phenotypes evident upon drug-withdrawal spanned transient cell-cycle slow-down to cell-death responses, the latter of which required a robust p-ERK rebound. Generally, drug withdrawal-induced p-ERK rebound up-regulated p38-FRA1-JUNB-CDKN1A and down-regulated proliferation, but only a robust p-ERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi-addiction across-the-board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant MUTNRAS or atypical MUTBRAF melanoma, treatment with a type I RAF inhibitor intensified p-ERK rebound elicited by MEKi-withdrawal, thereby promoting a cell-death predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi-addiction.

    更新日期:2017-09-19
  • Super-Enhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Michael R McKeown; M. Ryan Corces; Matthew L Eaton; Chris Fiore; Emily Lee; Jeremy T Lopez; Mei Wei Chen; Darren Smith; Steven M Chan; Julie L Koenig; Kathryn Austgen; Matt G Guenther; David A Orlando; Jakob Lovén; Christian C Fritz; Ravindra Majeti

    We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their superenhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong SE at the retinoic acid receptor alpha (RARA) gene locus. The presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of acute promyelocytic leukemia treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation. SIGNIFICANCE: We use the SE landscape of primary human AML to elucidate transcriptional circuitry and identify novel cancer vulnerabilities. A subset of patients were found to have an SE at RARA, which is predictive for response to SY-1425, a potent and selective RARα agonist, in preclinical models, forming the rationale for its clinical investigation in biomarker-selected patients. Cancer Discov; 7(10); 1–18. ©2017 AACR. See related commentary by Wang and Aifantis, p. 1065.

    更新日期:2017-09-18
  • A transposon screen identifies loss of primary cilia as a mechanism of resistance to Smo inhibitors
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Xuesong Zhao; Ekaterina Pak; Kimberly J. Ornell; Maria F. Pazyra-Murphy; Ethan L. MacKenzie; Emily J. Chadwick; Tatyana Ponomaryov; Joseph F. Kelleher; Rosalind A. Segal

    Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway-dependent cancers, the scope of mechanisms enabling resistance to Smo-inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to Smo-inhibitors and maintains a "persister" state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal novel patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.

    更新日期:2017-09-18
  • TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: an Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Alexandre Reuben; Rachel M. Gittelman; Jianjun Gao; Jiexin Zhang; Erik Yusko; Chang-Jiun Wu; Ryan Emerson; Jianhua Zhang; Christopher M Tipton; Jun Li; Kelly Quek; Vancheswaran Gopalakrishnan; Runzhe Chen; Luis Vence; Tina Cascone; Marissa Vignali; Junya Fujimoto; Jaime Rodriguez-Canales; Edwin R Parra; Latasha D. Little; Curtis Gumbs; Marie-Andrée Forget; Lorenzo Federico; Cara Haymaker; Carmen Behrens; Sharon Benzeno; Chantale Bernatchez; Boris Sepesi; Don L. Gibbons; Jennifer A. Wargo; William N. William; Stephen G. Swisher; John Heymach; Harlan Robins; J. Jack Lee; Padmanee Sharma; James P. Allison; P. Andrew Futreal; Ignacio I. Wistuba; Jianjun Zhang

    Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity. SIGNIFICANCE: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1–10. ©2017 AACR.

    更新日期:2017-09-15
  • Mitogen and Stress Signal Memory Regulates Daughter Cell Proliferation
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-15
    American Association for Cancer Research

    CCND1 and p53 transmitted to daughter cells in mitosis determine if cells are proliferative or quiescent.

    更新日期:2017-09-15
  • Melanoma Risk Variants Prevent MC1R Palmitoylation and Activation
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-15
    American Association for Cancer Research

    Palmitoylation-deficient MC1R variants accelerate BRAFV60E-driven melanomagenesis.

    更新日期:2017-09-15
  • ACTRT1 Inhibits Hedgehog Signaling to Suppress Basal Cell Carcinoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-15
    American Association for Cancer Research

    Coding or enhancer mutations in ACTRT1 reduce its expression to drive basal cell carcinoma.

    更新日期:2017-09-15
  • Glioblastoma Stem Cell Clonal Dynamics Drive Intratumor Heterogeneity
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-15
    American Association for Cancer Research

    GBM heterogeneity is primarily driven by the stochastic outcome of GBM stem cell hierarchical growth.

    更新日期:2017-09-15
  • Targeting the c-Rel Subunit of NF-κB Inhibits Treg Function in Melanoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-15
    American Association for Cancer Research

    Specific inhibition of c-Rel impairs activated Tregs to suppress melanoma growth in vivo.

    更新日期:2017-09-15
  • Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Apinya Jusakul; Ioana Cutcutache; Chern Han Yong; Jing Quan Lim; Mi Ni Huang; Nisha Padmanabhan; Vishwa Nellore; Sarinya Kongpetch; Alvin Wei Tian Ng; Ley Moy Ng; Su Pin Choo; Swe Swe Myint; Raynoo Thanan; Sanjanaa Nagarajan; Weng Khong Lim; Cedric Chuan Young Ng; Arnoud Boot; Mo Liu; Choon Kiat Ong; Vikneswari Rajasegaran; Stefanus Lie; Alvin Soon Tiong Lim; Tse Hui Lim; Jing Tan; Jia Liang Loh; John R McPherson; Narong Khuntikeo; Vajaraphongsa Bhudhisawasdi; Puangrat Yongvanit; Sopit Wongkham; Yasushi Totoki; Hiromi Nakamura; Yasuhito Arai; Satoshi Yamasaki; Pierce K.H. Chow; Alexander Yaw Fui Chung; London Lucien Peng Jin Ooi; Kiat Hon Lim; Simona Dima; Dan G Duda; Irinel Popescu; Philippe Broet; Sen-Yung Hsieh; Ming-Chin Yu; Aldo Scarpa; Jiaming Lai; Di-Xian Luo; Andre Lopes Carvalho; André Luiz Vettore; Hyungjin Rhee; Young Nyun Park; Ludmil Alexandrov; Raluca Gordan; Steven G Rozen; Tatsuhiro Shibata; Chawalit Pairojkul; Bin Tean Teh; Patrick Tan

    Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters—fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′ untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein–DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores—mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer. SIGNIFICANCE: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1–20. ©2017 AACR.

    更新日期:2017-09-15
  • Liquid Biopsy Technique May Allow Early Screening
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-13
    American Association for Cancer Research

    Researchers have developed a new liquid biopsy technique that may allow screening for certain types of cancer. The technique can detect tumor mutations from the small amount of blood DNA present early in the disease. In four types of cancer, the technique's overall sensitivity was between 56% and 83%, and it could pinpoint 62% of patients with early-stage cancer.

    更新日期:2017-09-13
  • Lasker Awards Honor Three Cancer Researchers
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-12
    American Association for Cancer Research

    Three top cancer researchers were among recipients of the prestigious Albert and Mary Lasker Foundation awards. Douglas R. Lowy, MD, and John T. Schiller, PhD, were honored for research leading to the development of the first human papillomavirus vaccine. The prize for basic medical research went to Michael N. Hall, PhD, who discovered the TOR signaling pathway and its role in regulating cell growth and metabolism.

    更新日期:2017-09-12
  • A unified approach to targeting the lysosome's degradative and growth signaling roles.
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Vito W. Rebecca; Michael C. Nicastri; Noel McLaughlin; Colin Fennelly; Quentin McAfee; Amruta Ronghe; Michel Nofal; Chun-Yan Lim; Eric Witze; Cynthia I. Chude; Gao Zhang; Gretchen M. Alicea; Shengfu Piao; Sengottuvelan Murugan; Rani Ojha; Samuel M. Levi; Zhi Wei; Julie S. Barber-Rotenberg; Maureen E. Murphy; Gordon B. Mills; Yiling Lu; Joshua Rabinowitz; Ronen Marmorstein; Qin Liu; Shujing Liu; Xiaowei Xu; Meenhard Herlyn; Roberto Zoncu; Donita C. Brady; David W. Speicher; Jeffrey D. Winkler; Ravi K. Amaravadi

    Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e. autophagy and macropinocytosis), while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQs) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.

    更新日期:2017-09-12
  • Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Aadel A. Chaudhuri; Jacob J. Chabon; Alexander F. Lovejoy; Aaron M. Newman; Henning Stehr; Tej D. Azad; Michael S. Khodadoust; Mohammad Shahrokh Esfahani; Chih Long Liu; Li Zhou; Florian Scherer; David M. Kurtz; Carmen Say; Justin N. Carter; David J. Merriott; Jonathan C. Dudley; Michael S. Binkley; Leslie Modlin; Sukhmani K. Padda; Michael F. Gensheimer; Robert B. West; Joseph B. Shrager; Joel W. Neal; Heather A. Wakelee; Billy W. Loo; Ash A. Alizadeh; Maximilian Diehn

    Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

    更新日期:2017-09-12
  • VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Xiaosai Yao; Jing Tan; Kevin Junliang Lim; Joanna Koh; Wen Fong Ooi; Zhimei Li; Dachuan Huang; Manjie Xing; Yang Sun Chan; James Zhengzhong Qu; Su Ting Tay; Giovani Wijaya; Yue Ning Lam; Jing Han Hong; Ai Ping Lee-Lim; Peiyong Guan; Michelle Shu Wen Ng; Cassandra Zhengxuan He; Joyce Suling Lin; Tannistha Nandi; Aditi Qamra; Chang Xu; Swe Swe Myint; James O. J. Davies; Jian Yuan Goh; Gary Loh; Bryan C. Tan; Steven G. Rozen; Qiang Yu; Iain Bee Huat Tan; Christopher Wai Sam Cheng; Shang Li; Kenneth Tou En Chang; Puay Hoon Tan; David Lawrence Silver; Alexander Lezhava; Gertrud Steger; Jim R. Hughes; Bin Tean Teh; Patrick Tan

    Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel Lindau (VHL) tumor suppressor. Roles for non-coding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Super-enhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator, whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/super-enhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase P300 without overtly affecting pre-existing promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.

    更新日期:2017-09-11
  • Galectin-3, a druggable vulnerability for KRAS-addicted cancers
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Laetitia Seguin; Maria F. Camargo; Hiromi I. Wettersten; Shumei Kato; Jay S. Desgrosellier; Tami von Schalscha; Kathryn C. Elliott; Erika Cosset; Jacqueline Lesperance; Sara M. Weis; David A. Cheresh

    Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein Galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, Galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/Galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals Galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancer, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.

    更新日期:2017-09-11
  • First-Ever CAR T-cell Therapy Approved in U.S.
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-08
    American Association for Cancer Research

    The first chimeric antigen receptor T-cell therapy, tisagenlecleucel, received FDA approval for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia who haven't responded to standard therapy or who have relapsed at least twice.

    更新日期:2017-09-08
  • Altered Vasculature in Bone Marrow Drives Leukemogenesis
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-08
    American Association for Cancer Research

    Nitric oxide promotes vascular permeability and hypoxia in the bone marrow to drive AML.

    更新日期:2017-09-08
  • LMO1 Cooperates with MYCN to Promote Neuroblastomagenesis and Metastasis
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-08
    American Association for Cancer Research

    Transgenic expression of LMO1 promotes neuroblastoma metastasis in a MYCN-driven zebrafish model.

    更新日期:2017-09-08
  • Z-endoxifen Is Active in Endocrine-Refractory Metastatic Breast Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-08
    American Association for Cancer Research

    The tamoxifen metabolite Z-endoxifen has acceptable tolerability and antitumor activity.

    更新日期:2017-09-08
  • Osimertinib May Be an Effective First-Line Therapy in EGFR-Mutant NSCLC
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-08
    American Association for Cancer Research

    Osimertinib achieved objective responses in 77% of patients with treatment-naïve NSCLC.

    更新日期:2017-09-08
  • Gilead Buying Kite for $11.9 Billion
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-06
    American Association for Cancer Research

    Gilead Sciences will buy Kite Pharma—and its autologous CAR T-cell technology—for $11.9 billion. The acquisition will help Gilead build its oncology portfolio and boost its revenues.

    更新日期:2017-09-06
  • Equipping NK Cells with CARs
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-06
    American Association for Cancer Research

    Adding a chimeric antigen receptor (CAR) to natural killer (NK) cells is garnering interest as a therapeutic strategy because this immune cell type doesn't cause graft-versus-host disease, making its widespread, off-the-shelf use feasible. Based on promising preclinical data, a phase I/II trial of one such CAR NK-cell therapy is under way, targeting CD19 in hematologic malignancies.

    更新日期:2017-09-06
  • CDK4/6 Inhibitors Induce Antitumor Immunity
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-01
    American Association for Cancer Research

    CDK4/6 inhibitors not only induce cell-cycle arrest but also promote antitumor immunity by stimulating the production of type III interferons, which enhance tumor antigen presentation, and suppress regulatory T cells. The immune effects of these drugs provide a rationale for combining CDK4/6 inhibitors with checkpoint blockade agents.

    更新日期:2017-09-04
  • Recurrent tumor cell-intrinsic and -extrinsic alterations during MAPKi-induced melanoma regression and early adaptation
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Chunying Song; Marco Piva; Lu Sun; Aayoung Hong; Gatien Moriceau; Xiangju Kong; Hong Zhang; Shirley Lomeli; Jin Qian; Clarissa C. Yu; Robert Damoiseaux; Mark C. Kelley; Kimberly B. Dahlman; Philip O. Scumpia; Jeffrey A. Sosman; Douglas B. Johnson; Antoni Ribas; Willy Hugo; Roger S. Lo

    Treatment of advanced V600BRAF mutant melanoma using a BRAF inhibitor (BRAFi) or its combination with a MEKi typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPKi therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or -positive fractions,, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK-dependency, while enhancing mesenchymal, angiogenic and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.

    更新日期:2017-09-04
  • VEGFR Inhibitor–Resistant Thyroid Cancer Responds to Cabozantinib
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-01
    American Association for Cancer Research

    Cabozantinib achieved partial responses in 40% of patients with differentiated thyroid cancer (DTC).

    更新日期:2017-09-04
  • In This Issue
    Cancer Discov. (IF 20.011) Pub Date : 2017-09-01
    American Association for Cancer Research

    See article, p. 963 In drug development for rare molecular targets, the limited number of patients can prevent sequential testing of first- and second-generation inhibitors. The TRK kinases represent one such target, and NTRK gene rearrangements can be targeted by the recently developed selective TRK tyrosine kinase inhibitor (TKI) larotrectinib. To combat acquired resistance, Drilon and colleagues developed LOXO-195, a TRK TKI designed to overcome resistance conferred by secondary TRK kinase domain mutations, in parallel with the early clinical development of larotrectinib. In vitro, LOXO-195 potently inhibited wild-type NTRK1/2/3 and several TRK kinase domain mutants that reduced larotrectinib sensitivity. Further, LOXO-195 suppressed the growth of tumors driven by oncogenic NTRK1/3 in mice. Based on these preclinical findings, the first two patients to develop larotrectinib resistance were treated with LOXO-195 using rapid safety- and pharmacokinetic-guided intrapatient dose-escalation study designs. An adult patient with LMNA–NTRK1-rearranged colorectal cancer who developed larotrectinib resistance due to an NTRK1 G595R acquired resistance mutation responded rapidly to LOXO-195 and achieved an ongoing partial response. After treatment the G595R allele was no longer detectable in cell-free DNA. A pediatric patient with ETV6–NTRK3-rearranged infantile fibrosarcoma with a G623R acquired resistance mutation also experienced rapid tumor regression, though her cancer recurred. In addition to demonstrating that LOXO-195 may overcome resistance to larotrectinib in patients with NTRK-rearranged tumors, this study illustrates the utility of a drug development approach that anticipates resistance to first-generation kinase inhibitors and enables parallel generation of next-generation kinase inhibitors, particularly in a rare patient population.

    更新日期:2017-09-04
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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