显示样式:     当前期刊: Cancer Discovery    加入关注    导出
我的关注
我的收藏
您暂时未登录!
登录
  • Trastuzumab Deruxtecan Is Safe and Active in HER2-Expressing Tumors
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-27
    American Association for Cancer Research

    Trastuzumab deruxtecan achieved responses in patients with breast, gastric, and gastroesophageal tumors.

    更新日期:2017-11-21
  • SLC38A9 Links mTORC1 Activity to Lysosomal Amino Acid Release
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-27
    American Association for Cancer Research

    SLC38A9 acts as a lysosomal arginine sensor to activate mTORC1 signaling and support tumor growth.

    更新日期:2017-11-21
  • Poziotinib Shows Promise for Rare Lung Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-21
    American Association for Cancer Research

    Poziotinib, an EGFR inhibitor that was previously shelved as ineffective against non–small cell lung cancer, is showing promising activity in a subset of patients with EGFR exon 20 insertions. According to preliminary data from a phase II trial, the drug led to a 73% overall response rate in patients with this disease subtype, which is typically highly resistant to standard therapy.

    更新日期:2017-11-21
  • FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST)
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Leili Ran; Yuedan Chen; Jessica Sher; Wai Pung E. Wong; Devan Murphy; Jenny Q. Zhang; Dan Li; Kemal Deniz; Inna Sirota; Zhen Cao; Shangqian Wang; Youxin Guan; Shipra Shukla; Katie Yang Li; Alan Chramiec; Yuanyuan Xie; Deyou Zheng; Richard P. Koche; Cristina R. Antonescu; Yu Chen; Ping Chi

    The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behaviour and shapes treatment responses in distinct cancer types. Here, we uncover that in GIST, the forkhead family member, FOXF1, directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal (ICC) lineage-specification and GIST tumorigenesis. Further, FOXF1 co-localizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST-lineage specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo. The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behaviour and treatment response.

    更新日期:2017-11-21
  • Identified Selective USP7 Inhibitors Compete with Ubiquitin Binding
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-27
    American Association for Cancer Research

    Specific USP7 inhibitors stabilized p53 and exhibited toxicity in tumor cells in vitro and in vivo.

    更新日期:2017-11-20
  • Neoantigen Quality Predicts Immune Response, Survival
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-20
    American Association for Cancer Research

    A new mathematical model finds that tumor neoantigen quality trumps quantity when it comes to predicting response to immunotherapy and the likelihood of long-term survival among patients with cancer.

    更新日期:2017-11-20
  • RNA-Based Genetic Circuits Are a Potential Antitumor Immunotherapy
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-27
    American Association for Cancer Research

    Expression of synthetic RNA-based gene circuits in tumors induces an antitumor T-cell response.

    更新日期:2017-11-17
  • Nivolumab Induces Tumor Evolution in Patients with Melanoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-20
    American Association for Cancer Research

    Nivolumab treatment results in immunoediting and loss of tumor cells expressing neoantigens.

    更新日期:2017-11-17
  • BTSA1 Activates BAX to Promote Apoptosis in Acute Myeloid Leukemia
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-20
    American Association for Cancer Research

    The small-molecule BAX activator BTSA1 promotes apoptosis of AML cells in vitro and in vivo.

    更新日期:2017-11-17
  • Co-occurring Alterations Affect Outcomes in EGFR-Mutant Lung Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-17
    American Association for Cancer Research

    Sequencing cfDNA from 1,122 patients with EGFR-mutant lung cancer reveals co-occurring alterations.

    更新日期:2017-11-17
  • The Active Conformation of Integrin β7 May Be a Multiple Myeloma Target
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-17
    American Association for Cancer Research

    CAR T cells targeting active integrin β7 have cytotoxic activity against multiple myeloma (MM) cells.

    更新日期:2017-11-17
  • High BCAT1 Expression Mimics IDH Mutations in Acute Myeloid Leukemia
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-17
    American Association for Cancer Research

    High BCAT1 expression is linked to shorter survival in patients with IDH– and TET2–wild-type AML.

    更新日期:2017-11-17
  • Inflammation-Induced IgA+ Cells Promote Hepatocellular Tumorigenesis
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-17
    American Association for Cancer Research

    Chronic inflammation may promote hepatocellular carcinoma by suppressing cytotoxic T-cell activity.

    更新日期:2017-11-17
  • Breast Cancer Cells Recycle Ammonia to Generate Amino Acids
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-20
    American Association for Cancer Research

    Ammonia generated from glutamate metabolism enhances the proliferation of breast cancer cells.

    更新日期:2017-11-17
  • Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-16
    Joel D. Leverson; Deepak Sampath; Andrew J. Souers; Saul H. Rosenberg; Wayne J. Fairbrother; Martine Amiot; Marina Konopleva; Anthony Letai

    Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax. Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1–18. ©2017 AACR.

    更新日期:2017-11-16
  • Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Eirini Pectasides; Matthew D. Stachler; Sarah Derks; Yang Liu; Steven Maron; Mirazul Islam; Lindsay Alpert; Heewon Kwak; Hedy Kindler; Blase Polite; Manish R. Sharma; Kenisha Allen; Emily O'Day; Samantha Lomnicki; Melissa Maranto; Rajani Kanteti; Carrie Fitzpatrick; Christopher Weber; Namrata Setia; Shu-Yuan Xiao; John Hart; Rebecca Nagy; Kyoung-Mee Kim; Min-Gew Choi; Byung Hoon Min; Katie S. Nason; Lea O'Keefe; Masayuki Watanabe; Hideo Baba; Rick Lanman; Agoston T. Agoston; David J. Oh; Andrew Dunford; Aaron R. Thorner; Matthew D. Ducar; Bruce M. Wollison; Haley A. Coleman; Yuan Ji; Mitchell C. Posner; Kevin K. Roggin; Kiran Turaga; Paul Chang; Kyle Hogarth; Uzma Siddiqui; Andres Gelrud; Gavin Ha; Samuel S. Freeman; Justin Rhoades; Sarah Reed; Greg Gydush; Denisse Rotem; Jon Davison; Yu Imamura; Viktor Adalsteinsson; Jeeyun Lee; Adam J. Bass; Daniel V. Catenacci

    Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy. SIGNIFICANCE: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 1–12. ©2017 AACR.

    更新日期:2017-11-16
  • SEMA3C Depletion Promotes Neuroblastoma Metastatic Dissemination
    Cancer Discov. (IF 20.011) Pub Date : 2017-10-20
    American Association for Cancer Research

    A neuroblastoma chick embryo xenograft model recapitulates tumor initiation and dissemination.

    更新日期:2017-11-15
  • Rare Tumors in Kids May Respond to Tazemetostat
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-15
    American Association for Cancer Research

    In a phase I trial of the EZH2 inhibitor tazemetostat, children with INI1-deficient tumors—including relapsed or refractory malignant rhabdoid tumors, atypical teratoid rhabdoid tumors, epithelioid sarcomas, and poorly differentiated chordomas—responded well to treatment, with some experiencing durable responses.

    更新日期:2017-11-15
  • Wild Microbiome Stems Tumorigenesis in Lab Mice
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-15
    American Association for Cancer Research

    Replacing laboratory mice's gut microbiomes with the microbial communities of their wild counterparts alters the lab animals' immune systems and boosts their resistance to colorectal cancer development and influenza.

    更新日期:2017-11-15
  • mTOR and HDAC inhibitors converge on the TXNIP/thioredoxin pathway to cause catastrophic oxidative stress and regression of RAS-driven tumors
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Clare F. Malone; Chloe Emerson; Rachel Ingraham; William Barbosa; Stephanie Guerra; Haejin Yoon; Lin L. Liu; Franziska Michor; Marcia Haigis; Kay F. Macleod; Ophélia Maertens; Karen Cichowski

    Although agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here, we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin antioxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating apoptosis signal-regulating kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non–small cell lung cancers. Together, these studies identify a promising therapeutic combination for several currently untreatable malignancies and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes. SIGNIFICANCE: There are no effective therapies for NF1- or RAS-mutant cancers. We show that combined mTOR/HDAC inhibitors kill these RAS-driven tumors by causing catastrophic oxidative stress. This study identifies a promising therapeutic combination and demonstrates that selective enhancement of oxidative stress may be more broadly exploited for developing cancer therapies. Cancer Discov; 7(12); 1–14. ©2017 AACR.

    更新日期:2017-11-15
  • 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 posttreatment blood sample, indicating reliable identification of MRD. Posttreatment 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 patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest. SIGNIFICANCE: This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. Cancer Discov; 7(12); 1–10. ©2017 AACR. See related commentary by Comino-Mendez and Turner, p. 1368.

    更新日期:2017-11-15
  • Acalabrutinib Approved for MCL
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-10
    American Association for Cancer Research

    Cryo-electron microscopy, whose pioneers won the 2017 Nobel Prize in Chemistry, is gaining favor among scientists as a tool to probe cancer at the molecular level. To that end, the NCI recently launched a centralized, free service facility to better meet the needs of researchers interested in utilizing this otherwise highly expensive technology.

    更新日期:2017-11-14
  • Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Scott Gettinger; Jungmin Choi; Katherine Hastings; Anna Truini; Ila Datar; Ryan Sowell; Anna Wurtz; Weilai Dong; Guoping Cai; Mary Ann Melnick; Victor Y. Du; Joseph Schlessinger; Sarah B. Goldberg; Anne Chiang; Miguel F. Sanmamed; Ignacio Melero; Jackeline Agorreta; Luis M. Montuenga; Richard Lifton; Soldano Ferrone; Paula Kavathas; David L. Rimm; Susan M. Kaech; Kurt A. Schalper; Roy S. Herbst; Katerina Politi

    Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer. SIGNIFICANCE: As programmed-death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1–16. ©2017 AACR.

    更新日期:2017-11-14
  • 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 patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance. SIGNIFICANCE: Using a transposon screen and clinical datasets, we identified mutations in ciliogenesis genes as a new class of resistance to SMO inhibitors. Mechanistically, cilia-mutant tumors can either grow slowly in a “persister” state or evolve and progress rapidly in an “aggressive” state. Cancer Discov; 7(12); 1–14. ©2017 AACR. See related commentary by Goranci-Buzhala et al., p. 1374.

    更新日期:2017-11-14
  • Basket Study Yields Approval for Rare Blood Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-13
    American Association for Cancer Research

    The FDA, in a regulatory first, approved a targeted therapy based on a basket study. The move, which expanded the indications for the BRAF inhibitor vemurafenib to include Erdheim–Chester disease, points to a new approval pathway for drugs that treat rare cancers.

    更新日期:2017-11-13
  • 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 cancers, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors. SIGNIFICANCE: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin αvβ3 as a biomarker to identify mutant KRAS–addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin αvβ3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1–16. ©2017 AACR.

    更新日期:2017-11-11
  • BLU-285 Targets KIT/PDGFRA Conformation and Activating Loop Mutations
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-10
    American Association for Cancer Research

    The small-molecule inhibitor BLU-285 inhibits clinically relevant KIT and PDGFRA mutations.

    更新日期:2017-11-11
  • Dabrafenib plus Trametinib Is Active in BRAFV600E Anaplastic Thyroid Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-10
    American Association for Cancer Research

    Dual BRAF/MEK inhibition achieves responses in 69% of BRAFV600E anaplastic thyroid cancers (ATC).

    更新日期:2017-11-11
  • NTZ Increases β-catenin Citrullination to Suppress WNT Signaling
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-10
    American Association for Cancer Research

    The antiparasitic drug NTZ inhibits WNT signaling and APC-mutant colorectal cancer cell growth.

    更新日期:2017-11-11
  • The DNA Transposase PGBD5 Sensitizes Tumors to Inhibition of DNA Repair
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-10
    American Association for Cancer Research

    PGBD5 expression in pediatric solid tumors confers sensitivity to inhibitors of DNA damage signaling.

    更新日期:2017-11-11
  • GPX4 Inhibition Selectively Targets Drug-Tolerant Persister Cells
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-10
    American Association for Cancer Research

    Targeting GPX4 induces selective cell death of drug-tolerant persister tumor cells by ferroptosis.

    更新日期:2017-11-11
  • NIH Initiative Aims to Improve Immunotherapy
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-09
    American Association for Cancer Research

    The NIH has launched a new collaboration with 11 biopharmaceutical companies and four academic cancer centers to identify the most effective biomarkers for immunotherapy. The public–private partnership will analyze patient samples from clinical trials and aims to develop a standard panel of biomarkers to determine which patients are likely to benefit from immunotherapy and to track their responses.

    更新日期:2017-11-09
  • Genetic predictors of response to systemic therapy in esophagogastric cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Yelena Y. Janjigian; Francisco Sanchez-Vega; Philip Jonsson; Walid K. Chatila; Jaclyn F. Hechtman; Geoffrey Y. Ku; Jamie C. Riches; Yaelle Tuvy; Ritika Kundra; Nancy Bouvier; Efsevia Vakiani; Jianjiong Gao; Zachary J. Heins; Benjamin E. Gross; David P. Kelsen; Liying Zhang; Vivian E. Strong; Mark Schattner; Hans Gerdes; Daniel G. Coit; Manjit Bains; Zsofia K. Stadler; Valerie W. Rusch; David R. Jones; Daniela Molena; Jinru Shia; Mark E. Robson; Marinela Capanu; Sumit Middha; Ahmet Zehir; David M. Hyman; Maurizio Scaltriti; Marc Ladanyi; Neal Rosen; David H. Ilson; Michael F. Berger; Laura Tang; Barry S. Taylor; David B. Solit; Nikolaus Schultz

    The incidence of esophagogastric cancer is rapidly rising but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of metastatic esophagogastric cancer patients. There was no association between HRD defects and response to platinum-based chemotherapy. Patients with MSI-H tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single EBV+ patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and co-mutations in the receptor tyrosine kinase, RAS, PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab, and guide strategies to overcome drug resistance.

    更新日期:2017-11-09
  • Treating Recurrent Glioma with Toca 511
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-08
    American Association for Cancer Research

    Findings from a phase I study suggest that delivering high concentrations of the chemotherapy 5-FU directly to brain tumors via the retroviral vector vocimagene amiretrorepvec, or Toca 511, may benefit patients with recurrent high-grade glioma. This investigational treatment was well tolerated and induced robust, durable responses lasting a median of 3 years.

    更新日期:2017-11-08
  • FDA Approves Second CAR T-cell Therapy
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-07
    American Association for Cancer Research

    The FDA approved the chimeric antigen receptor T-cell therapy axicabtagene ciloleucel, making it the second such treatment for blood cancers in the United States. The therapy is indicated for adults with certain non-Hodgkin lymphomas who have tried at least two other treatments.

    更新日期:2017-11-07
  • Mutation Load Offers Predictive Biomarker in SCLC
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-03
    American Association for Cancer Research

    Tumor mutation burden offers a promising predictive biomarker for patients with small cell lung cancer. An exploratory analysis presented at the World Conference on Lung Cancer showed that the patients with large numbers of mutations in their cancer cells were more likely to respond—and for a longer time—to a single checkpoint inhibitor or a combination of them than those with a low mutation load.

    更新日期:2017-11-03
  • Lorlatinib in ALK+ NSCLC: Robust Phase II Efficacy Seen
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-03
    American Association for Cancer Research

    The investigational ALK inhibitor lorlatinib, whose early clinical activity was first reported last year, continues to look promising in advanced ALK-positive or ROS1-positive non–small cell lung cancer. In a phase II study, robust responses were seen in previously untreated patients, as well as those who had received as many as three prior ALK inhibitors.

    更新日期:2017-11-03
  • CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Jiehui Deng; Eric S. Wang; Russell W. Jenkins; Shuai Li; Ruben Dries; Kathleen Yates; Sandeep Chhabra; Wei Huang; Hongye Liu; Amir R. Aref; Elena Ivanova; Cloud Peter Paweletz; Michaela Bowden; Chensheng W. Zhou; Grit S. Herter-Sprie; Jessica A. Sorrentino; John E. Bisi; Patrick H. Lizotte; Ashley A. Merlino; Max M. Quinn; Lauren E. Bufe; Annan Yang; Yanxi Zhang; Hua Zhang; Peng Gao; Ting Chen; Megan E. Cavanaugh; Amanda J. Rode; Eric Haines; Patrick J. Roberts; Jay C. Strum; William G. Richards; Jochen H. Lorch; Sareh Parangi; Viswanath Gunda; Genevieve M. Boland; Raphael Bueno; Sangeetha Palakurthi; Gordon J. Freeman; Jerome Ritz; W. Nicholas Haining; Norman E. Sharpless; Haribabu Arthanari; Geoffrey I. Shapiro; David A. Barbie; Nathanael S. Gray; Kwok-Kin Wong

    Immune checkpoint blockade, exemplified by antibodies targeting the programmed death-1 (PD-1) receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T cell activation, contributing to anti-tumor effects in vivo, due in part to de-repression of Nuclear Factor of Activated T cell (NFAT) family proteins and their target genes, critical regulators of T cell function. Although CDK4/6 inhibitors decrease T cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.

    更新日期:2017-11-03
  • Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids
    Cancer Discov. (IF 20.011) Pub Date : 2017-01-01
    Russell W. Jenkins; Amir R. Aref; Patrick H. Lizotte; Elena Ivanova; Susanna Stinson; Chensheng W. Zhou; Michaela Bowden; Jiehui Deng; Hongye Liu; Diana Miao; Meng Xiao He; William Walker; Gao Zhang; Tian Tian; Chaoran Cheng; Zhi Wei; Sangeetha Palakurthi; Mark Bittinger; Hans Vitzthum; Jong Wook Kim; Ashley Merlino; Max Quinn; Chandrasekar Venkataramani; Joshua A. Kaplan; Andrew Portell; Prafulla C. Gokhale; Bart Phillips; Alicia Smart; Asaf Rotem; Robert E. Jones; Lauren Keogh; Maria Anguiano; Lance Stapleton; Zhiheng Jia; Michal Barzily-Rokni; Israel Cañadas; Tran C. Thai; Marc R. Hammond; Raven Vlahos; Eric S. Wang; Hua Zhang; Shuai Li; Glenn J. Hanna; Wei Huang; Mai P. Hoang; Adriano Piris; Jean-Pierre Eliane; Anat O. Stemmer-Rachamimov; Lisa Cameron; Mei-Ju Su; Parin Shah; Benjamin Izar; Manisha Thakuria; Nicole R. LeBoeuf; Guilherme Rabinowits; Viswanath Gunda; Sareh Parangi; James M. Cleary; Brian C. Miller; Shunsuke Kitajima; Rohit Thummalapalli; Benchun Miao; Thanh U. Barbie; Vivek Sivathanu; Joshua Wong; William G. Richards; Raphael Bueno; Charles H. Yoon; Juan Miret; Meenhard Herlyn; Levi A. Garraway; Eliezer M. Van Allen; Gordon J. Freeman; Paul T. Kirschmeier; Jochen H. Lorch; Patrick A. Ott; F. Stephen Hodi; Keith T. Flaherty; Roger D. Kamm; Genevieve M. Boland; Kwok-Kin Wong; David Dornan; Cloud Peter Paweletz; David A. Barbie

    Ex vivo systems that incorporate features of the tumor microenvironment (TME) and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations, and respond to ICB in short-term 3-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo. Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.

    更新日期:2017-11-03
  • The MHC I Genotype Influences Early Driver Events in Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-03
    American Association for Cancer Research

    The incidence of recurrent oncogenic alterations in a tumor is influenced by the MHC I genotype.

    更新日期:2017-11-03
  • IL1R8 May Be a Natural Killer Cell Checkpoint Protein
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-03
    American Association for Cancer Research

    Loss of IL1R8 increases NK cell number and maturation to suppress tumorigenesis and metastasis.

    更新日期:2017-11-03
  • Lorlatinib Is Well Tolerated and Has Activity in ALK+ and ROS1+ NSCLC
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-03
    American Association for Cancer Research

    Lorlatinib achieved systemic and intracranial responses in patients with ALK- and ROS1-positive NSCLC.

    更新日期:2017-11-03
  • Glucose Indirectly Fuels the TCA Cycle in Tumors via Lactate
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-03
    American Association for Cancer Research

    Circulating lactate derived from glucose is preferentially used as fuel for the TCA cycle over glucose.

    更新日期:2017-11-03
  • H3.3K27M Expression Combined with Trp53 Loss Induces High-Grade Glioma
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-03
    American Association for Cancer Research

    In utero expression of H3.3K27M with Trp53 loss in mice recapitulates human pediatric high-grade glioma.

    更新日期:2017-11-03
  • In This Issue
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    American Association for Cancer Research

    See article, p. 1238 Adoptive transfer of T cells expressing chimeric antigen receptors (CAR) has led to striking clinical responses in some patients with refractory leukemia and lymphoma, but the clinical efficacy of this approach is limited by the expansion and persistence of CAR-T cells, particularly in solid tumors. Efforts have been made to engineer CAR-T cells to coexpress immunostimulatory cytokines (so-called “armored” CAR-T cells) because CARs cannot recapitulate the function of cytokines in T-cell activation, but systemic accumulation of cytokines secreted by armored CAR-T cells has the potential to cause severe adverse events such as neurotoxicity or cytokine release syndrome. Shum and colleagues devised a method to selectively deliver cytokine signals to CAR-T cells through coexpression of a constitutively active interleukin 7 receptor (C7R), which triggers the IL7 signaling axis in CAR-T cells without a requirement for extracellular ligand and without stimulating bystander lymphocytes. Consistent with the known stimulatory effect of IL7 signaling on tumor-specific T cells, expression of C7R significantly increased the survival, proliferation, and antitumor activity of several types of CAR-T cells in vitro and in vivo without promoting autonomous or antigen-independent T-cell growth. In addition to demonstrating a requirement for immunostimulatory cytokine signaling for sustained activity of CAR-T cells against solid tumors, these findings suggest a strategy for safer delivery of cytokine signals to CAR-T cells that could potentially reduce the risk of severe adverse events associated with CAR-T cell therapy.

    更新日期:2017-11-02
  • Trapping Cancers as They Adapt to Survive
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Rizwan Haq

    Summary: The evolution of cancer cells limits the efficacy of nearly all treatments for patients with solid tumors. Characterizing how cancers adapt to treatment could therefore lead to approaches that overcome resistance to therapy. In this issue of Cancer Discovery, Song and colleagues describe the evolution of melanomas upon exposure to BRAF inhibitors, demonstrating that adaptive changes in the tumor create a vulnerability that can be targeted with immune checkpoint inhibitors. Cancer Discov; 7(11); 1216–7. ©2017 AACR. See related article by Song et al., p. 1248.

    更新日期:2017-11-02
  • Targeting the Lysosome for Cancer Therapy
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Christina G. Towers; Andrew Thorburn

    Summary: Lysosomes are the recycling centers of the cell where organelles and proteins are degraded during autophagy and macropinocytosis; they also serve as signaling hubs that control the activity of mTORC1. In this issue, Rebecca and colleagues report the development of a new type of lysosomal inhibitor for cancer therapy that can inhibit multiple lysosomal activities that are needed for tumor cell survival and growth. Cancer Discov; 7(11); 1218–20. ©2017 AACR. See related article by Rebecca et al., p. 1266.

    更新日期:2017-11-02
  • Insights into Epigenetic Remodeling in VHL-Deficient Clear Cell Renal Cell Carcinoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Christopher J. Ricketts; W. Marston Linehan

    Summary: Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the von Hippel–Lindau tumor suppressor gene (VHL), and the functional tumorigenic consequences of this loss have been used to develop therapies for advanced ccRCC, such as targeting activation of the HIF pathway. Yao and colleagues elucidate how VHL loss contributes to chromatin alteration at both gene promoters and enhancers/superenhancers, in both an HIF-dependent as well as independent manner, and how this may provide additional targets for therapeutic intervention in advanced ccRCC. Cancer Discov; 7(11); 1221–3. ©2017 AACR. See related article by Yao et al., p. 1284.

    更新日期:2017-11-02
  • Tissue Force Programs Cell Fate and Tumor Aggression
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Jason J. Northey; Laralynne Przybyla; Valerie M. Weaver

    Biomechanical and biochemical cues within a tissue collaborate across length scales to direct cell fate during development and are critical for the maintenance of tissue homeostasis. Loss of tensional homeostasis in a tissue not only accompanies malignancy but may also contribute to oncogenic transformation. High mechanical stress in solid tumors can impede drug delivery and may additionally drive tumor progression and promote metastasis. Mechanistically, biomechanical forces can drive tumor aggression by inducing a mesenchymal-like switch in transformed cells so that they attain tumor-initiating or stem-like cell properties. Given that cancer stem cells have been linked to metastasis and treatment resistance, this raises the intriguing possibility that the elevated tissue mechanics in tumors could promote their aggression by programming their phenotype toward that exhibited by a stem-like cell. Significance: Recent findings argue that mechanical stress and elevated mechanosignaling foster malignant transformation and metastasis. Prolonged corruption of tissue tension may drive tumor aggression by altering cell fate specification. Thus, strategies that could reduce tumor mechanics might comprise effective approaches to prevent the emergence of treatment-resilient metastatic cancers. Cancer Discov; 7(11); 1224–37. ©2017 AACR.

    更新日期:2017-11-02
  • Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Thomas Shum; Bilal Omer; Haruko Tashiro; Robert L. Kruse; Dimitrios L. Wagner; Kathan Parikh; Zhongzhen Yi; Tim Sauer; Daofeng Liu; Robin Parihar; Paul Castillo; Hao Liu; Malcolm K. Brenner; Leonid S. Metelitsa; Stephen Gottschalk; Cliona M. Rooney

    Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer. Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238–47. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1201

    更新日期:2017-11-02
  • Recurrent Tumor Cell–Intrinsic and –Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    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; Kimberley B. Dahlman; Philip O. Scumpia; Jeffrey A. Sosman; Douglas B. Johnson; Antoni Ribas; Willy Hugo; Roger S. Lo

    Treatment of advanced BRAFV600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (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 CD45-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. Significance: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell–inflamed, stromal adaptations, many of which are tumor cell–driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. Cancer Discov; 7(11); 1248–65. ©2017 AACR. See related commentary by Haq, p. 1216. This article is highlighted in the In This Issue feature, p. 1201

    更新日期:2017-11-02
  • A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    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 (DQ) 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 cancer, 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. Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. Cancer Discov; 7(11); 1266–83. ©2017 AACR. See related commentary by Towers and Thorburn, p. 1218. This article is highlighted in the In This Issue feature, p. 1201

    更新日期:2017-11-02
  • VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    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 noncoding 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. Superenhancer 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/superenhancer 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 preexisting 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. Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter–enhancer complexes. Cancer Discov; 7(11); 1284–305. ©2017 AACR. See related commentary by Ricketts and Linehan, p. 1221. This article is highlighted in the In This Issue feature, p. 1201

    更新日期:2017-11-02
  • Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Melinda Mata; Claudia Gerken; Phuong Nguyen; Giedre Krenciute; David M. Spencer; Stephen Gottschalk

    Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)–binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T cells expressing HER2–CARζ and a MyD88/CD40–based iCO molecule (HER2ζ.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ.iCO T cells without CID and T cells expressing HER2–CAR.CD28ζ. HER2ζ.iCO T cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2ζ.iCO T cells in vivo. Thus, expressing MyD88/CD40–based iCO molecules in CAR T cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors. Significance: Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion. Cancer Discov; 7(11); 1306–19. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1201

    更新日期:2017-11-02
  • Notch Shapes the Innate Immunophenotype in Breast Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Qiang Shen; Brenda Cohen; Weiyue Zheng; Ramtin Rahbar; Bernard Martin; Kiichi Murakami; Sara Lamorte; Patrycja Thompson; Hal Berman; Juan Carlos Zúñiga-Pflücker; Pamela S. Ohashi; Michael Reedijk

    Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment. Here, we show that Notch in tumor cells regulates the expression of two powerful proinflammatory cytokines, IL1β and CCL2, and the recruitment of tumor-associated macrophages (TAM). Notch also regulates TGFβ-mediated activation of tumor cells by TAMs, closing a Notch-dependent paracrine signaling loop between these two cell types. We use a mouse model in which Notch can be regulated in spontaneous mammary carcinoma to confirm that IL1β and CCL2 production, and macrophage recruitment are Notch-dependent. In human disease, expression array analyses demonstrate a striking association between Notch activation, IL1β and CCL2 production, macrophage infiltration, and BLBC. These findings place Notch at the nexus of a vicious cycle of macrophage infiltration and amplified cytokine secretion and provide immunotherapeutic opportunities in BLBC. Significance: BLBC is aggressive and has an unmet need for effective targeted treatment. Our data highlight immunotherapeutic opportunities in Notch-activated BLBC. Effective IL1β and CCL2 antagonists are currently in clinical review to treat benign inflammatory disease, and their transition to the cancer clinic could have a rapid impact. Cancer Discov; 7(11); 1320–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1201

    更新日期:2017-11-02
  • TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    Riadh Lobbardi; Jordan Pinder; Barbara Martinez-Pastor; Marina Theodorou; Jessica S. Blackburn; Brian J. Abraham; Yuka Namiki; Marc Mansour; Nouran S. Abdelfattah; Aleksey Molodtsov; Gabriela Alexe; Debra Toiber; Manon de Waard; Esha Jain; Myriam Boukhali; Mattia Lion; Deepak Bhere; Khalid Shah; Alejandro Gutierrez; Kimberly Stegmaier; Lewis B. Silverman; Ruslan I. Sadreyev; John M. Asara; Marjorie A. Oettinger; Wilhelm Haas; A. Thomas Look; Richard A. Young; Raul Mostoslavsky; Graham Dellaire; David M. Langenau

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. Impaired NHEJ is well known to cause genomic instability, including development of T-cell malignancies in KU70- and KU80-deficient mice. Collectively, our work has uncovered important roles for TOX in regulating NHEJ by elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation. Significance: TOX is an HMG box–containing protein that has important roles in T-ALL initiation and maintenance. TOX inhibits the recruitment of KU70/KU80 to DNA breaks, thereby inhibiting NHEJ repair. Thus, TOX is likely a dominant oncogenic driver in a large fraction of human T-ALL and enhances genomic instability. Cancer Discov; 7(11); 1336–53. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1201

    更新日期:2017-11-02
  • People
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    American Association for Cancer Research

    Peter Pisters, MD, MHCM, and Michael Teitell, MD, PhD, are highlighted.

    更新日期:2017-11-02
  • FDA Approves First Biosimilar to Treat Cancer
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    American Association for Cancer Research

    The FDA approved the VEGF inhibitor bevacizumab-awwb for the treatment of five types of cancer: nonsquamous non-small cell lung cancer, metastatic colorectal cancer, cervical cancer, renal cell carcinoma, and glioblastoma. A biosimilar to bevacizumab, the agent is the first such drug approved for the treatment of cancer.

    更新日期:2017-11-02
  • Approved Drugs Might Work in More Cancers
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    American Association for Cancer Research

    Researchers in the Netherlands presented preliminary results from a multiarm precision medicine trial at the recent ESMO 2017 Congress in Madrid, Spain. The trial, which matches patients with approved drugs based on mutations in their tumor and tissue type, has the potential to uncover treatment options for patients who have exhausted standard therapies, as well as those with rare cancers.

    更新日期:2017-11-02
  • Liquid Biopsy Technique May Allow Early Screening
    Cancer Discov. (IF 20.011) Pub Date : 2017-11-01
    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:2017-11-02
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.
期刊列表
复旦大学施章杰课题组招聘启事
2017年“高被引科学家”,化学/材料领域完整名单
期刊版块即将升级,期待您的宝贵意见
Angew. Chem. Int. Ed. 10月文章访问量Top10
征稿通知:2017年绿色复合材料与纳米技术国际会议
2017年中科院JCR分区化学大类列表
【问答】如何用荧光探针检测大脑中活性氧的水平?
试剂库存管理
化合物查询
down
wechat
bug