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  • Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    KRAS G12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.

    更新日期:2020-01-17
  • Test for Methylated Cell-Free DNA Identifies Colorectal Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    A noninvasive test for methylated cell-free DNA markers identified colorectal cancer.

    更新日期:2020-01-17
  • Algorithms May Assist Expert Pathologists in Prostate Cancer Diagnosis
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    Algorithms matching the performance of expert pathologists in prostate cancer diagnosis were designed.

    更新日期:2020-01-17
  • SWI/SNF Component ARID1A Mediates Breast Cancer Treatment Response
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-17
    American Association for Cancer Research

    ARID1A is required for response of ER+ breast cancer cells to tamoxifen and fulvestrant but not JQ1.

    更新日期:2020-01-17
  • Myc instructs and maintains pancreatic adenocarcinoma phenotype
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-15
    Nicole M Sodir; Roderik M. Kortlever; Valentin J.A. Barthet; Tania Campos; Luca Pellegrinet; Steven Kupczak; Panayiotis Anastasiou; Lamorna Brown Swigart; Laura Soucek; Mark J Arends; Trevor D. Littlewood; Gerard I Evan

    The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity and dismal prognosis. We show that acute activation of Myc in indolent PanIN epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune cell types and trigger transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch.

    更新日期:2020-01-15
  • Pediatric Cancer Survivorship Portal Released
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-10
    American Association for Cancer Research

    The St. Jude Cloud, an online resource for cancer researchers to download, upload, process, and visualize pediatric cancer data, has announced the release of the St. Jude Survivorship Portal, which contains a wealth of clinical and genomic data about survivors of childhood cancers.

    更新日期:2020-01-10
  • Characteristics and outcome of AKT1 E17K-mutant breast cancer defined through AACR GENIE, a clinicogenomic registry
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-10
    Lillian M Smyth; Qin Zhou; Bastien Nguyen; Celeste Yu; Eva M Lepisto; Monica Arnedos; Michael J. Hassett; Michele L Lenoue-Newton; Natalie Blauvelt; Semih Dogan; Christine M. Micheel; Chetna Wathoo; Hugo Horlings; Jan Hudecek; Benjamin E. Gross; Ritika Kundra; Shawn M Sweeney; Jianjiong Gao; Nikolaus Schultz; Andrew Zarski; Stuart M Gardos; Jocelyn Lee; Seth Sheffler-Collins; Ben H Park; Charles L Sawyers; Fabrice Andre; Mia Levy; Funda Meric-Bernstam; Phillipe L. Bedard; Alexia Iasonos; Deborah Schrag; David M Hyman; AACR Project GENIE Consortium

    AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of matched AKT1 E17K-mutant (n=153) and -wildtype (n=302) metastatic breast cancer patients. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wildtype controls (median OS, 24.1 vs 29.9, respectively; p=0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology.

    更新日期:2020-01-10
  • A Vaccine Enhances CAR-T Cell Efficacy against Solid Tumors
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-10
    American Association for Cancer Research

    Claudin 6 (CLDN6) may represent a novel target for CAR-T cell therapies aimed at solid tumors.

    更新日期:2020-01-10
  • Targeting CD73 May Improve Immunotherapy Efficacy in Glioblastoma
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-10
    American Association for Cancer Research

    CD73hi macrophages are enriched in glioblastoma and may contribute to immunotherapy resistance.

    更新日期:2020-01-10
  • Outer Radial Glia–Like Cells May Promote Glioblastoma Invasiveness
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-10
    American Association for Cancer Research

    Outer radial glia (oRG)–like glioma stem cells (GSC) were enriched in human glioblastomas.

    更新日期:2020-01-10
  • Variants at an HLA and an IL Locus Are Associated with NKTCL
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-10
    American Association for Cancer Research

    A genome-wide association study identified two risk loci for natural killer T-cell lymphoma (NKTCL).

    更新日期:2020-01-10
  • Circadian regulator CLOCK recruits immune suppressive microglia into the GBM tumor microenvironment
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-09
    Peiwen Chen; Wen-Hao Hsu; Andrew Chang; Zhi Tan; Zhengdao Lan; Ashley Zhou; Denise J Spring; Frederick F. Lang; Y. Alan Wang; Ronald A. DePinho

    Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSCs). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem cell self-renewal, which was amplified in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered pro-tumor immunity via transcriptional up-regulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK:BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease.

    更新日期:2020-01-09
  • In This Issue
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    See article, [p. 40][1] ![][2] Triggering adenosine 2A receptors (A2AR) on the cell surface can suppress the antitumor effects of various immune cells, making A2AR signaling a potentially useful immunotherapy target. Fong and colleagues conducted a phase I clinical trial of the

    更新日期:2020-01-09
  • Lessons from the A2A Adenosine Receptor Antagonist–Enabled Tumor Regression and Survival in Patients with Treatment-Refractory Renal Cell Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Michail V. Sitkovsky

    Summary: In this issue of Cancer Discovery , Fong and colleagues describe the encouraging observations of tumor regression, disease control, and survival of patients with otherwise refractory renal cell cancer with progressive disease after treatment with the conceptually novel oral antagonist of the A2A adenosine receptor (A2AR), ciforadenant. A2AR antagonists may represent the until now missing but critically important part of more effective immunotherapies of cancer, because they prevent the inhibition of tumor-reactive T and natural killer cells by blocking the immunosuppressive hypoxia–A2A–adenosinergic signaling, which represents an emerging immunosuppressive hallmark of tumors that are the most resistant to therapies. See related article by Fong et al., [p. 40][1] . [1]: /lookup/volpage/10/40?iss=1

    更新日期:2020-01-09
  • Can the Help Match the Hype? KRASG12C-Specific Inhibitors and Beyond
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Samuel J. Klempner; Aaron N. Hata

    Summary: Hallin and colleagues demonstrate the preclinical activity of the KRASG12C-specific inhibitor MRTX849 in a series of in vitro and in vivo studies with supporting pilot clinical efficacy. Variable responsiveness despite effective KRASG12C inhibition highlights both the promise and potential need for combinatorial strategies to optimally target KRASG12C-driven cancers. See related article by Hallin et al., [p. 54][1] . [1]: /lookup/volpage/10/54?iss=1

    更新日期:2020-01-09
  • Personalizing KRAS-Mutant Allele–Specific Therapies
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Chiara Falcomatà; Günter Schneider; Dieter Saur

    Summary: KRAS G12R mutations occur almost exclusively in pancreatic ductal adenocarcinoma. The results of a study that reveals specific differences in KRAS downstream signaling and metabolic rewiring of pancreatic cancer cells harboring KRAS G12R mutations promise to improve our possibilities to better stratify patients for individualized therapies. See related article by Hobbs et al., [p. 104][1] . [1]: /lookup/volpage/10/104?iss=1

    更新日期:2020-01-09
  • The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    John Kwon; Samuel F. Bakhoum

    The recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. The cGAS–STING pathway was discovered as an important DNA-sensing machinery in innate immunity and viral defense. Recent advances have now expanded the roles of cGAS–STING to cancer. Highly aggressive, unstable tumors have evolved to co-opt this program to drive tumorigenic behaviors. In this review, we discuss the link between the cGAS–STING DNA-sensing pathway and antitumor immunity as well as cancer progression, genomic instability, the tumor microenvironment, and pharmacologic strategies for cancer therapy. Significance: The cGAS–STING pathway is an evolutionarily conserved defense mechanism against viral infections. Given its role in activating immune surveillance, it has been assumed that this pathway primarily functions as a tumor suppressor. Yet, mounting evidence now suggests that depending on the context, cGAS–STING signaling can also have tumor and metastasis-promoting functions, and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment.

    更新日期:2020-01-09
  • Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Lawrence Fong; Andrew Hotson; John D. Powderly; Mario Sznol; Rebecca S. Heist; Toni K. Choueiri; Saby George; Brett G.M. Hughes; Matthew D. Hellmann; Dale R. Shepard; Brian I. Rini; Shivaani Kummar; Amy M. Weise; Matthew J. Riese; Ben Markman; Leisha A. Emens; Daruka Mahadevan; Jason J. Luke; Ginna Laport; Joshua D. Brody; Leonel Hernandez-Aya; Philip Bonomi; Jonathan W. Goldman; Lyudmyla Berim; Daniel J. Renouf; Rachel A. Goodwin; Brian Munneke; Po Y. Ho; Jessica Hsieh; Ian McCaffery; Long Kwei; Stephen B. Willingham; Richard A. Miller

    Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo . In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. Significance: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. See related commentary by Sitkovsky, [p. 16][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/10/16?iss=1 [2]: /lookup/volpage/10/1?iss=1

    更新日期:2020-01-09
  • The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Jill Hallin; Lars D. Engstrom; Lauren Hargis; Andrew Calinisan; Ruth Aranda; David M. Briere; Niranjan Sudhakar; Vickie Bowcut; Brian R. Baer; Joshua A. Ballard; Michael R. Burkard; Jay B. Fell; John P. Fischer; Guy P. Vigers; Yaohua Xue; Sole Gatto; Julio Fernandez-Banet; Adam Pavlicek; Karen Velastagui; Richard C. Chao; Jeremy Barton; Mariaelena Pierobon; Elisa Baldelli; Emanuel F. Patricoin; Douglas P. Cassidy; Matthew A. Marx; Igor I. Rybkin; Melissa L. Johnson; Sai-Hong Ignatius Ou; Piro Lito; Kyriakos P. Papadopoulos; Pasi A. Jänne; Peter Olson; James G. Christensen

    Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line– and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. Significance: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents. See related commentary by Klempner and Hata, [p. 20][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/10/20?iss=1 [2]: /lookup/volpage/10/1?iss=1

    更新日期:2020-01-09
  • PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Carlotta Costa; Ye Wang; Amy Ly; Yasuyuki Hosono; Ellen Murchie; Charlotte S. Walmsley; Tiffany Huynh; Christopher Healy; Rachel Peterson; Shogo Yanase; Charles T. Jakubik; Laura E. Henderson; Leah J. Damon; Daria Timonina; Ioannis Sanidas; Christopher J. Pinto; Mari Mino-Kenudson; James R. Stone; Nicholas J. Dyson; Leif W. Ellisen; Aditya Bardia; Hiromichi Ebi; Cyril H. Benes; Jeffrey A. Engelman; Dejan Juric

    The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN , through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo . Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. Significance: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

    更新日期:2020-01-09
  • Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Remi Klotz; Amal Thomas; Teng Teng; Sung Min Han; Oihana Iriondo; Lin Li; Sara Restrepo-Vassalli; Alan Wang; Negeen Izadian; Matthew MacKay; Byoung-San Moon; Kevin J. Liu; Sathish Kumar Ganesan; Grace Lee; Diane S. Kang; Charlotte S. Walmsley; Christopher Pinto; Michael F. Press; Wange Lu; Janice Lu; Dejan Juric; Aditya Bardia; James Hicks; Bodour Salhia; Frank Attenello; Andrew D. Smith; Min Yu

    Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. Significance: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo –cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

    更新日期:2020-01-09
  • Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    G. Aaron Hobbs; Nicole M. Baker; Anne M. Miermont; Ryan D. Thurman; Mariaelena Pierobon; Timothy H. Tran; Andrew O. Anderson; Andrew M. Waters; J. Nathaniel Diehl; Bjoern Papke; Richard G. Hodge; Jennifer E. Klomp; Craig M. Goodwin; Jonathan M. DeLiberty; Junning Wang; Raymond W.S. Ng; Prson Gautam; Kirsten L. Bryant; Dominic Esposito; Sharon L. Campbell; Emanuel F. Petricoin; Dhirendra K. Simanshu; Andrew J. Aguirre; Brian M. Wolpin; Krister Wennerberg; Udo Rudloff; Adrienne D. Cox; Channing J. Der

    Allele-specific signaling by different KRAS alleles remains poorly understood. The KRAS G12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. Significance: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers. See related commentary by Falcomatà et al., [p. 23][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/10/23?iss=1 [2]: /lookup/volpage/10/1?iss=1

    更新日期:2020-01-09
  • MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Juming Yan; Stacey Allen; Elizabeth McDonald; Indrajit Das; Jeffrey Y.W. Mak; Ligong Liu; David P. Fairlie; Bronwyn S. Meehan; Zhenjun Chen; Alexandra J. Corbett; Antiopi Varelias; Mark J. Smyth; Michele W.L. Teng

    Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1 −/− mice, compared with wild-type mice. The antitumor activity observed in Mr1 −/− mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1 −/− mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy. Significance: Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

    更新日期:2020-01-09
  • ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    Yun-Han Huang; Jing Hu; Fei Chen; Nicolas Lecomte; Harihar Basnet; Charles J. David; Matthew D. Witkin; Peter J. Allen; Steven D. Leach; Travis J. Hollmann; Christine A. Iacobuzio-Donahue; Joan Massagué

    TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGFβ pathway intact avert this apoptotic effect via ID1. ID1 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGFβ-mediated repression of ID1 . The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA. Significance: Half of PDAs escape TGFβ-induced tumor suppression without inactivating the TGFβ pathway. We report that ID1 expression is selected for in PDAs and that ID1 uncouples TGFβ-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

    更新日期:2020-01-09
  • People
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Michael Birrer, MD, PhD; Levi Garraway, MD, PhD; and Robert Winn, MD, are featured.

    更新日期:2020-01-09
  • Oncology Drug Shortages Persist
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Drug shortages in oncology have been an ongoing issue in the United States, leaving clinicians scrambling to ensure that patients have access to therapies. Depleted drug supplies have been particularly acute in pediatric oncology, and a recent shortage of vincristine demonstrates how shortages occur and how treatment centers respond—and highlights the need for better strategies to avoid or mitigate such situations.

    更新日期:2020-01-09
  • Tucatinib Impresses in Breast Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Recent results suggest that tucatinib, when combined with trastuzumab and capecitabine, is effective in patients with locally advanced inoperable or metastatic HER2-positive breast cancer who have received prior therapies: In a phase II trial, the drug extended overall survival and progression-free survival compared with trastuzumab and capecitabine alone, and improved progression-free survival in patients with brain metastases.

    更新日期:2020-01-09
  • Siglec-15: An Attractive Immunotherapy Target
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Siglec-15, which selectively drives immunosuppression in the tumor microenvironment, has emerged as a viable therapeutic target. In a phase I trial of NC318, a Siglec-15 antibody, encouraging efficacy was seen, including a complete response in non–small cell lung cancer refractory to PD-1 blockade.

    更新日期:2020-01-09
  • Bempegaldesleukin Ups Melanoma Responses
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Preliminary findings suggest that adding bempegaldesleukin to nivolumab may improve responses in patients with metastatic melanoma. In a phase I/II trial, the combination elicited responses in 20 out of 38 patients with newly diagnosed disease and was associated with relatively few side effects.

    更新日期:2020-01-09
  • Cancer Collaboration Aims to Boost Detection
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    A new collaboration sponsored by Cancer Research UK will attempt to boost early cancer detection. The partnership involves five institutions in the UK and United States that will to team up to develop and validate new technologies and biomarkers.

    更新日期:2020-01-09
  • Noted
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    A collection of recently published news items.

    更新日期:2020-01-09
  • Dueling KRASG12C Inhibitors Achieve Responses
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Clinical trials of two KRASG12C inhibitors, MRTX849 and AMG 510, have shown robust efficacy in phase I trials including patients with non-small cell lung cancer. Data on the effectiveness of the drugs in other tumor types, such as colorectal cancer, have been more limited. Regardless, researchers are excited about the possibility of targeting proteins long thought “undruggable.”

    更新日期:2020-01-09
  • Prime Editing Promises Greater Precision, Safety
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Cancer researchers are heralding the arrival of prime editing, an ultra-precise twist on CRISPR genome engineering, as a powerful new tool for disease modeling, target validation, and clinical applications.

    更新日期:2020-01-09
  • The PRIMPOL Protein Shields Replication Forks in BRCA-Deficient Cells
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    PRIMPOL shields replication forks after multiple rounds of cisplatin in BRCA-deficient cancer cells.

    更新日期:2020-01-09
  • The C-Terminal Domain of SMARCB1 Mediates Chromatin Remodeling
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    SWI/SNF component SMARCB1's C-terminal domain binds nucleosomes and mediates chromatin remodeling.

    更新日期:2020-01-09
  • Lorlatinib Is Active in ROS1-Positive Non–Small Cell Lung Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    In a phase I/II trial, lorlatinib was safe and effective in ROS1 -positive non–small cell lung cancer.

    更新日期:2020-01-09
  • Novel MYC-Targeting Drug Is Effective in Mouse Prostate Cancer Models
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    A new MYC inhibitor reduced tumor growth in mouse prostate cancer models.

    更新日期:2020-01-09
  • A Small-Molecule Drug Targeting STAT3 Causes Tumor Regression in Mice
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    SD-36, a small-molecule proteolysis-targeting chimera (PROTAC), causes STAT3 degradation in vivo .

    更新日期:2020-01-09
  • Adaptive Mutability May Underlie Some Resistance to Targeted Therapies
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Colorectal cancer cells react to targeted therapies by transiently increasing their mutation rate.

    更新日期:2020-01-09
  • MYC Superenhancer–Nuclear Pore Binding Increases MYC-Transcript Export
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    An oncogenic superenhancer recruits active MYC to the nuclear pore in colon-cancer cells.

    更新日期:2020-01-09
  • Rhabdoid Tumors Are Immunogenic and May Respond to Immunotherapy
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Despite their low mutational burden (TMB), human rhabdoid tumors provoke an immune response.

    更新日期:2020-01-09
  • CD80 Dimerization with PD-L1 in Cis Disrupts CTLA4–CD80 Interactions
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    PD-L1 can repress the CTLA4 axis to stimulate an immune response.

    更新日期:2020-01-09
  • Mutations in Receptor Tyrosine Kinases Drive Histiocytic Disorders
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Genomic analysis identified previously unknown potential histiocytosis-driving mutations.

    更新日期:2020-01-09
  • PIK3CA Double Mutations in Cis May Predict PI3Kα-Inhibitor Response
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Cis double PIK3CA mutations are common in cancers and increase sensitivity to PI3Kα inhibitors.

    更新日期:2020-01-09
  • The Leukemia-Driving Fusion Protein TCF3–HLF Is Regulated by EP300
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    The histone acetyltransferase EP300 regulates TCF3–HLF, which promotes acute lymphoblastic leukemia.

    更新日期:2020-01-09
  • Pembrolizumab Monotherapy Is Active in Metastatic Prostate Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    In patients with metastatic castration-resistant prostate cancer, pembrolizumab showed efficacy.

    更新日期:2020-01-09
  • Bone-Metastasis Microenvironment May Explain Immunotherapy Resistance
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Anti-CTLA4 caused Th1 expansion in primary prostate-cancer tumors, but not bone metastases.

    更新日期:2020-01-09
  • Peritumoral YAP and TAZ Expression Suppresses Tumor Growth in Mice
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Peritumoral expression of Hippo-pathway members YAP and TAZ restricts liver-tumor growth in mice.

    更新日期:2020-01-09
  • Immune Response to Commensal Viruses Protects Mice from Skin Cancer
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Adaptive immunity to commensal viruses reduced the risk of skin cancer in mice.

    更新日期:2020-01-09
  • A Phosphoswitch in Shelterin Component TRF2 Mediates Telomere Dynamics
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    Phosphorylation of shelterin component TRF2 modulates telomere accessibility across the cell cycle.

    更新日期:2020-01-09
  • Acknowledgment to Reviewers
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-01
    American Association for Cancer Research

    The Cancer Discovery editors wish to acknowledge with sincere appreciation the assistance of the following reviewers who have generously contributed their time and effort during the past year[1][1] in the appraisal of manuscripts. These reviewers have been enormously helpful in assessing the merit

    更新日期:2020-01-09
  • Next-Generation CAR T Cells Counter Exhaustion
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-08
    American Association for Cancer Research

    A new model for studying T-cell exhaustion in human cells has enabled scientists to discover a transcription factor that, when overexpressed, helps make chimeric antigen receptor T cells resistant to this mechanism of immune failure. A separate team has found that deleting a key phosphatase improved the antitumor function of engineered T cells as well.

    更新日期:2020-01-08
  • Multiple Myeloma: The CAR T-cell Therapy Landscape
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-08
    American Association for Cancer Research

    BCMA-targeting chimeric antigen receptor T cells increasingly look like a potent option for multiple myeloma. Across several candidates spotlighted during the 2019 American Society of Hematology Annual Meeting, high response rates were seen in patients whose disease was refractory to multiple standard therapies.

    更新日期:2020-01-08
  • Acalabrutinib Plus Obinutuzumab in Treatment-Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-08
    Jennifer A. Woyach; James S. Blachly; Kerry A Rogers; Seema A Bhat; Mojgan Jianfar; Gerard Lozanski; David M. Weiss; Barbara L Andersen; Michael Gulrajani; Melanie M. Frigault; Ahmed Hamdy; Raquel Izumi; Veerendra Munugalavadla; Cheng Quah; Min-Hui Wang; John C. Byrd

    Acalabrutinib is a selective irreversible Bruton tyrosine kinase inhibitor that does not affect interleukin-2 associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase 1b/2 study ([NCT02296918][1]) of patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naive and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2-6: 1000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naive) and 92% (relapsed/refractory). Thirty-two percent of treatment-naive and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naive) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naive and relapsed/refractory CLL. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02296918&atom=%2Fcandisc%2Fearly%2F2020%2F01%2F07%2F2159-8290.CD-19-1130.atom

    更新日期:2020-01-08
  • Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-08
    Patrizia Mondello; Saber Tadros; Matt Teater; Lorena Fontan; Aaron Y Chang; Neeraj Jain; Haopeng Yang; Shailbala Singh; Hsia-Yuan Ying; Chi-Shuen Chu; Man Chun John Ma; Eneda Toska; Stefan Alig; Matthew Durant; Elisa de Stanchina; Sreejoyee Ghosh; Anja Mottok; Loretta Nastoupil; Sattva S. Neelapu; Oliver Weigert; Giorgio Inghirami; Jose Baselga; Anas Younes; Cassian Yee; Ahmet Dogan; David A Scheinberg; Robert G Roeder; Ari M Melnick; Michael R Green

    CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-repressor complex. Accordingly, we show that HDAC3 selective inhibitors reverse CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen presentation genes. By reactivating these genes, exposure to HDAC3 inhibitor restored the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence HDAC3 inhibition represents a novel mechanism-based immune-epigenetic therapy for CREBBP mutant lymphomas.

    更新日期:2020-01-08
  • Regulatory T cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis.
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-07
    Yaqing Zhang; Jenny Lazarus; Nina G Steele; Wei Yan; Ho-Joon Lee; Zeribe C. Nwosu; Christopher J Halbrook; Rosa E. Menjivar; Samantha B. Kemp; Veerin Sirihorachai; Ashley Velez-Delgado; Katelyn Donahue; Eileen S. Carpenter; Kristee L. Brown; Valerie Irizarry-Negron; Anna C. Nevison; Alekya Vinta; Michelle A Anderson; Howard C Crawford; Costas A. Lyssiotis; Timothy L Frankel; Filip Bednar; Marina Pasca di Magliano

    Regulatory T cells (Tregs) are abundant ion human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression, and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts (myCAFs). Conversely, we observed an increase in chemokines Ccl3, Ccl6, and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathological CD4+ Tcell responses. Our data points to new mechanisms regulating fibroblast differentiation in pancreatic cancer and supports the notion that fibroblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis.

    更新日期:2020-01-07
  • Project GENIE Announces Biopharma Collaboration
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-06
    American Association for Cancer Research

    Project GENIE, a registry of real-world genomic and clinical cancer data, has announced a 5-year, $36 million collaboration with nine biopharmaceutical companies to obtain detailed information from at least 50,000 patients, which would be added to the 70,000 cases already in Project GENIE's database.

    更新日期:2020-01-06
  • Combo Poised to Become Standard in HCC
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-06
    American Association for Cancer Research

    Researchers may finally have identified a first-line treatment for hepatocellular carcinoma that is superior to the current standard. In a phase III trial, atezolizumab plus bevacizumab extended median progression-free survival and overall survival compared with sorafenib, and the combination was associated with a similar rate and severity of side effects as sorafenib.

    更新日期:2020-01-06
  • Circular DNA Throws Gene Regulation for a Loop
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-06
    American Association for Cancer Research

    Four recent studies help explain why extrachromosomal DNA, with its many oncogene amplifications and circular shape, is such a potent driver of tumor growth. The start-up company Boundless Bio aims to apply these insights to the treatment of intractable cancers in which extra loops of DNA are abundant.

    更新日期:2020-01-06
  • An SLC1A5 Variant Transports Glutamine to Mitochondria in Cancer Cells
    Cancer Discov. (IF 26.370) Pub Date : 2020-01-06
    American Association for Cancer Research

    A variant of SLC1A5 (SLC1A5_var) fueled pancreatic cancer cells’ mitochondria with glutamine.

    更新日期:2020-01-06
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