Abstract:
UNLABELLED:Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. SIGNIFICANCE:This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Sen M,Thomas SM,Kim S,Yeh JI,Ferris RL,Johnson JT,Duvvuri U,Lee J,Sahu N,Joyce S,Freilino ML,Shi H,Li C,Ly D,Rapireddy S,Etter JP,Li PK,Wang L,Chiosea S,Seethala RR,Gooding WE,Chen X,Kaminski N,Pandit K,Jodoi
10.1158/2159-8290.CD-12-0191subject
Has Abstractpub_date
2012-08-01 00:00:00pages
694-705issue
8eissn
2159-8274issn
2159-8290pii
2159-8290.CD-12-0191journal_volume
2pub_type
临床试验,杂志文章相关文献
Cancer Discovery文献大全abstract::Biotechnology startup Arvinas is developing proteolysis-targeting chimeras (PROTAC) that combat cancer by degrading disease-causing proteins. The company's first PROTACs will target prostate and breast cancers, and a recent deal with Pfizer will allow Arvinas to develop PROTACs for other cancer types. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2018-015
更新日期:2018-04-01 00:00:00
abstract::A new compound with anti-leukemia activity perturbs gene transcription by modulating super-enhancer activity. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-149
更新日期:2015-12-01 00:00:00
abstract::A study shows that analyzing the protein contents of exosomes and related extracellular vesicles can distinguish tumors from nearby noncancerous tissue, and profiling extracellular vesicle proteins obtained from plasma may also reveal cancer type. The results support using vesicle proteins for liquid biopsies. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2020-083
更新日期:2020-11-01 00:00:00
abstract:UNLABELLED:Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-11-0130
更新日期:2011-11-01 00:00:00
abstract::CD14+CD16-HLA-DRhi monocyte frequency was linked to response to anti-PD-1 in patients with melanoma. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-RW2018-016
更新日期:2018-03-01 00:00:00
abstract::Findings from a phase I/IIa study indicate that combining the investigational indoleamine 2,3-dioxygenase 1 inhibitor BMS-986205 with nivolumab is safe and boosts response rates among patients with bladder and cervical cancers. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-167
更新日期:2018-01-01 00:00:00
abstract::In the plasmaMATCH trial, researchers performed circulating tumor DNA testing on patients with advanced breast cancer and matched those with ESR1, HER2, or AKT1 alterations to targeted therapies. Patients with HER2 and AKT1 mutations experienced response rates greater than 22% with durable benefit. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2020-013
更新日期:2020-05-01 00:00:00
abstract::A new study of all 32 cancer types in The Cancer Genome Atlas identifies genomic alterations that increase the activity of the PI3K/AKT/mTOR pathway. The study, which combines mutation data with measures of protein levels and phosphorylation status, suggests that mutations in IDH1, VHL, and STK11 promote activation of...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-092
更新日期:2017-08-01 00:00:00
abstract::Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung canc...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-13-0741
更新日期:2014-05-01 00:00:00
abstract::Spliceosome inhibitors induced mRNA missplicing, retaining introns that formed double-stranded RNA. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2021-008
更新日期:2021-01-22 00:00:00
abstract::Asparagine promotes the survival of cancer cells in response to glutamine withdrawal. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2014-205
更新日期:2014-11-01 00:00:00
abstract:UNLABELLED:CD96 has recently been shown as a negative regulator of mouse natural killer (NK)-cell activity, with Cd96(-/-)mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-15-0944
更新日期:2016-04-01 00:00:00
abstract::Whether metastases were seeded mono- or polyclonally depended on cancer site and treatment. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-082
更新日期:2020-07-01 00:00:00
abstract::The APOBEC proteins fight off viruses by editing their genomes. A deletion that removes one of the proteins produces large numbers of mutations in the human genome, potentially leading to cancer. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2014-068
更新日期:2014-07-01 00:00:00
abstract::Although comprehensive genomic screening has not yet become routine when treating patients with cancer, widespread testing in those with advanced, refractory disease is feasible, according to the ongoing ProfiLER study. The study also found that patients who subsequently received a treatment matched to the genetic cha...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-094
更新日期:2017-08-01 00:00:00
abstract::In this issue of Cancer Discovery, Poulin and colleagues apply structural, biochemical, and biological profiling of two mutants of KRAS, one found most frequently in all cancers (G12D) and one found nearly exclusively in colorectal cancer (A146T). They provide compelling evidence that specific mutations will impart di...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-19-0406
更新日期:2019-06-01 00:00:00
abstract::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 strat...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-19-1255
更新日期:2020-01-01 00:00:00
abstract::A recent study suggests that natural killer (NK) cells may play an important role in antitumor response to immune checkpoint inhibitors. Researchers used mouse models to show that NK cells respond to PD-1 and PD-L1 inhibitors, information that could be used to develop immunotherapies that tap NK cells to combat cancer...
journal_title:Cancer discovery
pub_type: 评论,新闻
doi:10.1158/2159-8290.CD-NB2018-131
更新日期:2018-12-01 00:00:00
abstract:UNLABELLED:ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-14-0849
更新日期:2015-07-01 00:00:00
abstract::IFNγ-producing NK cells induced TME remodeling and orchestrated T cell-mediated tumor control. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-174
更新日期:2020-12-04 00:00:00
abstract::Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 pati...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-16-1223
更新日期:2017-02-01 00:00:00
abstract:UNLABELLED:Despite the impressive clinical activity of the second-generation antiandrogens enzalutamide and ARN-509 in patients with prostate cancer, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-50...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-13-0226
更新日期:2013-09-01 00:00:00
abstract::Researchers have used mass spectrometry to conduct proteomic analyses of 77 genomically characterized breast tumors. Through this approach, they've uncovered functional consequences of somatic mutations. For instance, EGFR overexpression in basal-like breast cancer is potentially driven by the loss of two genes, SKP1 ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2016-078
更新日期:2016-08-01 00:00:00
abstract::Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Because conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigens, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-20-0328
更新日期:2020-08-25 00:00:00
abstract::LKB1 inactivation generates a redox imbalance that promotes ADC-to-SCC transdifferentiation in NSCLC. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2015-089
更新日期:2015-07-01 00:00:00
abstract::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, mutat...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-17-0281
更新日期:2017-12-01 00:00:00
abstract::Amid concerns over the spread of COVID-19, oncology practices have "gone virtual," with video appointments scheduled for any service that does not require diagnostic testing or treatment. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2020-027
更新日期:2020-06-01 00:00:00
abstract::A report from the National Academies of Sciences, Engineering, and Medicine lays out 12 recommendations to help scientists decide whether to return research results to study participants and, if they do, how to improve the sharing of information. The most important change the report recommends is harmonizing contradic...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2018-102
更新日期:2018-09-01 00:00:00
abstract::Based on the results of two large international randomized trials, the FDA approved the anti-PD-L1 agent atezolizumab in October. It is the first PD-L1 inhibitor approved for use in patients with metastatic non-small cell lung cancer that has advanced in spite of treatment with platinum-based chemotherapy. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2016-143
更新日期:2016-12-01 00:00:00
abstract::Domchek and colleagues provide a case report of a 28-year-old woman with congenital abnormalities, inherited ovarian cancer, and carboplatin hypersensitivity. Interestingly, the woman had validated germline mutations in both BRCA1 alleles. These findings further implicate BRCA1 in the Fanconi anemia/BRCA pathway and h...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-13-0044
更新日期:2013-04-01 00:00:00