tbuckley/cabot-search huggingface dataset:
Abstract 5751: Induction of cancer stem cell like characteristics by overexpression of CDX1
Authors: SANG IL CHOI, Kyoung-Ok Hong, Mi Ree Park, Yun Hee Na, Soo-Jeong Cho
Journal: Cancer Research (2017)

Abstract Intestinal metaplasia (IM) has been regarded as the most significant risk factor for gastric cancer (GC). However, the molecular mechanisms of the pathogenesis of IM and the progression of GC remain unclear. The aim of this study was to evaluate the role of CDX1 in IM and GC using stable CDX1 overexpression in HFE 145 gastric epithelial cells, and its expression in patient samples. For CDX1 overexpression, we generated lentiviral CDX1 and infected is to HFE 145 cells. We found that CDX1 overexpression induced an increase of IM related markers such as villin and SI and a decrease of gastric epithelial marker such as MUC 5AC. Overexpression of CDX1 in HFE 145 cells caused an increase in cell proliferation (P&amp;lt;0.05) and showed 2.7-fold higher clonogenic ability than that of control cells. The expression of CDX1 induced in vitro invasiveness 1.9-fold higher compared to HFE 145 control cells with statistical significance (p=0.004), augmented the expression of MMP-9 and phosphorylation of FAK and paxillin. Overexpression of CDX1 also induced anchorage-independent colony formation and spheroid formation, and enhanced the expression of stem cell markers including SOX2, Oct4, NANOG and c-Myc in HFE 145 cells, suggesting CDX1-induced stem cell like phenotype of gastric epithelial cells. HFE 145 cells infected with CagA-positive Helicobacter pylori (G27 wild type) caused an increase in expression of CDX1 compared to HFE145 cells infected with CagA-negative H. pylori (G27 ΔCagE). Using luciferase promoter assay, we confirmed that the expression of CDX1 was regulated by the CagA secreted from H. pylori. In clinical practice, the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) staging system is often used to evaluate the degree of IM in biopsy samples or surgical specimen. We measured expression of CDX1, SI, and villin adjusted by glyceraldehyde 3-phosphate dehydrogenase expression using densitometry in 9 patients with various OLGIM stage (2 in stage 0, 1 in stage 1, 2 in stage 2, 1 in stage 3, 3 in stage 4). We were able to find out that the patients with higher OLGIM stage (stage 3-4) tended to have higher expression of CDX1 (3.935 vs. 0.416, p=0.160), SI (9.739 vs. 0.311, p=0.088), and villin (7.785 vs. 0.868, p=0.119) compared to patients with lower OLGIM stage (stage 0-2). Taken together, these results suggest that CDX1 overexpression could be one of the causes of GC tumorigenesis and progression. Further investigation on CDX1 molecule would encourage development of specific target for cancer treatment. Citation Format: SANG IL CHOI, Kyoung-Ok Hong, Mi Ree Park, Yun Hee Na, Soo-Jeong Cho. Induction of cancer stem cell like characteristics by overexpression of CDX1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5751. doi:10.1158/1538-7445.AM2017-5751
Abstract CT080: Pharmacokinetic and pharmacodynamic analysis of M7824, a dual anti-PD-L1 and TGFβ TRAP molecule, in the first-in-human phase I dose escalation study
Authors: Liang Cao, Zhigang Kang, Linghui Li, Julius Strauss, Isabelle Dussault, James Gulley
Journal: Cancer Research (2017)

Abstract Introduction: M7824 is a bifunctional molecule that blocks both PD-L1 and TGFβ1-3. In this first-in-human phase I dose escalation study, in addition to monitoring the pharmacokinetics of M7824, we aimed to confirm its mechanism of action, particularly against the TGFβ cytokines. Methods: Patients were treated with M7824 intravenously at 5 dose levels of 0.3, 1, 3, 10, and 20 mg/kg every two weeks. PK analyses were performed from samples up to day 85 (7th dose). PD-L1 target occupancy was measured in CD3+ PBMCs by flow cytometry from patient blood collected at pre-dose, Day 2 (D2), D15, and D43. Further, the blood levels of TGFβ1-3 and pro-inflammatory cytokines were measured at these time points with an additional time point at D8 using analytically validated Luminex bead- and ECLIA-based multiplex immunoassays. Results: Results indicated a half-life of 4-8 days for M7824, which increased with dose up to 3 mg/kg, and was subsequently dose independent at dose levels of &amp;gt; 3 mg/kg. M7824 PK exposure during the first cycle increased in an approximately dose-proportional manner between 3 to 20 mg/kg, without significant accumulation within the first 85 days of treatment. There was PD-L1 target occupancy plateaued at about 80% for dose levels 3-20 mg/kg which was maintained throughout the dosing interval. Furthermore, there was a small (1.7 fold on D2) but significant induction of IFNγ at 0.3-20 mg/kg (p=0.001, n=19). TGFβ1-3 blood levels were reduced by a minimum of 99%, 92%, and 91%, respectively, at all time points for dose levels 1-20 mg/kg. At the dose of 0.3 mg/kg, TGFβ1-3 levels were depleted at D2 and D8, but not at D15 with an average reduction of 63%, 42% and 67%, respectively. Moreover, there was a correlation between the drug PK levels and the TGFβ trapping. Thus, TGFβ1-3 trapping was achieved in the circulation at drug dose level of 1 mg/kg and above. Conclusion: This study demonstrates in vivo evidence for highly significant trapping (&amp;gt;90%) of circulating TGFβ molecules (β1, β2, β3) by the bifunctional agent M7824 at dose levels of 1 mg/kg and higher, in addition to its high degree of peripheral PD-L1 target occupancy (80%). Further studies to evaluate the PK/PD, safety, and efficacy profile of M7824 are ongoing. Citation Format: Liang Cao, Zhigang Kang, Linghui Li, Julius Strauss, Isabelle Dussault, James Gulley. Pharmacokinetic and pharmacodynamic analysis of M7824, a dual anti-PD-L1 and TGFβ TRAP molecule, in the first-in-human phase I dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT080. doi:10.1158/1538-7445.AM2017-CT080
Abstract 2260: Haplotypes of chromosome 17q21.31 affect liver metastasis by small intestinal neuroendocrine tumors
Authors: Shinta Kobayashi, Edaise da Silva, Tanupriya Contractor, Laura Tang, Chris R. Harris
Journal: Cancer Research (2017)

Abstract Neuroendocrine tumors are the most common tumors of the small intestine. Very little is known about genetic changes that cause SI-NETs, which have a very low frequency of mutations. SI-NETs are highly metastatic to the liver, and patients with liver metastases have a five year survival rate of less than 50%. Caucasian patients are more likely to develop metastasis than patients of other races. We have studied a 900 kB inversion at chromosome 17q21.31, which is common to Caucasians but rare in other races. Within a collection of 117 Caucasian patients with ileal carcinoids, patients with the inversion haplotype were significantly less likely to have liver metastasis. A second Caucasian-specific haplotype in this region, beta2, was also tested for potential association with metastasis of ileal carcinoids. Unlike the inversion haplotype, beta2 associates with increased metastasis of ileal carcinoids. We suspect that the fact that the metastasis-promoting beta2 haplotype is more common among Caucasians than the metastasis-suppressing inversion haplotype (44% incidence vs. 33% incidence) is probably why Caucasians wind up with a higher frequency of metastasis than races that carry neither beta2 nor the inversion. Citation Format: Shinta Kobayashi, Edaise da Silva, Tanupriya Contractor, Laura Tang, Chris R. Harris. Haplotypes of chromosome 17q21.31 affect liver metastasis by small intestinal neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2260. doi:10.1158/1538-7445.AM2017-2260
Abstract 5892: Induction of stromal fibrosis accelerates tumorigenesis in NeuT mice
Authors: Robert I. Glazer, Hongyan Yuan, Lu Jin
Journal: Cancer Research (2017)

Abstract Background: One of the central challenges in cancer prevention is the identification of factors in the tumor microenvironment (TME) that increase breast cancer susceptibility. The stromal composition of the breast is largely adipose and fibroblast tissue, and thus it is important to understand how alterations in these constituents affect in the onset of stromal fibrosis (SF) and cancer progression. To address these questions, MMTV-NeuT mice were crossed into the FAT-ATTAC (fat apoptosis through targeted activation of caspase 8) background (NeuT/ATTAC), wherein conditional dimerization of the FKBP-caspase 8 fusion transgene in female mice results in mammary fat ablation and its replacement with fibrotic tissue. Results: Induction of mammary fat ablation in NeuT/ATTAC mice over 4 weeks resulted in increased ductal proliferation and SF as denoted by increased collagen deposition and expression of Fibroblast Activation Protein and α-smooth muscle actin. Maintaining SF over 3-5 months resulted in a 40% reduction in tumor onset and a 2.5-fold increase in tumor multiplicity, which was associated with increased infiltration by myeloid-derived suppressor cells. Gene expression profiling of tumors from mice with and without SF identified increased expression of the immune-related genes Cxcl1, Ly6d and CD14, as well as acute phase proteins Saa1 and S100a6 in NeuT/ATTAC mice with SF. Conclusion: Induction of SF in an erbB2-dependent breast cancer model resulted in a tumor microenvironment more conducive to tumor progression and immune tolerance. These results suggest alternative therapeutic approaches that could be taken, eg. chemokine receptor antagonists, to increase the effectiveness of immunotherapy and chemotherapy. Supported by a grant from the Avon Foundation for Women and Award 1P30CA051008 from the National Cancer Institute, NIH, to the Lombardi Comprehensive Cancer Center. Citation Format: Robert I. Glazer, Hongyan Yuan, Lu Jin. Induction of stromal fibrosis accelerates tumorigenesis in NeuT mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5892. doi:10.1158/1538-7445.AM2017-5892
The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders Compared With Diagnosis-Specific Protocols for Anxiety Disorders
Authors: David H. Barlow, Todd J. Farchione, Jacqueline R. Bullis, Matthew W. Gallagher, Heather Murray-Latin, Shannon Sauer-Zavala, Kate H. Bentley, Johanna Thompson-Hollands, Laren R. Conklin, James F. Boswell, Amantia Ametaj, Jenna R. Carl, Hannah T. Boettcher, Clair Cassiello-Robbins
Journal: JAMA Psychiatry (2017)

Transdiagnostic interventions have been developed to address barriers to the dissemination of evidence-based psychological treatments, but only a few preliminary studies have compared these approaches with existing evidence-based psychological treatments.To determine whether the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) is at least as efficacious as single-disorder protocols (SDPs) in the treatment of anxiety disorders.From June 23, 2011, to March 5, 2015, a total of 223 patients at an outpatient treatment center with a principal diagnosis of panic disorder with or without agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, or social anxiety disorder were randomly assigned by principal diagnosis to the UP, an SDP, or a waitlist control condition. Patients received up to 16 sessions of the UP or an SDP for 16 to 21 weeks. Outcomes were assessed at baseline, after treatment, and at 6-month follow-up. Analysis in this equivalence trial was based on intention to treat.The UP or SDPs.Blinded evaluations of principal diagnosis clinical severity rating were used to evaluate an a priori hypothesis of equivalence between the UP and SDPs.Among the 223 patients (124 women and 99 men; mean [SD] age, 31.1 [11.0] years), 88 were randomized to receive the UP, 91 to receive an SDP, and 44 to the waitlist control condition. Patients were more likely to complete treatment with the UP than with SDPs (odds ratio, 3.11; 95% CI, 1.44-6.74). Both the UP (Cohen d, -0.93; 95% CI, -1.29 to -0.57) and SDPs (Cohen d, -1.08; 95% CI, -1.43 to -0.73) were superior to the waitlist control condition at acute outcome. Reductions in clinical severity rating from baseline to the end of treatment (β, 0.25; 95% CI, -0.26 to 0.75) and from baseline to the 6-month follow-up (β, 0.16; 95% CI, -0.39 to 0.70) indicated statistical equivalence between the UP and SDPs.The UP produces symptom reduction equivalent to criterion standard evidence-based psychological treatments for anxiety disorders with less attrition. Thus, it may be possible to use 1 protocol instead of multiple SDPs to more efficiently treat the most commonly occurring anxiety and depressive disorders.clinicaltrials.gov Identifier: NCT01243606.
Abstract 5714: AXL and GAS6 Co-expression in lung adenocarcinoma as a prognostic classifier
Authors: Masahiro Seike, Ritaro Noro, Cheol-Hong Kim, Fenfei Zou, Kaoru Kubota, Akihiko Gemma
Journal: Cancer Research (2017)

Abstract AXL, a receptor tyrosine kinase implicated in cell survival, proliferation, and migration, is also associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy. However, its prognostic significance in lung adenocarcinoma (AD) remains unclear. We therefore evaluated the prognostic significance of the expression of AXL and/or its ligand, growth arrest-specific 6 (GAS6), in completely resected lung AD. We evaluated the relationship between AXL, GAS6, and vimentin expression, as determined by immunohistochemistry (IHC) analysis, with overall survival and disease-free survival in 113 patients with stages I-III lung AD. Protein expression was also assayed using western blot analysis in 10 lung AD cell lines. AXL-positive (AXL+), GAS6-positive (GAS6+), or AXL+/GAS6+ staining was significantly associated with vimentin-positive (vimentin+) expression. AXL+/GAS6+ and vimentin+ showed a negative tendency toward an association with EGFR mutation. AXL+, GAS6+, or AXL+/GAS6+ statuses significantly correlated with poor overall survival. In stage I cases, an AXL+/GAS6+ status significantly correlated with poor overall survival and disease-free survival, especially in cases with wild-type EGFR. In multivariate analysis, AXL/GAS6 classifications in stage I as well as in stages I-III lung AD were found to be independent factors for poor patient outcomes. Unlike lung AD cell lines with mutant EGFR, those with wild-type EGFR closely correlated with AXL and vimentin expression by western blotting. AXL+ and GAS6+ expression is relevant to a poor prognosis in resected lung AD patients at stage I. AXL/GAS6 might serve as crucial predictive and prognostic biomarkers and targets to identify individuals at high risk of post-operative death. Citation Format: Masahiro Seike, Ritaro Noro, Cheol-Hong Kim, Fenfei Zou, Kaoru Kubota, Akihiko Gemma. AXL and GAS6 Co-expression in lung adenocarcinoma as a prognostic classifier [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5714. doi:10.1158/1538-7445.AM2017-5714
Abstract 3682: Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non-small cell lung cancer
Authors: Dennis O. Adeegbe, Yan Liu, Patrick Lizotte, Yusuke Kamihara, Mark Awad, David Barbie, Jerome Ritz, Simon Jones, Steven Quayle, Peter Hammerman, Kwok-Kin Wong
Journal: Cancer Research (2017)

Abstract Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. This study evaluated the immunoregulatory properties of two classes of drugs that modulate the epigenome, histone deacetylase (HDAC) and bromodomain inhibitors with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes associated with enhanced T-cell priming and function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight immunomodulatory effects of two epigenetic modifiers that together promote T-cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for NSCLC treatment. Citation Format: Dennis O. Adeegbe, Yan Liu, Patrick Lizotte, Yusuke Kamihara, Mark Awad, David Barbie, Jerome Ritz, Simon Jones, Steven Quayle, Peter Hammerman, Kwok-Kin Wong. Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3682. doi:10.1158/1538-7445.AM2017-3682
Abstract 2028: PDE3A modulation for cancer therapy
Authors: Xiaoyun Wu, Timothy Lewis, Luc de Waal, Galen Gao, Jian Zhang, Monica Schenone, Colin Garvie, Brett Diamond, Selena Lorrey, Andrew Cherniack, Steven Corsello, Alex Burgin, Todd Golub, Stuart Schreiber, Matthew Meyerson, Heidi Greulich
Journal: Cancer Research (2017)

Abstract In a differential cytotoxicity screen, we identified a novel small molecule modulator of phosphodiesterase 3A (PDE3A) that kills cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal, Nat Chem Biol, 2016). Treatment with this cell-selective cytotoxic small molecule, DNMDP, induces complex formation between PDE3A and SLFN12, resulting in apoptosis. Inhibition of PDE3A enzymatic activity is not sufficient for cancer cell killing, and expression of both PDE3A and SLFN12 are required. Although the mechanism of signaling to the apoptosis machinery remains unclear, we examined more closely the role of the PDE3A-SLFN12 complex in cancer cell killing mediated by DNMDP. We found that cancer cell lines made resistant to DNMDP by persistent exposure downregulated SLFN12 expression and that re-expression of SLFN12 was sufficient to restore sensitivity. Furthermore, ectopic expression of PDE3A and SLFN12 are sufficient to sensitize cancer cells to DNMDP. These data underscore the tight correlation of PDE3A-SLFN12 complex formation and cancer cell killing mediated by DNMDP. Citation Format: Xiaoyun Wu, Timothy Lewis, Luc de Waal, Galen Gao, Jian Zhang, Monica Schenone, Colin Garvie, Brett Diamond, Selena Lorrey, Andrew Cherniack, Steven Corsello, Alex Burgin, Todd Golub, Stuart Schreiber, Matthew Meyerson, Heidi Greulich. PDE3A modulation for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2028. doi:10.1158/1538-7445.AM2017-2028
Abstract 2431: Single cell gene expression profiling in breast cancer cells with the Her2/neu gene knockout by CRISPR-Cas9
Authors: Xiaoyang Wang, Chip Lomas, Michael A. Tycon, Craig Betts, Suzanne Weaver
Journal: Cancer Research (2017)

Abstract The Her2/neu gene is amplified and overexpressed in 15%-30% of breast cancers. The overexpression of this oncogene is strongly correlated with decreased survival, increased cancer relapse, and poor prognosis. Although therapy has been successfully developed to target this oncogene, a better understanding of this oncogene will provide further insight for breast cancer biology and future drug development. In recent years, the CRISPR-Cas9 system has emerged as an efficient method for genetic engineering, enabling targeted gene knockout with minimal off-target effects. In this study, we employed a plasmid-based CRISPR-Cas9 system to knock out the Her2/neu gene in breast cancer cells. Puromycin selected, GFP-positive (two indicators of the incorporation of the CRISPR-Cas9 system), Her2-negative individual cells were index-sorted using a BD FACSMelody™ system into individual wells of a 96-well BD™ Precise plate with sample barcoding and molecular indexing. A whole transcriptome amplification (WTA) assay was performed to obtain a gene expression profile for each of the Her2/neu knockout cells. Her2 gene knockout was performed on two cell lines: T47D, a ductal carcinoma-derived breast cancer cell line with no Her2 amplification that shows low to intermediate Her2/neu expression; and SKBR3, an adenocarcinoma-derived breast cancer cell line known for Her2/neu gene amplification and overexpression. For comparison, WTA assays were also carried out on parental cells without gene editing. Comparison of the gene expression profiles reveals downstream changes in gene expression correlated to the Her2 knockout. The profiling of gene expression in Her2/neu CRISPR-Cas9 knockout cells on a single cell level promises to provide insight into the mechanisms in these aggressive cancers that could help future drug discovery. For Research Use Only. Not for use in diagnostic or therapeutic procedures. 23-19341-00 Citation Format: Xiaoyang Wang, Chip Lomas, Michael A. Tycon, Craig Betts, Suzanne Weaver. Single cell gene expression profiling in breast cancer cells with the Her2/neu gene knockout by CRISPR-Cas9 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2431. doi:10.1158/1538-7445.AM2017-2431