tbuckley/cabot-search huggingface dataset:
Abstract 4154: Resistance to BET inhibitors involves the β-catenin pathway in uveal melanoma
Authors: Grazia Ambrosini, Benjamin Tycko, Chaterine Do, Gary K. Schwartz
Journal: Cancer Research (2017)

Abstract Uveal melanoma (UM) is an aggressive intraocular malignancy with high tendency to metastasize to the liver. Currently available drugs have shown limited clinical activity in patients with UM and there is an urgent need for new effective therapies. Recent findings from our laboratory demonstrated that UM cells are sensitive to BET inhibitors (BETi) through the induction of cell cycle arrest and apoptosis. However, despite the initial inhibitory effects, UM cells acquire resistance to this class of drugs following chronic drug exposure. In order to understand the mechanistic basis for BETi resistance in UM, we assessed genome-wide CpG methylation patterns in UM cell lines that had been rendered resistant to the clinical BET inhibitor PLX51107 (Plexxikon, Berkeley, CA) following chronic drug exposure. The comparison between BET inhibitor-resistant versus sensitive cell lines revealed differential methylation of 1700 genes, including several involved in Wnt/β-catenin signaling, as well as other signaling pathways. Immunoblotting analysis confirmed that β-catenin protein was induced and activated in the resistant cells, while depletion of β-catenin by siRNA re-sensitized the resistant cells to the BET inhibitor. We then explored several combinations of PLX51107 with drugs that block β-catenin transcriptional activity through inhibition of its phosphorylation by PAK4 or through the inhibition of binding partners like Cdk8 and CBP. All these combinations increased the activity of the BET inhibitor in both sensitive and resistant cells, and these effects were synergistic, with combination indexes (CI) &amp;lt;1. These observations support the evidence that acquired resistant to BET inhibitors is mediated, at least in part, by activation of the Wnt/β-catenin pathway, and inhibitors of this pathway may provide a means to overcome acquired BET inhibitor resistance in UM patients treated with this class of drugs. Citation Format: Grazia Ambrosini, Benjamin Tycko, Chaterine Do, Gary K. Schwartz. Resistance to BET inhibitors involves the β-catenin pathway in uveal melanoma [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 4154. doi:10.1158/1538-7445.AM2017-4154
Abstract 5457: OGT restrains the NRF2 antioxidant pathway via O-GlcNAcylation of KEAP1
Authors: Po-Han Chen, Timothy J. Smith, Jianli Wu, Michael Boyce, Jen-Tsan Ashley Chi
Journal: Cancer Research (2017)

Abstract O-GlcNAcylation is a reversible post-translational modification that adds an O-linked β-N-acetylglucosamine (O-GlcNAc) moiety onto serine/threonine residues of target proteins. This modification is regulated by only two enzymes: O-GlcNAc transferase (OGT, the writer) and O-GlcNAcase (OGA, the eraser) in mammals. Recent studies have revealed that OGT expression and O-GlcNAc modifications are elevated in several cancers, but specific O-GlcNAc targets are not well defined. We conducted a global transcriptome profiling in MDA-MB-231 breast cancer cells to search for signaling events that respond to O-GlcNAc fluctuation. We found significant up-regulation of genes involved in the NRF2-dependent stress response when OGT activity is inhibited in different tumor types. We also discovered a strong positive correlation of gene signatures between low OGT activity and NRF2 activation in multiple human tumor gene expression datasets. NRF2, the primary regulator of redox balance, is usually activated by oxidative stress and repressed under basal conditions by the KEAP1-CUL3 ubiquitin ligase complex. However, we found that OGT inhibition increases NRF2 protein level through reducing poly-ubiquitination of NRF2 in the absence of oxidative stress. By chemical sugar labeling and mass spectrometry assays, we identified that KEAP1 is directly O-GlcNAcylated by OGT especially within the BTB and Kelch motifs. Of all 11 putative O-GlcNAc sites on KEAP1, we found serine 104 is responsible for regulating NRF2 activity through affecting KEAP1-CUL3 interaction. Interestingly, we found the amount of intracellular glucose co-vary with KEAP1 O-GlcNAcylation and NRF2 protein, suggesting that glucose metabolites may utilize the nutrient sensing O-GlcNAcylation to fine-tune the antioxidant response. We propose that cancer cells could utilize O-GlcNAcylation, specifically on KEAP1, to regulate NRF2-mediated stress responses in response to the dynamics of intracellular glucose level. Since the NRF2 pathway is inappropriately activated in certain tumor types due to dysregulated function of KEAP1, such as non-small cell lung cancer, where it provides stress resistance and a growth advantage. Our study could provide new insight into redox cancer biology and provide novel strategy to modulate NRF2 activity during tumor development. Citation Format: Po-Han Chen, Timothy J. Smith, Jianli Wu, Michael Boyce, Jen-Tsan Ashley Chi. OGT restrains the NRF2 antioxidant pathway via O-GlcNAcylation of KEAP1 [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 5457. doi:10.1158/1538-7445.AM2017-5457
Abstract 3434: Loss of regulation of β-Catenin expression by miR-214 and oncogenic role of miR-214 in metastatic melanoma cells
Authors: Kirthana Prabhakar, Ashika Jayanthy, Vijay Setaluri
Journal: Cancer Research (2017)

Abstract Dysregulation of β-catenin facilitates melanoma metastasis by activating the transcription of oncogenes like Myc, CyclinD1 and TCF-1. It is important to understand the regulation of β-catenin to develop strategies to target Wnt signaling for melanoma treatment. MicroRNAs are small non-coding RNAs that are primarily involved in post-transcriptional regulation of target genes. Hence, miRNAs can be used to manipulate protein levels by causing instability of the transcript or by inhibiting translation. MiR-214 has been documented as regulator of β-catenin in cancer cells other than melanoma cells. The role of miR-214 in regulation of β-catenin has not been investigated. In this study, we investigated regulation of β-catenin by miR-214 in melanoma cell lines and studied the effect of overexpression miR-214 on the malignant phenotype of metastatic melanoma cells and their sensitivity to MAP kinase inhibitors. Our data show that β-catenin is upregulated in a panel of metastatic melanoma cells and the expression levels of β-catenin is negatively correlated with endogenous expression of miR-214. However, overexpression of miR-214 by transfection with a miRNA mimic did not show significant decrease in β-catenin mRNA or protein expression. RNA-Seq showed that multiple isoforms of β-catenin transcript are present in melanoma where the binding site is absent or mutated. The alternatively spliced transcript with no binding site for miR-214 is seen to be more abundant than the other isoforms. Paradoxically, overexpression of miR-214 increased survival, proliferation and migration of metastatic melanoma. In addition, miR-214 overexpression decreased their sensitivity to vemurafenib and selumetinib. In melanoma cells with acquired resistance (in vitro), miR-214 overexpression further enhanced their resistance to MEK inhibitor, but not vemurafenib. In light of the published studies that proposed that miR-214 acts as tumor suppressor by negatively regulating β-catenin, our study is interesting since we find that in metastatic melanoma miR-214 has oncogenic role. Ongoing studies are aimed at understanding the mechanisms by which miR-214 promotes malignant behavior of melanoma cells. Citation Format: Kirthana Prabhakar, Ashika Jayanthy, Vijay Setaluri. Loss of regulation of β-Catenin expression by miR-214 and oncogenic role of miR-214 in metastatic melanoma cells [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 3434. doi:10.1158/1538-7445.AM2017-3434
Abstract 1846: Immunocompetent mouse allograft models for development of therapies to target breast cancer metastasis therapies to target breast cancer metastasis
Authors: Yu-an Yang, Howard Yang, Ying Hu, Peter Watson, Huaitian Liu, Thomas R. Geiger, Miriam R. Anver, Diana Haines, Philip Martin, Maxwell P. Lee, Kent W. Hunter, Lalage M. Wakefield
Journal: Cancer Research (2017)

Abstract Effective drug development to combat metastatic disease in breast cancer would be aided by the availability of well-characterized preclinical animal models that (a) metastasize with high efficiency, (b) metastasize in a reasonable time-frame, (c) have an intact immune system, and (d) capture some of the heterogeneity of the human disease. To address these issues, we have assembled a panel of twelve mouse mammary cancer cell lines that can metastasize efficiently on implantation into syngeneic immunocompetent hosts. Genomic characterization shows that more than half of the 30 most commonly mutated genes in human breast cancer are represented within the panel. Transcriptomically, most of the models fall into the luminal A or B intrinsic molecular subtypes, despite the predominance of an aggressive, poorly-differentiated or spindled histopathology in all models. Patterns of immune cell infiltration, proliferation rates, apoptosis and angiogenesis differed significantly among models. Inherent within-model variability of the metastatic phenotype mandates large cohort sizes for intervention studies but may also capture some relevant non-genetic sources of variability. The varied molecular and phenotypic characteristics of this expanded panel of models should aid in model selection for development of anti-metastatic therapies in vivo, and serve as a useful platform for predictive biomarker identification. Citation Format: Yu-an Yang, Howard Yang, Ying Hu, Peter Watson, Huaitian Liu, Thomas R. Geiger, Miriam R. Anver, Diana Haines, Philip Martin, Maxwell P. Lee, Kent W. Hunter, Lalage M. Wakefield. Immunocompetent mouse allograft models for development of therapies to target breast cancer metastasis therapies to target breast cancer metastasis [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 1846. doi:10.1158/1538-7445.AM2017-1846
Abstract 3869: Cell surface vimentin targeted mAb 86C increases sensitivity to temozolomide mediated cell death in glioma stem cells
Authors: Hyangsoon Noh, Jun Yan, Konrad Gabrusiewicz, Shulin Li
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive brain tumor in pediatric patients. The current standard of care including radiation and chemotherapy is not effective in most patients due to multiple factors such as resistance and poor blood-brain barrier (BBB) penetration. The development of strategies to reduce resistance and to increase sensitivity to chemotherapy may ameliorate the problems. Glioma stem cells (GSCs) are considered the source of relapse and chemoresistance. Sensitization of temozolomide TMZ resistance in GSC is therefore integral for therapeutic efficacy. Our lab has discovered that cell surface vimentin (CSV) is presented on patient-derived GSCs. In this study, we demonstrate that the treatment of GSCs with anti-CSV antibody (86C) sensitizes them to TMZ. We found that the combination of 86C and TMZ induced additional antitumor effects in 8 out of 12 GSCs. Mechanistic study of the four resistance GSCs revealed slow re-surface rate of CSV from CSV- GSCs and low CSV expression on GSCs as possible contributing factors. GSCs with rapid CSV resurfacing from CSV- GSCs was more sensitive to combination treatment compared to GSCs with a slow recovering from CSV- GSCs. Furthermore, the metabolism study shows these four resistance cells have high intrinsic mitochondria activity compared to sensitive cells. The combination of TMZ with 86C may represent a valuable strategy to reverse GSC chemoresistance. Citation Format: Hyangsoon Noh, Jun Yan, Konrad Gabrusiewicz, Shulin Li. Cell surface vimentin targeted mAb 86C increases sensitivity to temozolomide mediated cell death in glioma stem cells [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 3869. doi:10.1158/1538-7445.AM2017-3869
Abstract 2088: The activity of the FGFR selective inhibitor Debio 1347 is correlated with high mRNA expression
Authors: Franck Brichory, Anna Pokorska-Bocci, Paolo Nuciforo, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Anne Vaslin
Journal: Cancer Research (2017)

Abstract Dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway due to receptor overexpression, gene amplification, point mutations or fusions/chromosomal translocations is associated with cancer development and progression. Debio 1347 (CH5183284) is an oral selective FGFR inhibitor (FGFR1, 2 and 3) currently in clinical development. The aim of this study was to investigate Debio 1347 activity in patient derived xenograft (PDX) mouse models harboring diverse FGFR alterations in multiple indications. The trial was conducted in 66 PDX models of diverse histotypes selected according to their FGFR1, 2 and 3 alteration status. Debio 1347 was administered orally once daily at 40 up to 80 mg/kg for 10 to 22 consecutive days (N=3/group). Tumor volume was compared to the vehicle control group and measured by caliper twice weekly. Treatment response was determined by relative treatment-to-control ratios (ΔT/ΔC) of which a responding model was defined as ΔT/ΔC &amp;lt;0. PDX tumors were collected at the end of the treatment period and extensively characterized using FISH, nCounter Gene Expression and immunohistochemistry (IHC). Effect on downstream Dual Specificity Phosphatase 6 (DUSP6) signaling was also investigated by qPCR and RNA in situ hybridization (ISH). Debio 1347 induced tumor regression in 33% of PDX models that exhibited a gene copy number gain and/or the presence of a FGFR fusion gene and/or an FGFR mutation. In addition, Debio 1347 treatment led to tumor regression in 29% of models that did not harbor any FGFR genetic alteration. In contrast, all models that responded to Debio 1347 were shown to display a high expression level (mRNA) of at least one FGFR gene. These findings suggest that high expression of at least one FGFR might be a better predictor of sensitivity to Debio 1347 than genetic alteration. Furthermore, response to Debio 1347 was associated with a decrease in DUSP6 mRNA levels, suggesting that it could be a reliable pharmacodynamic biomarker in clinical trials. These results provide new mechanistic insights into the predictive sensitivity to Debio 1347 and will help refine patient selection for FGFR-targeted therapy. Citation Format: Franck Brichory, Anna Pokorska-Bocci, Paolo Nuciforo, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Anne Vaslin. The activity of the FGFR selective inhibitor Debio 1347 is correlated with high mRNA expression [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 2088. doi:10.1158/1538-7445.AM2017-2088
Abstract 3790: Circulating tumor cells at disease recurrence in patients with head and neck cancer after curative therapy
Authors: Jason Chia-Hsun Hsieh, Ting-Hsiuan Yeh, Hung-Ming Wang, Yung-Chang Lin, Nina Ming-Jung Lin, Siou-Ru Ye, Jane Ying-Chieh Lee, Min-Hsien Wu
Journal: Cancer Research (2017)

Abstract Background: Circulating tumor cell (CTC) has been prognostic and predictive in numerous types of cancer; however, its role in early diagnosis of relapse remains unclear. Methods: Eighty-six patients were prospectively enrolled between March 2015 and June 2016. Among these patients, 51 head and neck squamous cell carcinoma (HNSCC) patients had suspicious recurrent lesion(s), whilst 35 HNSCC patients were newly diagnosed. CTC test was performed by negative selection strategy and CD45-negative and EpCAM-positive cells were identified as CTCs. Biopsy on suspicious lesion(s) and CTC analysis were performed simultaneously. We analyzed the differences of CTC numbers among HNSCC patients with true recurrence, biopsy-negative and newly-diagnosed. Results: Mean±standard deviation(SD) of CTC numbers in baseline at diagnosis (n=35), true recurrence (n=40) and biopsy-negative (n=11) groups were 41.98±32.02, 81.75±64.91 and 16.55±6.82 cells/mL, respectively. The difference of CTC numbers among three groups was significant (P &amp;lt;0.001). CTCs (mean±SD) among different failure types were 110.89±84.69, 105.67±50.77, 73.31±37.82 and 59.11±54.09 in lung metastasis, second primary tumor, extrapulmonary metastasis and locoregional recurrence respectively and significantly different (P = 0.049). Also, CTC numbers between first cancer (baseline at diagnosis) and second primary tumor were different (P = 0.004). Conclusion: CTCs numbers are significantly higher in true recurrence than the biopsy-negative group when a patient had a lesion suspected to be a recurrence. CTC test may be useful to help distinguish true recurrence in HNSCC patients after curative therapy. Citation Format: Jason Chia-Hsun Hsieh, Ting-Hsiuan Yeh, Hung-Ming Wang, Yung-Chang Lin, Nina Ming-Jung Lin, Siou-Ru Ye, Jane Ying-Chieh Lee, Min-Hsien Wu. Circulating tumor cells at disease recurrence in patients with head and neck cancer after curative 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 3790. doi:10.1158/1538-7445.AM2017-3790
Mechanoresponsive stem cells to target cancer metastases through biophysical cues
Authors: Linan Liu, Shirley X. Zhang, Wenbin Liao, Henry P. Farhoodi, Chi W. Wong, Claire C. Chen, Aude I. Ségaliny, Jenu V. Chacko, Lily P. Nguyen, Mengrou Lu, George Polovin, Egest J. Pone, Timothy L. Downing, Devon A. Lawson, Michelle A. Digman, Weian Zhao
Journal: Science Translational Medicine (2017)

Despite decades of effort, little progress has been made to improve the treatment of cancer metastases. To leverage the central role of the mechanoenvironment in cancer metastasis, we present a mechanoresponsive cell system (MRCS) to selectively identify and treat cancer metastases by targeting the specific biophysical cues in the tumor niche in vivo. Our MRCS uses mechanosensitive promoter-driven mesenchymal stem cell (MSC)-based vectors, which selectively home to and target cancer metastases in response to specific mechanical cues to deliver therapeutics to effectively kill cancer cells, as demonstrated in a metastatic breast cancer mouse model. Our data suggest a strong correlation between collagen cross-linking and increased tissue stiffness at the metastatic sites, where our MRCS is specifically activated by the specific cancer-associated mechano-cues. MRCS has markedly reduced deleterious effects compared to MSCs constitutively expressing therapeutics. MRCS indicates that biophysical cues, specifically matrix stiffness, are appealing targets for cancer treatment due to their long persistence in the body (measured in years), making them refractory to the development of resistance to treatment. Our MRCS can serve as a platform for future diagnostics and therapies targeting aberrant tissue stiffness in conditions such as cancer and fibrotic diseases, and it should help to elucidate mechanobiology and reveal what cells "feel" in the microenvironment in vivo.
Abstract 3140: MUC1 expression as a prognosis marker and a new therapeutic target in patient with duodenal adenocarcinoma
Authors: Satomi Shiba, Atsushi Miki, Hideyuki Ohzawa, Takumi Teratani, Yasunaru Sakuma, Joji Kitayama, Alan Kawarai Lefor, Naohiro Sata
Journal: Cancer Research (2017)

Abstract Background: Mucin1 (MUC1) is a glycoprotein as a member of the mucin family. The expression has been associated with poor prognosis in patients with several types of cancer. Duodenal cancer is rare, therefore details are not known including carcinogenesis and clinical treatment. We verify the association of MUC1 expression and prognosis in patient with duodenal adenocarcinoma. We also assess the function of MUC1 in vitro. Materials and Methods: Between 1989 and 2014, eighteen patients of duodenal adenocarcinoma with surgery at Jichi Medical University Hospital were included in this study. MUC1 expression was evaluated immunohistochemically with anti-MUC1 antibody to examine the association of MUC1 expression and prognosis clinicopathologically. A human-derived duodenal cancer cell line, HuTu-80, is used for the experiments of invasiveness and proliferation in vitro. The invasive capacity was evaluated by transfection of siRNA into HuTu80 with matrigel invasion assay. Viability assay with the anti-MUC1 peptide GO201 was assessed to determine whether MUC1 associate with cell growth of duodenal adenocarcinoma. Results: Seven cases were MUC1 positive and 11 were MUC1 negative immunohistochemically. TMN staging was not associated with MUC1 expression. Kaplan-Meir analysis showed a poor prognosis with MUC1 positive patients in cumulative overall survivals (MUC1 positive : MUC1 negative, 18M : 52M; HR:20.6, 95%CI 3.247-130.7,p=0.002). Lymph node metastasis of MUC1 positive patients (71.4%) was significantly higher than MUC1 negative patients (9%) (p = 0.01). In vitro experiment, the expression of MUC1 was confirmed by RT-PCR and flowcytometry. Knockdown experiment with transduction of siRNAs to HuTu80 decreased the expression of the MUC1 gene. Transduction of siRNAs significantly reduced invasive capacity (47.02±21.65%, 95%CI 3.046-102.9, p= 0.04). Growth of HuTu80 cells was inhibited by GO201 (5 μM : 95%CI 0.109-0.3565, 10μM :95%CI 0.024-0.389 p&amp;lt;0.0001). Conclusions: MUC1 expression is a predictive marker for poor prognosis in patients with duodenal adenocarcinoma. Functional Interference of MUC1 core protein reduces cell growth and invasiveness. Taken together, MUC1 is associated with malignant potential and a novel target for the treatment. Citation Format: Satomi Shiba, Atsushi Miki, Hideyuki Ohzawa, Takumi Teratani, Yasunaru Sakuma, Joji Kitayama, Alan Kawarai Lefor, Naohiro Sata. MUC1 expression as a prognosis marker and a new therapeutic target in patient with duodenal adenocarcinoma [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 3140. doi:10.1158/1538-7445.AM2017-3140