tbuckley/cabot-search huggingface dataset:
Abstract 1720: Circulating tumor cell (CTC) enrichment and DNA mutation detection by sequencing
Authors: Ruqin Kou, Eric Zhao, Conrad Leung, Priya Gogoi, Will Chow, Yixin Wang
Journal: Cancer Research (2017)

Abstract Molecular analysis of circulating tumor cells (CTCs) is hindered by low sensitivity and high level of background leukocytes of currently available CTC enrichment technologies. The Celsee PREP100 device captures CTCs with high sensitivity and allows the captured CTCs to be retrieved for molecular analysis. To evaluate the potential of utilizing PREP100 in CTC molecular analysis, we first prepared mock samples using cultured prostate cancer cells PC3 and LnCAP and analyzed captured cells by PCR amplicon sequencing. Using Celsee PREP100, we were able to recover the average of 79% (ranging from 40% to 100%) of 110 - 1,100 PC3 cells and 60 - 1,500 LnCAP cells and detect p.K139fs*3 deletion in PC3 cells and T877A mutation in LnCAP cells. In addition, we also spiked in the two cell lines into normal donor blood samples and analyzed the captured cells by PCR amplicon sequencing. Preliminary experiments showed that 40% of 250 spiked PC3 cells and 74% of 50 spiked LnCAP cells were captured. Further, we were able to detect p.K139fs*3 deletion in the retrieved 50 - 1,000 spiked PC3 cells. Our results illustrate that Celsee PREP100 system represents a promising technology for capturing and molecular characterization of CTCs. Citation Format: Ruqin Kou, Eric Zhao, Conrad Leung, Priya Gogoi, Will Chow, Yixin Wang. Circulating tumor cell (CTC) enrichment and DNA mutation detection by sequencing [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 1720. doi:10.1158/1538-7445.AM2017-1720
Abstract 75: Cardiomyocyte-specific Conditional Deletion of GSK-3β Leads to Global Metabolic Defects and Cardiac Dysfunction in a HFD Induced Obesity Model
Authors: Hind Lal, Firdos Ahmad, Vipin K Verma, Samvruta Tumuluru, Shan Parikh, Qinkun Zhang, Thomas L Force
Journal: Circulation Research (2016)

Obesity has reached epidemic proportions worldwide and is associated with increased risk of cardiovascular and metabolic disease, resulting in enhanced morbidity and mortality. Indeed, the primary cause of mortality in patients with diabetes is cardiovascular disease, accounting for 50-80% of deaths. Numerous studies have implicated GSK-3β in the pathogenesis of insulin resistance, metabolic syndrome and diabetes. However, these studies are primarily relies on non-isoform specific inhibitors. We and others have reported not only isoform-specific functions of GSK-3 but also their distinct roles in various tissues. At present, all available inhibitors of GSK-3 are non-isoform-specific; therefore it’s impossible to assess the isoform-specific functions by employing these agents. The primary goal of present study was to determine the role of cardiac GSK-3β in obesity-induced metabolic perturbations and cardiac dysfunction. An oral glucose tolerance test (GTT) was performed on cardiomyocyte-specific GSK-3β KO (GSK-3β KO) and controls. At baseline, GSK-3β KO and controls displays a comparable lean mass, fat mass and oral glucose tolerance. To determine the functional role of cardiac GSK-3β in obesity-induced glucose intolerance, GSK-3β KO and controls were subjected to HFD for 24 wks and an oral GTT assay was performed on fasting mice (6h). The hyperglycemic response was significantly increased in the obese GSK-3β KO mice in comparison to obese WT mice. Importantly, body weight and food consumption were comparable between groups confirming that observed glucose intolerance in GSK-3β KO were not confounded by variable body mass composition. Furthermore, HFD leads to accelerated cardiac dysfunction in GSK-3β KO hearts compared to controls as reflected by significantly reduced ejection fraction (EF) and functional shortening. In summary, these data suggest that cardiac-specific deletion of GSK-3β lead to systemic glucose intolerance and cardiac dysfunction. These findings suggest that cardiac GSK-3β is required for the maintenance of global metabolic homeostasis and cardiac function in diabetic hearts and strategies to maintain GSK-3β activity may lead to therapeutic benefits for the disease.
Abstract 1679: BET inhibitors suppress PD-L1 expression in pancreatic stellate cells
Authors: Kazumi Ebine, Brian T. DeCant, Katharine A. Collier, Thao N. Pham, Krishan Kumar, Hidayatullah G. Munshi
Journal: Cancer Research (2017)

Abstract Single agent treatment with T-cell checkpoint inhibitors has not been effective in pancreatic ductal adenocarcinoma (PDAC) patients. The PDAC stroma, which can account for as much as 80-90% of the tumor mass, can act as a physical and an immunologic barrier to T-cell-mediated therapies. Transgenic mouse models have shown that ablation of pancreatic stellate cells (PSCs), key regulators of fibrosis in vivo, can sensitize PDAC tumors to immune checkpoint therapies. Recently, inhibitors targeting bromodomains and extra-terminal (BET) proteins, a number of which are currently being evaluated in clinical trials for solid tumors, were shown to induce stellate cells to become quiescent and decrease collagen production. The BET family of proteins binds to acetylation motifs present in histones and enables recruitment of transcription factors and other chromatin regulators during RNA transcription. We have found that PSCs express significantly increased PD-L1 levels compared to pancreatic cancer cell lines. We show that BET inhibitors, and in particular specific knockdown of BRD4 protein, decrease basal and IFN-γ-mediated PD-L1 expression in primary stellate cells. We also show that, in contrast to a recent report using cancer cells, c-MYC does not mediate basal or IFN-γ-mediated PD-L1 expression in stellate cells. Instead, we show that the IFN-γ-mediated PD-L1 expression is regulated by IRF1, suggesting cross talk between BRD4 and IRF1 in the regulation of PD-L1 expression. Ongoing in vivo experiments will evaluate the role of BET inhibitors in the regulation of PD-L1 in mouse models of pancreatic cancer. Citation Format: Kazumi Ebine, Brian T. DeCant, Katharine A. Collier, Thao N. Pham, Krishan Kumar, Hidayatullah G. Munshi. BET inhibitors suppress PD-L1 expression in pancreatic stellate 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 1679. doi:10.1158/1538-7445.AM2017-1679
Abstract 1669: Multiplex immunohistochemical staining of PD-L1, PD-1, CD3, CD4, CD8, CD68, FoxP3, and Ki-67 and image analysis of tumor and invasive margin in human FFPE NSCLC tissue
Authors: Lisa M. Dauffenbach, Gela C. Sia, Jianping Zheng, Natalia Jun, Eric P. Olsen, Christopher A. Kerfoot
Journal: Cancer Research (2017)

Abstract Evaluating the density of immune cell subtypes and their relative spatial positioning in cancers has become an important tool in understanding response to immune checkpoint inhibitors. The purpose of this study was to investigate protein expression of PD-L1, PD-1, CD3, CD4, CD8, CD68, FoxP3, and Ki-67 with four multiplex immunohistochemical assays (Ki-67+CD8, CD3+CD4+Ki-67, FoxP3+PD-1+CD8, and CD68+PD-L1+CD3) using DAB, red, and green chromogens within formalin-fixed, paraffin embedded non-small cell lung (NSCLC) tissues. The Ki-67+CD8 multiplex was developed to evaluate the density of cytotoxic T cells and the percentage that are proliferating. The CD3+CD4+Ki-67 multiplex characterizes the frequency of CD4+ T cells and evaluate proliferation in this subset. The FoxP3+PD-1+CD8 multiplex evaluates the regulatory T cell subset and evaluates PD-1 expression. The CD68+PD-L1+CD3 multiplex characterizes PD-L1 expression on macrophages and T cells. Cell densities were evaluated in the center of tumor and invasive margin regions, and image analysis was performed to quantitate each stain as a single agent and co-expression within each multiplex assay. Citation Format: Lisa M. Dauffenbach, Gela C. Sia, Jianping Zheng, Natalia Jun, Eric P. Olsen, Christopher A. Kerfoot. Multiplex immunohistochemical staining of PD-L1, PD-1, CD3, CD4, CD8, CD68, FoxP3, and Ki-67 and image analysis of tumor and invasive margin in human FFPE NSCLC tissue [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 1669. doi:10.1158/1538-7445.AM2017-1669
Abstract 1366: Structural basis of impaired GTP hydrolysis in oncogenic mutants of KRAS
Authors: Timothy Tran, Sathiya Dharmaiah, Oleg Chertov, Timothy Waybright, William Gillette, Dominic Esposito, Dwight Nissley, Frank McCormick, Andrew Stephen, Dhirendra Simanshu
Journal: Cancer Research (2017)

Abstract RAS mutations are found in one-third of all human cancers. Among the three RAS isoforms - HRAS, KRAS and NRAS, KRAS is the most commonly mutated gene (in 86% of RAS-driven cancers) and the mutations are often detected in pancreatic, colorectal and lung cancers. RAS proteins function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. The active or inactive state of RAS proteins is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). In the GTP-bound state, RAS proteins interact with a variety of effector proteins, such as Raf, PI3K, and RalGDS, leading to activation of several signaling cascades within the cell. In 98% of the cases, oncogenic RAS mutations are found at amino acid positions G12, G13, and Q61 which impair intrinsic and GAP-mediated GTPase function resulting in accumulation of constitutively GTP-bound RAS in cells. To gain insights into the effect of oncogenic mutations on overall structure and GTP hydrolysis, we solved high-resolution crystal structures of wild type and six oncogenic mutants (G12C, G12D, G12V, G13D, Q61L and Q61R) of KRAS4b in complex with GMPPNP (a non-hydrolysable GTP analog) and magnesium. Comparison of GDP and GMPPNP bound structures of wild type (WT) KRAS4b suggests conformational changes that occur when KRAS4b transitions from inactive to active state. Comparison of mutant and wild-type KRAS structures has shown the appearance of new pockets in some cases that could be exploited for structure-based drug design. Structural superposition of mutants vs. wild type KRAS4b in complex with GMPPNP/Mg2+, and KRAS4b mutants vs. WT-HRAS bound to RASA1-GAP provides a rationale for impaired intrinsic and GAP-mediated GTP hydrolysis in the KRAS mutants. Citation Format: Timothy Tran, Sathiya Dharmaiah, Oleg Chertov, Timothy Waybright, William Gillette, Dominic Esposito, Dwight Nissley, Frank McCormick, Andrew Stephen, Dhirendra Simanshu. Structural basis of impaired GTP hydrolysis in oncogenic mutants of KRAS [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 1366. doi:10.1158/1538-7445.AM2017-1366
Abstract 3333: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor
Authors: Toni M. Brand, Mari Iida, Kelsey L. Corrigan, Cara M. Braverman, John P. Coan, Bailey G. Flanigan, Andrew P. Stein, Ravi Salgia, Jana Rolff, Randall J. Kimple, Deric L. Wheeler
Journal: Cancer Research (2017)

Abstract The epidermal growth factor receptor (EGFR) is an important therapeutic target in patients with various cancers. Unfortunately, resistance to anti-EGFR therapeutics is common. Previous studies in our laboratory identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab: First, the nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab; and second, the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. On the basis of these findings, we hypothesized that AXL could mediate the nuclear translocation of EGFR in the setting of cetuximab resistance. We found that NSCLC cetuximab-resistant clones and patient-derived xenografts (PDXs) had increased abundance of nuclear EGFR (nEGFR) and AXL. Cellular fractionation techniques, super resolution microscopy, and electron microcopy revealed that genetic loss of AXL diminished the nuclear translocation and accumulation of EGFR. Building on previous studies indicating that SRC family kinases (SFKs) and HER family ligands mediate the nuclear translocation of EGFR, we found that AXL knockdown down-regulated the expression of the SFKs YES and LYN, and the ligand neuregulin-1 (NRG1). Furthermore, AXL knockdown decreased the interaction between EGFR and HER3 and the nuclear abundance of HER3. Nuclear localization of EGFR could be rescued only upon simultaneous overexpression of Lyn and NRG1 in cells depleted of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK activation and NRG1 expression are necessary and sufficient to regulate this process. Citation Format: Toni M. Brand, Mari Iida, Kelsey L. Corrigan, Cara M. Braverman, John P. Coan, Bailey G. Flanigan, Andrew P. Stein, Ravi Salgia, Jana Rolff, Randall J. Kimple, Deric L. Wheeler. The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor [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 3333. doi:10.1158/1538-7445.AM2017-3333
Abstract 2066: Delivery of 2`F-PS2 PTGER3 siRNA-DOPC enhances anti-tumoral activity in cisplatin resistant ovarian cancer model
Authors: Emine Bayraktar, Cristian Rodriguez-Aguayo, Zahid Siddik, Gabriel Lopez-Berestein
Journal: Cancer Research (2017)

Abstract RNAi-based therapeutics approaches holds a big promise for clinical translation. However, siRNAs are very weak and highly susceptible to degradation by nucleases. Nanoparticle delivery systems and chemical modifications of small interfering RNA (siRNA) can enhance efficient intracellular delivery and resistance to degradation for various siRNAs resulting in an increase in their clinical therapeutic potential. Here, we hypothesized that DOPC nanoparticles incorporated with a chemically fluoro phosphorodithioate (2`F-PS2) modified-PTGER3 siRNA will enhance the stability, prolong the silencing effect in vitro and increase the anti-tumoral effect when is combined with cisplatin in vivo. We screened 51 different chemically modified PTGER3-siRNAs which have 2'-F-PS2 or 2'-O-methyl modification on selectively protected nuclease-sensitive sites. We determined PTGER3 gene expression after siRNA-2'-F-PS2 or 2'-O-methyl modified mediated silencing, stability, time-response silencing effect and the therapeutic effect in xenograft OC in vivo model. We demonstrated that siRNA-2'-F-PS2 prolong the stability for more than 24 hours and enhance the silencing for more than 96 hours. Moreover, we found that PTGER3-silencing effect can control the expression of CFTR multidrug resistant pump by regulating ERK-ELK1-ETS1-CFTR axis, resulting in an increase of the cisplatin uptake, decreased the tumor-associated angiogenesis and tumor growth in xenograft OC in vivo model. SiRNA-PTGER3-2'-F-PS2 modification increase the stability and time-response silencing effect, leading to a synergistic anti-tumor in combination with cisplatin in ovarian cancer models. Citation Format: Emine Bayraktar, Cristian Rodriguez-Aguayo, Zahid Siddik, Gabriel Lopez-Berestein. Delivery of 2`F-PS2 PTGER3 siRNA-DOPC enhances anti-tumoral activity in cisplatin resistant ovarian cancer model [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 2066. doi:10.1158/1538-7445.AM2017-2066
Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect
Authors: Fabio Sonvico, Chiara Conti, Gaia Colombo, Francesca Buttini, Paolo Colombo, Ruggero Bettini, Marco Barchielli, Barbara Leoni, Luca Loprete, Alessandra Rossi
Journal: Journal of Controlled Release (2017)
Abstract 959: Targeting neuronal activity regulated neuroligin-3 dependency for high-grade glioma therapy
Authors: Humsa S. Venkatesh, Lydia T. Tam, Pamelyn J. Woo, Michelle Monje
Journal: Cancer Research (2017)

Abstract Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. Here, we demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) fail to grow in Nlgn3 knock out mice. Using genetic mouse models, we illustrate that Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of an ADAM10 inhibitor robustly blocks pGBM and DIPG xenograft growth via modulation of the tumor microenvironment. This work defines the therapeutic potential of and an effective strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG. Note: This abstract was not presented at the meeting. Citation Format: Humsa S. Venkatesh, Lydia T. Tam, Pamelyn J. Woo, Michelle Monje. Targeting neuronal activity regulated neuroligin-3 dependency for high-grade glioma 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 959. doi:10.1158/1538-7445.AM2017-959
Abstract 362: Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma
Authors: Yojiro Makino, Jeong-Hwan Yoon, Eunjin Bae, Mitsuyasu Kato, Keiji Miyazawa, Tatsuo Ohira, Norihiko Ikeda, Masahiko Kuroda, Mizuko Mamura
Journal: Cancer Research (2017)

Abstract Cancer-associated inflammation develops resistance to the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) harboring oncogenic EGFR mutations. Stat3-mediated Interleukin (IL)-6 signaling and Smad-mediated transforming growth factor-β (TGF-β) signaling play crucial regulatory roles in cancer-associated inflammation. Here we show that Stat3 represses Smad3 in cooperation with c-Ski and SnoN, whereby renders gefitinib-sensitive HCC827 cells resistant. IL-6 signaling via phosphorylated Stat3 induced gefitinib resistance. By contrast, TGF-β upregulated gefitinib sensitivity. We found that IL-6 signaling via phosphorylated Stat3 repressed, whereas TGF-β upregulated the expression of Smad3 in HCC827 cells. Promoter analyses showed that Stat3 synergized with c-Ski/SnoN to repress Smad-induced transcription of the Smad3 gene. Smad3 induced apoptosis by upregulating pro-apoptotic genes such as Caspase 3 and downregulating anti-apoptotic genes such as Bcl2. Our results suggest that preventing IL-6/Stat3-induced loss of Smad3 can be a therapeutic strategy to prevent gefitinib resistance in NSCLCs with gefitinib-sensitive EGFR mutation. Citation Format: Yojiro Makino, Jeong-Hwan Yoon, Eunjin Bae, Mitsuyasu Kato, Keiji Miyazawa, Tatsuo Ohira, Norihiko Ikeda, Masahiko Kuroda, Mizuko Mamura. Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung 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 362. doi:10.1158/1538-7445.AM2017-362
Abstract 3314: Synergistic effects of chemotherapy-induced autophagy and epigenetic remodeling
Authors: Liliya Tyutyunyk, Joseph Landry, Tareq Saleh, David Gewirtz
Journal: Cancer Research (2017)

Abstract Cytotoxic chemotherapy has been shown to enhance tumor cell immunogenicity by promoting the secretion of damage-associated molecular pattern (DAMP) molecules which, in turn, stimulates the immune response. These effects can be further stimulated by combining chemotherapy with an immunotherapy designed to enhance effector cell (CD8 T cell or NK cell) anti-tumor activity. Our studies demonstrate that knockdown of the epigenetic regulator NURF increases DNA damage (gamma H2AX staining) and autophagy (acridine orange staining) in breast tumor cells exposed to doxorubicin and enhances growth inhibition as well as suppressing the capacity of the cells to recover and proliferate. Similar increases in autophagy were observed using a small molecule inhibitor of NURF, suggesting that NURF can be targeted therapeutically. Sensitization was not observed with ionizing radiation or cisplatin. Studies are in progress to assess the nature of autophagy in the NURF KD and NURF WT cells, distinguishing between the cytoprotective, cytotoxic, cytostatic and nonprotective forms. How NURF regulates doxorubicin induced DNA damage is being investigated by mapping sites of damage genome wide. It is anticipated that enhanced cell autonomous tumor cell sensitivity in concert with improvements in tumor cell antigenicity (cell non-autonomous sensitization) achieved by NURF depletion could improve anti-tumor immunogenicity, achieve tumor regression, reduce metastasis, and possibly achieve long term remission in breast cancer. Citation Format: Liliya Tyutyunyk, Joseph Landry, Tareq Saleh, David Gewirtz. Synergistic effects of chemotherapy-induced autophagy and epigenetic remodeling [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 3314. doi:10.1158/1538-7445.AM2017-3314