tbuckley/cabot-search huggingface dataset:
Abstract 4772: Stearoyl-CoA Desaturase (SCD1) regulates liver tumor initiating cells through modulating ER stress
Authors: Kin Fai Ma, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Kin Wah Lee
Journal: Cancer Research (2017)

Abstract Sorafenib is the FDA approved drug for patients with advanced hepatocellular carcinoma (HCC), but the survival benefit is only modest, partly due to drug resistance. Increasing evidence shows that tumor-initiating cells (T-ICs) are intrinsically resistant to conventional treatments, and targeting signaling pathways in T-ICs provides potential therapeutic targets for HCC. In our established enriched T-IC population, we identified the activation of a lipogenesis pathway in which expression of stearoyl-CoA desaturase-1 (SCD1), an enzyme involved in the conversion of saturated into monounsaturated fatty acids, was most significant. SCD1 overexpression is frequently found in HCC samples and is significantly associated with poorer patient survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of T-ICs, including tumorigenicity, self-renewal, differentiation, drug resistance and the expression of liver T-IC markers. Interestingly, SCD1 was markedly upregulated in our established sorafenib-resistant cell lines as well as patient-derived xenografts (PDTXs), and its overexpression predicts the clinical response of HCC patients to sorafenib treatment. Consistently, pharmacological inhibition of SCD1 suppressed T-IC phenotypes and enhanced sensitivity to sorafenib treatment. Using a patient-derived xenograft model, we found that a novel SCD1 inhibitor (SSI-4) in combination with sorafenib demonstrated a maximal tumor suppressive effect. Induction of endoplasmic reticulum (ER) stress-mediated T-IC differentiation can account for the enhanced sensitivity towards sorafenib treatment upon SCD1 suppression. In conclusion, SCD1-induced ER stress may specifically increase the sensitivity of liver T-ICs to the effects of sorafenib treatment. Targeting SCD1 in combination with sorafenib therapy may be a novel therapeutic regimen against HCC. Citation Format: Kin Fai Ma, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Kin Wah Lee. Stearoyl-CoA Desaturase (SCD1) regulates liver tumor initiating cells through modulating ER stress [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 4772. doi:10.1158/1538-7445.AM2017-4772
Front-Line Concurrent Chemoradiotherapy (CCRT) Followed Consolidation Chemotherapy in Localized NASAL NK/T-Cell Lymphoma
Authors: H.-J. Tsai, S.-F. Lin, C.-C. Chen, T.-Y. Chen, W.-C. Su, W.-L. Hwang, J.-C. Lin, T.-J. Chiou, W.-Y. Kao, C.-F. Chiu, Y.-F. Chang, S.-M. Chang, I.-J. Su, M.-C. Chang
Journal: Annals of Oncology (2012)
Abstract 5420: PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer cells
Authors: Yan Feng, Weiguo Lv, Xing Xie, Yan Yu
Journal: Cancer Research (2017)

Abstract Aerobic glycolysis is a dominant pathway for energy production in cancer cells, but the association of this phenomenon with chemoresistance remains still uncertain. Here, we found that the expression of phosphoglycerate mutase 1 (PGAM1), a key catalytic enzyme in aerobic glycolysis, was significantly higher in paclitaxel-resistant ovarian cancer cell line SKOV3. Up-regulated PGAM1 expression by gene transfection and down-regulated PGAM1 expression by siRNA knockdown altered the process of aerobic glycolysis, paclitaxel sensitivity and DNA damage response 1 (REDD1) expression in ovarian cancer cells (SKOV3 and A2780). Further, the change of the concentration of pyruvic acid or lactic acid in culture medium and REDD1 expression by gene transfection or siRNA knockdown also altered the sensitivity to paclitaxel. REDD1 knockdown of by siRNA reversed partially paclitaxel resistance induced by PGAM1 over-expression in cancer cells, vice versa. Structural interaction between PGAM1 and REDD1 was predicted by molecular docking. Our results suggested that PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer cells. Citation Format: Yan Feng, Weiguo Lv, Xing Xie, Yan Yu. PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer 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 5420. doi:10.1158/1538-7445.AM2017-5420
Abstract 5013: A 3D culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer
Authors: Bhuminder Singh, Cunxi Li, Ramona Graves-Deal, Haiting Ma, Alina Starchenko, William H. Fry, Yuanyuan Lu, Yang Wang, Galina Bogatcheva, Mohseen P. Khan, Ginger L. Milne, Shilin Zhao, Gregory D. Ayers, Nenggan Li, Mary K. Washington, Timothy J. Yeatman, Oliver G. McDonald, Qi Liu, Robert J. Coffey
Journal: Cancer Research (2017)

Abstract We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated within type-I collagen in 3D. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent malignant properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained the parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), cetuximab strongly inhibited growth of CC, whereas SC was resistant to growth inhibition and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, to cetuximab in SC restored cetuximab sensitivity. To characterize genome-wide divergence between CC and SC, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most upregulated genes in CC was the tumor suppressor 15-PGDH/HPGD and the most upregulated gene in SC was versican (VCAN) in 3D and xenografts. Analysis of a human CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a new mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic sensitivities and disease-relevant genes for CRC. Citation Format: Bhuminder Singh, Cunxi Li, Ramona Graves-Deal, Haiting Ma, Alina Starchenko, William H. Fry, Yuanyuan Lu, Yang Wang, Galina Bogatcheva, Mohseen P. Khan, Ginger L. Milne, Shilin Zhao, Gregory D. Ayers, Nenggan Li, Mary K. Washington, Timothy J. Yeatman, Oliver G. McDonald, Qi Liu, Robert J. Coffey. A 3D culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal 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 5013. doi:10.1158/1538-7445.AM2017-5013
Abstract 291: Sequential treatment with the Wee1 inhibitor, AZD1775, enhances the effect of trabectedin in the L-sarcomas
Authors: Elgilda Musi, Grazia Ambrosini, Gary K. Schwartz
Journal: Cancer Research (2017)

Abstract Soft tissue sarcomas are heterogeneous mesenchymal neoplasms and account for 1% of all cancers in adults. Over 50 sarcomas subtypes have been classified and many have very limited treatment options. Chemotherapies such as doxorubicin, dacarbazine and gemcitabine have had very low response rates. Two of the most common subtypes of sarcomas are liposarcoma and leiomyosarcoma, also referred to as the L-sarcomas. Trabectedin, a marine derived compound from the sea sponge, Ecteinascidia turbinate, has recently been approved for the treatment of L-sarcomas which has shown a modest effect over common therapies. As a DNA damaging agent, we hypothesized that trabectedin would induce a G2 cell cycle arrest and subsequent inhibition of Wee1 would abrogate this cell cycle checkpoint and induce apoptosis. We therefore examined the effects of trabectedin followed by AZD1775, a Wee1 inhibitor, in a panel of 6 sarcoma cell lines including liposarcoma (LS141, DDLS) and leiomyosarcoma (SK-LMS, SK-UT1, SK-UT1b). IC50s concentrations of trabectedin were determined to be between 0.5 to 2nM, while IC50s for AZD1775 were in the range of 100-200 nM. In vitro results have shown an enhanced inhibition of cell viability with combination treatment in all cell lines at concentrations of 1nM trabectedin for 24hrs followed by 100nM AZD1775 for 48hrs. We also examined biochemical effects with sequential drug treatment (24hrs trabectedin followed by 24hrs AZD1775) which presented an increase of cyclin A1 and cyclin B1 indicative of G2 cell cycle arrest along with increase of phospho-H2AX, indicative of DNA damage by trabectedin, while subsequent treatment with the Wee1 inhibitor showed decrease of phosphorylation of CDC2 (Tyr15). Flow cytometric analysis indicated G2/M cell cycle arrest with trabectedin and abrogation of G2/M with AZD1775. These observations correlated with enhanced apoptosis as measured by biochemical PARP cleavage and DNA content (sub-G1 population). Taken together these results provide a foundation for the development of the sequential treatment of trabectedin followed by the Wee1 inhibitor, AZD775, in the L-sarcomas. Citation Format: Elgilda Musi, Grazia Ambrosini, Gary K. Schwartz. Sequential treatment with the Wee1 inhibitor, AZD1775, enhances the effect of trabectedin in the L-sarcomas [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 291. doi:10.1158/1538-7445.AM2017-291
Abstract LB-265: 5’ gap-mediated long patch base excision repair
Authors: Jordan Woodrick, Sharon Camacho, Swetha Parvathaneni, Sudha Sharma, Rabindra Roy
Journal: Cancer Research (2017)

Abstract The base excision repair (BER) pathway is one of the most frequently used DNA repair mechanisms in the cell and modulates many human pathophysiological conditions related to DNA damage. Through live cell and in vitro reconstitution experiments, we have discovered a novel step in a sub-pathway of the conventional long-patch BER that involves formation of a 9 nt gap 5’ to the lesion, which is mediated by RECQ1 DNA helicase and ERCC1-XPF endonuclease in cooperation with PARP1 and RPA. The novel step is employed during repair of a variety of DNA lesions, including oxidative and alkylation damage. Moreover, RECQ1 regulates the autoribosylation status of PARP1 and the choice between long-patch and single-nucleotide BER, which regulates cellular toxicity to DNA damage. Taken together, our results propose a revised model of the long-patch BER pathway and characterize a crucial regulation point for pathway choice in BER. Citation Format: Jordan Woodrick, Sharon Camacho, Swetha Parvathaneni, Sudha Sharma, Rabindra Roy. 5’ gap-mediated long patch base excision repair [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 LB-265. doi:10.1158/1538-7445.AM2017-LB-265
Abstract 203: Cardiomyocyte T-tubule Membrane Turns Over, Releasing BIN1 Containing Microparticles into Blood
Authors: Bing Xu, Ying Fu, TingTing Hong
Journal: Circulation Research (2015)

Bridging integrator 1 (BIN1) is a cardiac muscle protein that folds cardiomyocyte T-tubule membrane. BIN1 is intrinsic to cardiac health, and is reduced in acquired heart failure. Interestingly, we have found that BIN1 is also blood available, and that plasma BIN1 correlates with cardiac function, suggesting cardiac origin of plasma BIN1. We found that low plasma BIN1 correlates with failing muscle and predicts ventricular arrhythmia. However, the paradigm does not exist for an intracellular membrane associate cardiomyocyte protein to be homeostatically turned over into blood. In this study, using a mouse model with cardiac specific deletion of Bin1 gene, we identified with biochemical techniques that plasma BIN1 levels directly correlate with cardiac tissue BIN1 levels, indicating cardiac origin. Furthermore, investigations using both super-resolution fluorescent imaging and flow cytometry analysis revealed that adult ventricular cardiomyocytes constantly release BIN1 into blood via membrane microparticle production. Microparticles are small membrane vesicles shed from plasma membrane of a variety of cell types including platelets, leukocytes, and endothelial cells. Using super-resolution three-dimensional stochastic optical reconstruction microscopy (3D-STORM), we found similar to the blood cells, isolated adult mouse cardiomyocytes release Annexin V positive microparticles with diameters ranging between 0.1 to 1.0 μm. These microparticles also carry BIN1 protein. Flow cytometry was also used to detect and quantify microparticles &lt;1.0 μm in size from medium bathing a pure population of adult mouse cardiomyocytes. BIN1 microparticle release is proportional to actin stability and amount of T-tubule membrane folds. Compared to wild type cardiomyocytes, microparticle release is significantly reduced from myocytes with heterozygous deletion of Bin1 gene. These data indicate that cardiomyocyte membrane undergoes dynamic turnover, releasing T-tubule folds into blood as microparticles. Furthermore, plasma BIN1 can be used as a direct measure of cardiomyocyte health and reserve.
Phase I Dose-Escalation Study of the Anti-CD70 Antibody ARGX-110 in Advanced Malignancies
Authors: Philippe Aftimos, Christian Rolfo, Sylvie Rottey, Fritz Offner, Dominique Bron, Marie Maerevoet, Jean-Charles Soria, Mahan Moshir, Torsten Dreier, Luc Van Rompaey, Jean-Marie Michot, Karen Silence, Anna Hultberg, Domenica Gandini, Hans de Haard, Vincent Ribrag, Marc Peeters, Alain Thibault, Nicolas Leupin, Ahmad Awada
Journal: Clinical Cancer Research (2017)

Purpose: The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies.Experimental Design: Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N = 26). ARGX-110 was administered intravenously every 3 weeks until progression or intolerable toxicity. Dose-limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.Results: Dose-limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRR). Of the 20 SAEs reported, five events, all IRRs, were considered related to ARGX-110. ARGX-110 demonstrates dose proportionality over the dose range 1 to 10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10 to 13 days. The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related antitumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematologic malignancies.Conclusions: This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics, and preliminary antitumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies. Clin Cancer Res; 23(21); 6411-20. ©2017 AACR.
Response to Radiotherapy After Breast-Conserving Surgery in Different Breast Cancer Subtypes in the Swedish Breast Cancer Group 91 Radiotherapy Randomized Clinical Trial
Authors: Martin Sjöström, Dan Lundstedt, Linda Hartman, Erik Holmberg, Fredrika Killander, Anikó Kovács, Per Malmström, Emma Niméus, Elisabeth Werner Rönnerman, Mårten Fernö, Per Karlsson
Journal: Journal of Clinical Oncology (2017)

Purpose To evaluate the effect of adjuvant radiotherapy (RT) after breast conservation surgery in different breast cancer subtypes in a large, randomized clinical trial with long-term follow-up. Patients and Methods Tumor tissue was collected from 1,003 patients with node-negative, stage I and II breast cancer who were randomly assigned in the Swedish Breast Cancer Group 91 Radiotherapy trial between 1991 and 1997 to breast conservation surgery with or without RT. Systemic adjuvant treatment was sparsely used (8%). Subtyping was performed with immunohistochemistry and in situ hybridization on tissue microarrays for 958 tumors. Results RT reduced the cumulative incidence of ipsilateral breast tumor recurrence (IBTR) as a first event within 10 years for luminal A–like tumors (19% v 9%; P = .001), luminal B–like tumors (24% v 8%; P &lt; .001), and triple-negative tumors (21% v 6%; P = .08), but not for human epidermal growth factor receptor 2–positive (luminal and nonluminal) tumors (15% v 19%; P = .6); however, evidence of an overall difference in RT effect between subtypes was weak ( P = .21). RT reduced the rate of death from breast cancer (BCD) for triple-negative tumors (hazard ratio, 0.35; P = .06), but not for other subtypes. Death from any cause was not improved by RT in any subtype. A hypothesized clinical low-risk group did not have a low risk of IBTR without RT, and RT reduced the rate of IBTR as a first event after 10 years (20% v 6%; P = .008), but had no effect on BCD or death from any cause. Conclusion Subtype was not predictive of response to RT, although, in our study, human epidermal growth factor receptor 2–positive tumors seemed to be most radioresistant, whereas triple-negative tumors had the largest effect on BCD. The effect of RT in the presumed low-risk luminal A–like tumors was excellent.
Abstract 1353: Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding, and block invasion of NSCLC
Authors: Elizabeth Ntantie, Jerrine Fletcher, Felix Amissah, Olufisayo O. Salako, Augustine T. Nkembo, Rosemary A. Poku, Nazarius S. Lamango
Journal: Cancer Research (2017)

Abstract Non-small Cell Lung Cancer (NSCLC) malignancy is dependent on cellular processes that promote metastasis. F-actin organization is central to cell migration, invasion, adhesion and angiogenesis which are all processes involved in metastasis. F-actin remodeling is enhanced by the overexpression and/or hyper-activation of some members of the Rho family of small GTPases. Therefore agents that mitigate hyperactive Rho proteins may be clinically relevant for controlling metastasis. We previously reported the synthesis and characterization of polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential inhibitors of the cancer phenotype. In this report, we investigate the potential role of PCAIs against NSCLC malignancy and show that as low as 0.5 µM PCAIs significantly inhibit 2D and 3D NCI-H1299 cell migration by 48% and 45%, respectively. PCAIs at 1 µM inhibited 2D and 3D NCI-H1299 cell invasion through Matrigel by 50% and 85%, respectively. Additionally, exposure to 5 µM of the PCAIs, NSL-BA-040 caused a 38% drop in F-actin intensity at the cell membrane 24 h post treatment. Importantly, this drop in F-actin was accompanied by a 73% reduction in the number of filopodia per cell. Interestingly, the polyisoprenyl group of the PCAIs is essential for these effects, as NSL-100, an analog that lacks the farnesyl moiety, does not elicit similar effects on F-actin assembly and organization. Put together, our findings indicate that PCAIs disrupt F-actin assembly and organization to suppress cell motility and invasion and point towards a potential role of PCAIs as effective therapies for NSCLC metastasis and invasion. Citation Format: Elizabeth Ntantie, Jerrine Fletcher, Felix Amissah, Olufisayo O. Salako, Augustine T. Nkembo, Rosemary A. Poku, Nazarius S. Lamango. Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding, and block invasion of NSCLC [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 1353. doi:10.1158/1538-7445.AM2017-1353
Abstract 4929: Cooperation between the microbiota and oncogenic mutations leading to the development of colon cancer
Authors: Dana Van De Hey, Susan Payne, Cheri Pasch, Linda Clipson, Kristina Matkowskyj, Dustin Deming
Journal: Cancer Research (2017)

Abstract Background: The microbiome of the colon has been shown to play a role in colon cancer tumorigenesis. Inflammation is a key step in the formation of tumors, and it is possible that microbiota induce this inflammation, further stimulating tumor growth. The interaction between mutant cells in the colon and the microbiota has been understudied. We hypothesized that eradication of the intestinal microbiota could prevent tumorigenesis in the colon despite the presence of oncogeneic mutations. Methods: We have previously generated a transgenic murine model in which a constitutively active PI3K is expressed in the distal small intestine and colon (FC3K). These mice develop aggressive cancers in the proximal colon via a non-canonical mechanism without loss of APC. In addition, we developed a murine model possessing both PIK3CA mutations and loss of APC (FCAK3K). These mice were treated with vancomycin in their drinking water. Necropsy was performed at specific time-points or at moribund to determine tumor counts and size. Spheroid cultures were also utilized to determine the potential for cytotoxic effects of vancomycin treatment. Results: Treatment with vancomycin in FC3K mice at weaning resulted in a reduction in tumor incidence and growth and prolonged survival, indicated by a 42% tumor frequency and median lifespan of 101 days, compared to 100% frequency and 86.5-day lifespan of control mice (p&amp;lt;0.001). In the tumors that formed there was no difference in the epithelial mesenchymal transition (EMT), Ki67 index, nuclear localization of CTNNB1, or activation of the PI3K/AKT/mTOR signaling pathway. FCAK3K spheroid and mouse models portrayed ineffectiveness of vancomycin through an absent change in spheroid diameter and also 100% frequency of both treated and control mice. Conclusion: The above results indicate that colon cancers induced by PIK3CA mutations are at least partially dependent on the microbiota for tumorigenesis. This dependence appears to be overcome in the setting of both APC and PIK3CA mutations. Citation Format: Dana Van De Hey, Susan Payne, Cheri Pasch, Linda Clipson, Kristina Matkowskyj, Dustin Deming. Cooperation between the microbiota and oncogenic mutations leading to the development of colon 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 4929. doi:10.1158/1538-7445.AM2017-4929