bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1029: Rab1A and Rab1B promote esophageal squamous cell carcinoma through activating mTORC1 signaling and inhibiting autophagy
Authors: Yang Xian-Zi , Wang Ren , Li Xiao-Xing , Yang Yang , Wang Hui-Yun , Zheng. X. F. Steven 
Published: July 2016

Abstract
Background: Rab1A has recently been shown to act as an oncogene and promote colorectal and liver tumorigenesis. In this study, we aim to understand the potential role of Rab1A and its homolog Rab1B in esophageal squamous cell carcinoma (ESCC) and the underlying molecular mechanisms.
Methods: The expressions of Rab1A and Rab1B in139 paired human ESCC tissues and adjacent normal tissues were evaluated by immunohistochemistry. A series of in vitro and in vivo assays were performed to elucidate the biological functions of Rab1A and Rab1B, and their role in the regulation of mTOR signaling, autophagy and ESCC tumorigenesis.
Results: The level of Rab1A and Rab1B is elevated in ESCC tissues, which is positively correlated with tumor TNM stages and N stages. The overall expression of Rab1A and Rab1B is an independent predictor of patient survival (P&lt;0.01). Down-regulation of Rab1A and Rab1B individually and in combination in ESCC cells inhibits cell proliferation and migration, and enhances autophagy. Mechanistically, Rab1A and Rab1B activate mTORC1 to enhance growth and suppress autophagy.
Conclusion: Our results suggest that Rab1A and Rab1B cooperatively regulate ESCC proliferation and autophagy by activating mTORC1 signaling. They may serve as promising prognostic biomarkers and/or potential molecular targets of ESCC treatments.
Citation Format: Xian-Zi Yang, Ren Wang, Xiao-Xing Li, Yang Yang, Hui-Yun Wang, X. F. Steven Zheng. Rab1A and Rab1B promote esophageal squamous cell carcinoma through activating mTORC1 signaling and inhibiting autophagy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1029.
Abstract 1034: Leptin induces early onset and aggressiveness of pancreatic cancer
Authors: Harbuzariu Adriana , Rampoldi Antonio , Daley-Brown Danielle S. , Harmon Tia L. , Beech Derrick J. , Oprea-Ilies Gabriela , Gonzalez-Perez Ruben R. 
Published: July 2016

Abstract
Background: During the past 30 years, pancreatic cancer (PC) has constantly been the fourth leading cause of cancer death. PC is usually advanced at the time of diagnosis, with an overall five years survival rate of less than 5%. Obesity, characterized by high levels of leptin, is pandemic in United States and a risk factor for PC. Notch abnormal signaling is linked to carcinogenesis, tumor angiogenesis and self renewal capacity of PC stem cells (PCSC). We have previously shown that leptin induces proliferation of PC cell lines, increases Notch expression, PCSC and tumorsphere formation. To test leptin effects in a PC mouse model, a specific and potent signaling inhibitor bound to nanoparticles, IONP-LPrA2 was produced by us.
Hypothesis: High levels of leptin induce early onset and multiplicity of PC xenografts, which is abrogated by IONP-LPrA2 treatment.
Methods: Human PC cell line MiaPaCa-2 was challenged with leptin or IONP-LPrA2. The expression of pluripotency associated genes (STAT3, Oct4, Sox2 and NANOG) was evaluated. MiaPaCa-2 cells forming tumorspheres were treated with leptin or IONP-LPrA2 and inoculated into CD1 nu/nu mice. Untreated tumorspheres were inoculated as controls. A group of mice were injected twice a week with IONP-LPrA2. Tumor onset and growth were assessed. PC xenografts were analyzed for expression of Ki67 (proliferation marker), leptin targeted molecules (Notch), PCSC markers etc.
Results: Leptin induced the expression of PCSC pluripotency markers. Moreover, leptin treatment of tumorspheres induced early tumor onset and multiplicity. Also, leptin increased proliferation, PCSC and oncogenic markers in PC xenografts. IONP-LPrA2 reduced leptin effects. No changes of mice food intake and body weight were observed.
Conclusions: This observation might imply that obese patients are at high risk to develop PC. Inhibition of leptin signaling may be used as preventative or therapeutic strategy for PC, especially in obese patients.
Acknowledgements: this work was supported by DOD W81XWH-13-1-0382; NIH/SBIR 1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR 03034 and 1C06 RR18386).
Citation Format: Adriana Harbuzariu, Antonio Rampoldi, Danielle S. Daley-Brown, Tia L. Harmon, Derrick J. Beech, Gabriela Oprea-Ilies, Ruben R. Gonzalez-Perez. Leptin induces early onset and aggressiveness of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1034.
Abstract 1036: Cellular phenotypes of a novel series of 3-phosphoglycerate dehydrogenase inhibitors
Authors: Mainolfi Nello , Friedman Adam , Moyer Mikel P. , Suri Vipin , Manfredi Mark 
Published: July 2016

Abstract
PHGDH (3-phosphoglycerate dehydrogenase) is the first enzyme branching from glycolysis into the serine synthetic pathway and it oxidizes 3-phosphoglycerate into phospho-hydroxypyruvate using nicotinamide adenine dinucleotide (NAD) as cofactor.[1] Increases in PHGDH expression at both mRNA and protein levels have been observed in nearly 70% of estrogen receptor-negative breast cancers; in addition a fraction of malignant breast and melanoma cells are dependent on elevated expression of 3-phosphoglycerate dehydrogenase (PHGDH).[2] Furthermore, serine starvation has been shown to have a dramatic effect on tumor growth during in vivo mouse xenograft experiments.[3] PHGDH has been a target of interest in the pharma/biotech industry for several years since the initial reports in early 2012 of its relevance in cancer2 where PHGDH amplified and overexpressing cancer cell lines have been shown to possess unique sensitivity to PHGDH knockdown that cannot be rescued by nutritional serine. The mechanisms underlying these studies have been subject to intense investigation but remain unclear. We have been able to successfully identify first in class small molecule inhibitors of this target with nanomolar cellular potency, high degree of selectivity and oral bioavailability. In several cancer cell lines, these compounds inhibited glucose derived serine flux with nanomolar median inhibitory concentrations without significantly affecting glucose derived lactate. These compounds also inhibited glucose derived serine in animal studies and have the potential to be highly useful tools for understanding the role of PHGDH in tumor progression. The data presented here will provide unexpected insights on the role of PHGDH in serine biosynthesis and the dependency of cancer cells on PHGDH catalytic function.
References
[1] Snell, K. Enzymes of serine metabolism in normal, developing and neoplastic rat tissues. Advances in enzyme regulation. 1984; 22:325-400.
[2] Cantor, J.R.; Sabatini, D. M. Cancer Cell Metabolism: One Hallmark, Many Faces, Cancer Discovery. 2012; 2(10):881-898.
[3] Maddocks et al., Serine starvation induces stress and p53-dependent metabolic remodeling in cancer cells Nature, 2013, 493(7433):542-6
Citation Format: Nello Mainolfi, Adam Friedman, Mikel P. Moyer, Vipin Suri, Mark Manfredi. Cellular phenotypes of a novel series of 3-phosphoglycerate dehydrogenase inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1036.
Abstract 1045: Targeting NAMPT in Ewing's sarcoma cells
Authors: Mutz Cornelia N. , Schwentner Raphaela , Bouchard Eric , Mejia Edgard M. , Katschnig Anna M. , Kauer Maximilian O. , Aryee Dave N.T. , Garten Antje , Banerji Versha , Kovar Heinrich 
Published: July 2016

Abstract
Ewing Sarcoma (ES) is the second most common bone cancer in children and adolescents with a high metastatic potential. Tumor development is driven by the specific t(11;22)(q24;q12) chromosomal translocation resulting in the generation of the chimeric transcription factor EWS-FLI1.
NAD is a key metabolite of energy metabolism being involved in cellular redox reactions, DNA repair, and in the maintenance of genomic stability serving as a donor of ADP-ribose. This study describes targeting NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in salvage generation of NAD, by FK866 in ES cells. Using FK866 has been proposed as a treatment option for various inflammatory diseases as well as cancer, rendering ES cells with high NAMPT expression especially susceptible to FK866-induced cytotoxicity.
Here we report that NAMPT inhibition in ES cells leads to exhaustive NAD depletion, followed by a delayed reduction of ATP levels and concomitantly to apoptosis-mediated cell death. These effects can be reversed by nicotinic acid, a substrate for the NAD salvage generation. However, the use of a doxycycline-inducible shRNA against EWS-FLI1 revealed that the cytotoxic activity of NAMPT inhibition is significantly lowered in the absence of EWS-FLI1. EWS-FLI1-low ES cells have higher viability and lower rates of apoptosis throughout inhibitor treatment compared to cells with high EWS-FLI1 expression. Additionally, changes in mitochondrial respiration and glycolytic rate can be observed when comparing untreated versus EWS-FLI1 knockdown ES cells after NAMPT inhibition. Interestingly, loss of EWS-FLI1 leads to elevated NAD levels and results in alteration of RNA expression of some enzymes involved in the NAD synthesis pathway. These results might explain the high susceptibility of Ewing Sarcoma cells to FK866 treatment.
Taken together, our data reveal evidence of an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of ES cells and suggests NAMPT inhibition as a potential new treatment approach for Ewing Sarcoma in combination with standard therapies.
Supported by the Austrian Science fund, grant I1225-B19; and the Research Manitoba and CancerCare Manitoba Foundation.
Citation Format: Cornelia N. Mutz, Raphaela Schwentner, Eric Bouchard, Edgard M. Mejia, Anna M. Katschnig, Maximilian O. Kauer, Dave N.T. Aryee, Antje Garten, Versha Banerji, Heinrich Kovar. Targeting NAMPT in Ewing's sarcoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1045.
Abstract 1049: Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust in vivo efficacy and increased therapeutic index with niacin supplementation
Authors: Quanz Maria , Merz Claudia , Bernthaler Andreas , Kaulfuss Stefan , Richter Anja , Bauser Marcus , Haegebarth Andrea 
Published: July 2016

Abstract
Nicotinamide adenine dinucleotide (NAD+) is an important metabolite and cofactor for a number of cellular processes including genomic stability and epigenetic regulation. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate limiting enzyme in NAD+ salvaging from nicotinamide. Many tumor cells have an increased need for NAD+ and are therefore highly sensitive to NAMPT inhibition. We have developed a selective and potent small molecule inhibitor, Cmpd1, which inhibits the NAMPT enzyme with sub-nanomolar potency. In cells, Cmpd1 treatment leads to an almost complete reduction of both NAD- and ATP-levels, followed by the induction of cell death. In order to identify sensitive cancer subtypes and associated biomarkers, we analyzed cell sensitivity to NAMPT inhibition in a panel of 240 cell lines. Small cell lung cancer and hematological malignancies were particularly sensitive to NAMPT inhibition. Overall, expression levels of NAMPT and NAD+ consuming enzymes correlated well with sensitivity to NAMPT inhibition.
In order to investigate the effect of niacin on the antiproliferative effect of NAMPT inhibition across the cell panel, we further analyzed the cell sensitivity in the presence of niacin. Cells with a functional Preiss-Handler pathway can generate NAD+ from niacin, independent of NAMPT. We found that the antiproliferative effect of Cmpd1 was neutralized by niacin in 60% of the analyzed cells. The mRNA levels of nicotinate phosphoribosyltransferase 1 (NAPRT1), a central enzyme of the Preiss-Haendler pathway, predicted well the niacin rescue status of the cells. In vivo, niacin supplementation led to an at least 10-fold increase in the maximum tolerated dose of Cmpd1 in mice. Antitumor efficacy of Cmpd1 was abolished by niacin supplementation in xenografts derived from NAPRT1 expressing cells, but not in NAPRT1-deficient models. These data demonstrate that the therapeutic index of NAMPT inhibitors may be increased in NAPRT1-deficient tumors by niacin supplementation.
Citation Format: Maria Quanz, Claudia Merz, Andreas Bernthaler, Stefan Kaulfuss, Anja Richter, Marcus Bauser, Andrea Haegebarth. Pharmacological characterization of a novel potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with robust in vivo efficacy and increased therapeutic index with niacin supplementation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1049.
Abstract 1065: Reduced expression of microRNA-200 family associated with aggressiveness and poorer patient outcome of clear cell renal cell carcinomas
Authors: Gotoh Masahiro , Arai Eri , Matsuda Akio , Fujimoto Hiroyuki , Matsumoto Kenji , Kanai Yae 
Published: July 2016

Abstract
[Introduction] The aim of this study was to clarify the significance of alterations of microRNA (miRNA) expression during renal carcinogenesis.
[Materials and methods] Expression profiles of miRNA were examined using the SurePrint G3 miRNA Expression microarray in paired samples of cancerous tissue (T) and non-cancerous renal cortex tissue (N) from 95 patients with clear cell renal cell carcinomas (RCCs). The expression levels of miRNA and mRNA were quantified by reverse transcription PCR (RT-PCR) using TaqMan system. The MetaCore pathway analysis by GeneGo was performed using miRNAs of which expression levels were significantly altered during renal carcinogenesis.
[Results] The expression levels of 39 and 169 miRNAs were increased (T/N&gt; = 2) and reduced (T/N&lt;0.5) in T samples relative to the corresponding N samples, respectively. MetaCore pathway analysis revealed that such expression alterations of the 208 miRNAs were significantly accumulated in four pathways, which included “Development microRNA-dependent inhibition of epithelial-mesenchymal transition (EMT) pathway” (P = 8.695×10−15). The expression levels of any of 5 EMT-related miRNAs, i.e. miR-200a, miR-200c, miR-141, miR-429 and miR-200b, called as miR-200 family, were reduced in 93 (98%) of the examined 95 RCCs. Quantitative RT-PCR analysis verified that the expression levels of miR-200 family were significantly reduced in T samples relative to the corresponding N samples. Additionally, the mRNA expression levels of the ZEB1 and ZEB2 genes, which were downstream targets of miR-200 family, were significantly increased, and their target CDH1 gene expression was further decrease in T samples. The expression levels of miR-200 family in T samples were significantly correlated with clinicopathological parameters reflecting tumor aggressiveness, such as invasive macroscopic configuration, higher histological grade, vascular involvement, renal vein tumor thrombus, invasive growth pattern, tumor necrosis, distant metastasis and higher histological TNM stage. Moreover, the expression levels of miR-200 family were significantly correlated with both of cancer-free and overall survival rates of patients with clear cell RCCs.
[Conclusions] These data suggested that reduced expression of miR-200 family may participate in the malignant progression resulting in poorer patient outcome of clear cell RCCs, via regulation of the EMT pathway.
Citation Format: Masahiro Gotoh, Eri Arai, Akio Matsuda, Hiroyuki Fujimoto, Kenji Matsumoto, Yae Kanai. Reduced expression of microRNA-200 family associated with aggressiveness and poorer patient outcome of clear cell renal cell carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1065.
Abstract 107: Unsupervised analysis of cancer-cell intrinsic transcriptional traits defines a new classification system for colorectal cancer with improved predictive and prognostic value
Authors: Bertotti Andrea , Isella Claudio , Bellomo Sara E. , Brundu Francesco , Galimi Francesco , Ficarra Elisa , Trusolino Livio , Medico Enzo 
Published: July 2016

Abstract
Recent work built on published transcriptional subtypes of colorectal cancer (CRC) has shown that tumor stromal content heavily impacts CRC classification, with clinical and biological implications. Lineage-dependent transcriptional components of stromal origin could therefore dominate over more subtle, yet relevant, gene expression traits inherent to cancer cells. Based on the notion that in patient-derived xenografts (PDXs) stromal cells of the human tumor are substituted by their murine counterparts, we assessed cancer-cell intrinsic transcriptional features by human-specific expression profiling on 515 PDXs from 244 CRC patients. We identified five CRC intrinsic subtypes (CRIS) endowed with molecular, functional and phenotypic peculiarities, many of which were not previously evidenced: CRIS-A was a MIN-like, KRAS-mutated, and secretory subtype with sustained glycolytic metabolism and inflammatory traits; CRIS-B grouped a subset of poorly differentiated tumors with active TGFβ signaling and EMT features; CRIS-C clustered KRAS wild-type CIN tumors exhibiting elevated EGFR pathway activity and MYC copy number gains; CRIS-D tumors were characterized by a typical stem phenotype with high WNT signaling, associated with strong enrichment in IGF2 amplification/overexpression and FGFR autocrine stimulation; CRIS-E again displayed WNT-related features, but associated with a Paneth-like phenotype and a TP53-mutated genotype. CRIS subtypes successfully categorized independent sets of primary and metastatic CRC tumors, with limited overlap on existing transcriptional classes and unprecedented predictive and prognostic performances. Integration of stroma-centered transcriptional profiles with cancer-cell intrinsic classification by CRIS further enhanced prognostic significance.
Citation Format: Andrea Bertotti, Claudio Isella, Sara E. Bellomo, Francesco Brundu, Francesco Galimi, Elisa Ficarra, Livio Trusolino, Enzo Medico. Unsupervised analysis of cancer-cell intrinsic transcriptional traits defines a new classification system for colorectal cancer with improved predictive and prognostic value. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 107.
Abstract 1081: Activity of microRNA replacement reagent, MRX34, in multiple myeloma in vivo model
Authors: Jung Woo June , Koh Youngil , Kim Sinil , Park Hyejoo , Yoon Sung-Soo 
Published: July 2016

Abstract
Background: Despite recent progress in multiple myeloma (MM) treatment with the advent of new targeted anticancer agents such as Bortezomib, Lenalidomide and, Thalidomide MM still remains incurable. To improve clinical outcome of MM patients, many research have been trying to develop novel targeted drugs. Recent studies demonstrated that microRNA Replacement reagent could be a promising therapeutic strategy in patients with hematologic malignancies. Hence, we tried to examine the efficacy of MRX34, a microRNA-34 replacement reagent, in MM animal model.
Methods: We examined the anti-tumor activity of a MRX34 against 3MM cell lines (LP1, MOLP-8, and U266), and investigated the survival effects through which this novel agent shows anti-MM activity. For an animal study, we used NRG (NOD-Rag1null IL2rgnull, CB-17 SCID) mice that were injected with MM cells via tail vein. MOLP-8, LP1 and U266 cells were injected Intravenous 106 cells of NRG. When tumors were measurable, mice were assigned to 3 treatment groups receiving the vehicle alone (control), MRX34 0.3mg/kg treatment group and, MRX34 1mg/kg treatment group were given Intravenous 5 times a week.
Results: Median survival of mice injected with LP1, MOLP-8 and U266 cell lines were 28days, 29 days and 34days respectively without any treatment. When mice were treated with MRX-34, median survival was 33days, 37days and 42days respectively. There was a significant survival advantage with MRX-34 treatment in MOLP-8 and U266 cell lines. For monoclonal proteins, mice treated with MRX34 group are suppressed M-protein level almost 30% less than M-protein.
Summary / Conclusion: Our data indicated that MRX34 had beneficial effects in multiple myeloma animal model. Mice treated with MRX34 showed M-protein suppression and survival advantage. Our results warrant further clinical studies using this novel agent in MM.
Citation Format: Woo June Jung, Youngil Koh, Sinil Kim, Hyejoo Park, Sung-Soo Yoon. Activity of microRNA replacement reagent, MRX34, in multiple myeloma in vivo model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1081.