bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 473: A tumor and immune related miRNA signature predicts progression-free survival of melanoma patients treated with ipilimumab
Authors: Tarhini Ahmad , Vallabhaneni Priyanka , Floros Theofanis , LaFramboise William A. , Benos Panayiotis V. , Santana dos Santos. Lucas 
Published: July 2016

Abstract
Background
Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study (Tarhini et al, PLOS One 2014). MicroRNA (miRNA) expression profiles of tumors of treated patients were investigated for their therapeutic predictive value.
Methods
Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks x2 doses) bracketing surgery. Tumor specimens were obtained at baseline and following ipilimumab at definitive surgery (week 6-8). MiRNA expression profiling was performed on the tumor biopsies of 30 patients using Affymetrix miRNA array (v.4). Significance Analysis of Microarrays (SAM) was performed to test the association of each differentially expressed miRNA molecule with outcome. Targets of the selected miRNAs were obtained from miRTarBase (http://mirtarbase.mbc.nctu.edu.tw). Functional annotation analysis of the list of miRNA target genes were performed using DAVID (https://david.ncifcrf.gov). The FDR method was used to adjust for multiple testing in SAM and the functional analysis.
Results
An expression profile consisting of a 4-miRNA signature was associated with improved progression free survival. The signature consisted of miR-34c (previously reported to suppress cancer growth and invasion), miR-711 (reported as a prognostic marker in cutaneous T-cell lymphomas and to target and suppress Heat Shock Protein 70 highly expressed in melanoma), miR-641 (activates MAPK by targeting NF1 and cooperates with its host gene AKT2 in human cancer) and miR-22 (reported to function as a tumour suppressor). Functional annotation analysis of target genes for the 4-miRNA signature was statistically significantly enriched for various cancer-related pathways including regulation of cell proliferation (GO:0042147), regulation of apoptosis (GO:0042981), MAPK signaling pathway (hsa04010) and positive regulation of T cell activation (GO:0050870).
Conclusions
MiRNA expression profiling identified a 4-miRNA signature that is significantly associated with PFS in advanced melanoma patients treated with neoadjuvant ipilimumab. Preliminary results show that targets of these 4 miRNAs are biologically relevant and important. These findings warrant further investigation in relation to ipilimumab and other immunotherapeutics.
Citation Format: Ahmad Tarhini, Priyanka Vallabhaneni, Theofanis Floros, William A. LaFramboise, Panayiotis V. Benos, Lucas Santana dos Santos. A tumor and immune related miRNA signature predicts progression-free survival of melanoma patients treated with ipilimumab. [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 473.
Abstract 4731: Targeted therapies for prostate cancer: Strategies for efficient combinatorial approaches
Authors: Butt Nasir A. , Dhar Swati , Kumar Avinash , Rimando Agnes M. , Zhang Xu , Levenson Anait S. 
Published: July 2016

Abstract
Metastasis-associated protein 1(MTA1) is a cancer progression- related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). MTA1/HDAC unit is a part of the multi-protein nucleosome remodeling and deacetylation (NuRD) complex. In our previous studies we found that MTA1 expression is significantly increased in prostate-specific Pten-null model, and that potent natural analog of resveratrol, pterostilbene (PTER), exerts its anti-tumorigenic effects by blocking MTA1-associated inactivation (deacetylation) of tumor suppressors. SAHA (suberoylanilide hydroxamine, vorinostat) is a histone deacetylase (HDAC) inhibitor that has been shown to be an effective inhibitor of tumor cell growth. We hypothesize that targeting MTA1/HDAC unit of NuRD complex using PTER in combination with SAHA could act additively or synergistically to block prostate tumor progression in vivo with higher efficacy and lower toxicity. In the current study, we utilized the prostate-specific Pten-null mouse model to evaluate the MTA1/HDAC mediated anti-cancer efficacy of combinatorial approach for dietary PTER and clinically approved HDAC inhibitor, SAHA. After a series of carefully designed breeding strategies and genotyping, we collected 30 prostate-specific luciferase expressing Pten knockout (Pten f/f; Rosa26Luc/+; Pb-Cre4) male mice for our experiments. Prostate-specific luciferase expression allowed non-invasive monitoring of prostate tumor growth in these animals. Mice were randomized into four groups: Vehicle control (10% DMSO); PTER (10 mg/kg bw) alone, SAHA (50 mg/kg bw) alone, and PTER + SAHA. Compounds were injected daily, i.p., starting at 8 weeks of age. Mice were sacrificed at week 18. Histopathological (H&E, SMA, CK-8), immunohistochemical (Ki-67, cleaved caspase-3, CD31) and molecular evaluation (MTA1, pAkt, AR) of prostate tissues showed beneficial effects of treatments alone and more so in combination compared to the control group.
Citation Format: Nasir A. Butt, Swati Dhar, Avinash Kumar, Agnes M. Rimando, Xu Zhang, Anait S. Levenson. Targeted therapies for prostate cancer: Strategies for efficient combinatorial approaches. [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 4731.
Abstract 4756: N-cadherin signaling predicts prognosis in medulloblastoma subtypes
Authors: Sverdlov Maria , Downing Michael P. , Kang Shuqi , Chenn Anjen 
Published: July 2016

Abstract
Identification of signaling pathways that drive the clinical behavior of tumors will guide specific molecular therapies. Medulloblastoma, the most common malignant pediatric solid tumor, shows considerable clinical and molecular diversity, providing impetus for specific targeted therapies of predicted molecular drivers. Here we show a gene signature derived from in vitro experimental inhibition of N-cadherin in medulloblastoma (MB) cells predicts survival in human MB in two large independent patient cohorts. Patients with high N-cadherin signature scores had earlier death and reduced overall survival. We found novel heterogeneity in proposed MB molecular subgroups, with significant differences in survival predicted by the N-cadherin signature in sonic hedgehog (SHH) and c2 tumors. In cultured MB cells, N-cadherin cell-cell interactions activated beta-catenin signaling and increased expression of the cancer stem cell regulator Sox2, known to be critical in the growth and relapse of SHH MB. Inhibition of N-cadherin reduced beta-catenin signaling and Sox2. Together, these findings indicate N-cadherin activity predicts the survival of patients with MB and suggest that differential activity of cellular pathways can identify novel disease subgroups and reveal molecular mechanisms with therapeutic significance.
Citation Format: Maria Sverdlov, Michael P. Downing, Shuqi Kang, Anjen Chenn. N-cadherin signaling predicts prognosis in medulloblastoma subtypes. [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 4756.
Abstract 4775: Astrocyte elevated gene-1(AEG-1)as a potential diagnostic/prognostic marker for prostate cancer
Authors: Andavolu Radhika Gade , Stafford Catherine , Herling Patrick , Bianco Isabella , Cardenas Jean-Luc , Go Henry , Rubakovic Svetlana , Andavolu Murthy V. 
Published: July 2016

Abstract
AEG-1/MTDH/LYRIC was initially identified as a HIV-1-inducible gene in primary human fetal astrocytes. Astrocyte Elevated Gene-1 (AEG-1) is ubiquitously overexpressed in all or most cancers and plays a regulatory role in diverse and multiple processes of carcinogenesis. AEG1 is a multi-functional regulator of normal and abnormal physiology; it contributes to broad-spectrum resistance to various chemotherapeutics; and it was recently proposed as the first potential ‘pan-cancer’ gene However, despite its critical relevance to carcinogenesis, until now genetic polymorphisms for this important gene have not been studied for association with cancer susceptibility. For example, though studies have reported AEG-1 gene expression in animal models and tumor tissues, no studies have been reported in Caucasians on the AEG-1 gene polymorphisms in large samples to establish an association with cancers. We report a PCR-RFLP screening protocol for AEG-1 gene polymorphism which is cost effective, simple and reproducible. This study also shows the strong association of AEG-1 gene with prostate cancer risk and metastasis.
DNA and RNA was isolated from 232 normal healthy age matched male Caucasians and 129 prostate cancer patients recruited in the study with an informed consent. AEG-1 gene polymorphism (rs2438211) was screened using PCR-RFLP method. Patients were compared with normal healthy controls and also within patient group comparisons were made between primary and metastasis cases. Genotype analysis was done using IBM SPSS 22 software and gene expression analysis was done using RT2 profiler PCR Array Data analysis version 3.5 (SABIOSCIENCES).
A strong association of AEG-1 gene polymorphism with prostate cancer (p&lt;0.0001) was observed. A high frequency of the mutant allele was observed in patients (27%) as compared to normal healthy controls (7.9%).This study also highlights the possible effect of AEG-1 interaction with other genes (p53, BCCIP) contributing to tumorigenesis.
Citation Format: Radhika Gade Andavolu, Catherine Stafford, Patrick Herling, Isabella Bianco, Jean-Luc Cardenas, Henry Go, Svetlana Rubakovic, Murthy V. Andavolu. Astrocyte elevated gene-1(AEG-1)as a potential diagnostic/prognostic marker for prostate 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 4775.
Abstract 4776: Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers
Authors: Bapat Samhita , Dichwalkar Tanmay , Pancholi Priya , Bennett Byron L. , Sehdev Vikas 
Published: July 2016

Abstract
Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to variable P53 status and overactive mechanisms that mediate drug resistance. Platinum based compounds like Cisplatin (CDDP) are frequently used for treatment of UGCs. However, clinical use of CDDP is limited due to development of drug resistance and dose limiting side-effects resulting in nausea, vomiting, neutropenia, thrombocytopenia and renal toxicity. In this study we investigated the anticancer potency of a novel CDDP derivative (dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum) (DCTF-CDDP) and compared it to CDDP in P53 wild type and mutant models of UGCs. Methods: For this study, we evaluated the effect of CDDP or its derivative (DCTF-CDDP) on AGS (P53 wild type) and FLO-1 (P53 mutant) UGC cell viability, survival, and expression of apoptotic markers. Results: The cell viability data indicated that DCTF-CDDP treatment was comparatively more effective than CDDP at inhibiting AGS (CDDP IC50: 6.3 ± 0.2 μM; DCTF IC50: 1.7 ± 0.5μM) and FLO-1 (CDDP IC50: 2.5 ± 0.68 μM; DCTF IC50: 0.5 ± 0.6μM) UGC cancer cell viability. The clonogenic cell survival assay data also showed that DCTF-CDDP was significantly (p&lt;0.05) more potent at suppressing UGC cell survival when compared to CDDP. Similarly, the western blot data also showed that treatment with increasing concentrations (1, 2.5, and 5 μM) of CDDP and DCTF-CDDP for 24h induced higher levels of P53/P73 and cleaved PARP with DCTF-CDDP treatment in UGC cells. Conclusions: Our in vitro data indicate that DCTF-CDDP is significantly more potent at inhibiting cell viability and inducing apoptosis in P53 wild type and mutant UGC cells. Our study suggests that DCTF-CDDP could be an effective CDDP derivative that can be used to achieve better therapeutic outcome at lower doses and toxic side effects.
Citation Format: Samhita Bapat, Tanmay Dichwalkar, Priya Pancholi, Byron L. Bennett, Vikas Sehdev. Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers. [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 4776.
Abstract 4777: The role of BAG3 in human leukemia cells’ response to the experimental anticancer drug laromustine
Authors: Rice Kevin P. , Loya Amanda J. , Gross Kayla M. 
Published: July 2016

Abstract
The experimental anticancer drug laromustine, which demonstrates moderate clinical efficacy against acute myelogenous leukemia and glioblastoma multiforme, yields two reactive electrophiles in situ. Therapeutic cytotoxicity is principally due to a 2-chloroethylating species that can cause lethal DNA crosslinks. However, the second electrophile, methyl isocyanate, triggers acute toxicity in cultured cancer cells and synergizes with the cogenerated 2-chloroethylating activity. The mechanism by which laromustine kills cancer cells likely includes apoptosis. We measured changes in transcription for 88 genes relating to this cell death pathway cultured human promyelocytic (HL-60) cells using quantitative real-time reverse transcriptase PCR. Cultured cells were treated with drug for six hours before harvesting mRNA for analysis. Of these genes, the expression of BAG3, whose encoded protein is also known as CAIR-1 or Bis, was increased by more than 300 fold in cells exposed to laromustine. By forming a complex with heat shock protein 70 (Hsp70), it is thought that BAG3 promotes anti-apoptotic activity by interfering with protein chaperones and release of cytochrome-c. We are also examining effects on the entire transcriptome upon treatment with laromustine using GeneChip Microarrays. Finally, we have created a stable BAG3 knockdown cell line using an shRNA construct via lentiviral transfection. Substantial differences in laromustine-induced cytotoxicity in differing BAG3 backgrounds would suggest a mechanistic role in a cell's defense against laromustine and possibly an improved clinical approach.
Citation Format: Kevin P. Rice, Amanda J. Loya, Kayla M. Gross. The role of BAG3 in human leukemia cells’ response to the experimental anticancer drug laromustine. [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 4777.
Abstract 4784: FGFR-selective inhibitor Debio 1347 induces tumor regressions in FGFR2-altered gastric cancer PDX models
Authors: Franck Brichory , Pokorska-Bocci Anna , Nuciforo Paolo , Rigotti Stefania , Lembrez Nathalie , Vuagniaux Grégoire , Moulon Corinne , Vaslin Anne 
Published: July 2016

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. In gastric cancer, alterations of FGFR2 are observed in a subset of patients, overexpression being more frequently observed as compared to FGFR2 amplifications. In addition, FGFR2 amplification and ERBB2, EGFR, MET and KRAS amplifications are mutually exclusive suggesting that FGFR targeted therapy would be most effective in the FGFR2-amplified subgroup of patients. Debio 1347 (CH5183284) is an oral selective FGFR inhibitor currently in clinical development. The aim of the study was to investigate the preclinical activity of Debio 1347 in patient derived xenograft (PDX) mouse models harboring diverse FGFR alterations in multiple indications, including gastric cancer.
The mouse trial was conducted in 39 different PDX models selected according to FGFR1, 2 and 3 alterations status. Debio 1347 was administered orally once daily and tumor volume was monitored for 14 consecutive days. PDX tumors were extensively characterized using FISH, RNAseq, nCounter Gene Expression and immunohistochemistry (IHC), and FGFR molecular alterations were correlated with Debio 1347 efficacy. The level of tumor heterogeneity for FGFR2 amplification and expression and its impact on drug response were also assessed.
In gastric cancer, Debio 1347 induced tumor regression in models harboring the commonly found FGFR2 amplification. Interestingly, Debio 1347 was also highly effective in models with high FGFR2 expression but without FGFR2 amplification, indicating that not only gene amplification drives the activity of Debio 1347 in this indication, but also the expression level of FGFR2.
Altogether, these data demonstrate that Debio 1347 could be highly effective in gastric cancer patients harboring FGFR2 amplification and/or high FGFR2 expression. Debio 1347 is currently investigated in a Phase I trial in selected patients harboring FGFR alterations (NCT01948297).
Citation Format: Brichory Franck, Anna Pokorska-Bocci, Paolo Nuciforo, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Anne Vaslin. FGFR-selective inhibitor Debio 1347 induces tumor regressions in FGFR2-altered gastric cancer PDX models. [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 4784.
Abstract 4806: Enhancing the efficacy of tosedostat through carboxylesterase induction
Authors: Hong Priscilla Wei Ling , Smith Amanda Melanie , Johnson Lambro Angelo , Loo Dorothy , Stoll Thomas , Hill Michelle M. , Moore Andrew S. 
Published: July 2016

Abstract
Malignant cells, including acute myeloid leukaemia (AML), have high protein turnover to support their accelerated cell growth. Aminopeptidases regulate proteolysis, supplying free amino acids for new protein synthesis. Inhibition of aminopeptidases depletes free amino acids, impairing new protein production, leading to impaired cell growth and proliferation. Hence, aminopeptidase inhibition is of particular interest as a therapeutic strategy for AML. Tosedostat (CHR-2797) is an aminopeptidase inhibitor which is converted to its active metabolite, CHR-79888, by intracellular carboxylesterases (CES). This active metabolite is poorly membrane permeable, resulting in intracellular accumulation. Tosedostat has shown promise as a potential therapeutic strategy for AML and is well-tolerated in adult patients. However, its efficacy in paediatric AML has not been established. We set out to investigate the use of tosedostat for paediatric AML and enhance its efficacy through CES1 induction. It is hypothesised that inducing CES will lead to increased CHR-79888 production and subsequently, increased tosedostat efficacy. The IC50 of tosedostat across 11 AML cell lines (6 paediatric and 5 adult), determined by resazurin reduction assay, was approximately 13μM. Biochemical assays demonstrated that tosedostat inhibited cellular aminopeptidase activity in a concentration-dependent manner. However, this inhibitory effect was reversible with rapid, but incomplete, enzyme activity recovery upon drug withdrawal, irrespective of initial concentration or treatment duration. Quantitative PCR and immunoblotting revealed no correlation between CES expression and sensitivity to tosedostat. Cellular CES1 activity was also measured. Benzil and Bis(4-nitrophenyl)phosphate (BNPP) were used to modulate cellular CES1 activity. Assays of CES1 enzyme kinetics demonstrated that following temporary exposure to the reversible CES inhibitor benzil, there is a rebound in CES1 activity in AML cells. Consistent with this observation, pre-treatment by benzil increased CES1 activity, especially in MV4-11 cells. Moreover, reduced cell viability with tosedostat treatment following benzil pre-treatment correlated with the induction of CES1 activity in AML cell lines. Together, these data suggest that enhanced tosedostat efficacy through induction of CES activity is a novel therapeutic approach to treat AML.
Citation Format: Priscilla Wei Ling Hong, Amanda Melanie Smith, Lambro Angelo Johnson, Dorothy Loo, Thomas Stoll, Michelle M. Hill, Andrew S. Moore. Enhancing the efficacy of tosedostat through carboxylesterase induction. [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 4806.
Abstract 481: Low-molecular-mass secretome profiling identifies prognostic biomarkers for oral cavity squamous cell carcinomas
Authors: Chang Kai-Ping , Yu Jau-Song 
Published: July 2016

Abstract
The profiling of cancer cell secretomes is considered to be a good strategy for identifying cancer- related biomarkers, but few studies have focused on identifying low-molecular-mass (LMr) proteins (&lt;15 kDa) in cancer cell secretomes. Here, we used tricine-SDS-gel-assisted fractionation and LC-MS/MS to systemically identify LMr proteins in the secretomes of five oral cavity squamous cell carcinoma (OSCC) cell lines. Cross-matching of these results with nine OSCC tissue transcriptome datasets allowed us to identify 33 LMr genes/ proteins that were highly upregulated in OSCC tissues and secreted/released from OSCC cells. Immunohistochemistry and quantitative real-time PCR were used to verify the overexpression of two candidates, HMGA2 and MIF, in OSCC tissues. The overexpressions of both proteins were associated with cervical metastasis, perineural invasion, deeper tumor invasion, higher overall stage, and a poorer prognosis for post-treatment survival. Functional assays further revealed that both proteins promoted the migration and invasion of OSCC cell lines in vitro. Collectively, our data indicate that the tricine-SDS-gel/LC-MS/MS approach can be used to efficiently identify LMr proteins from OSCC cell secretomes, and suggest that HMGA2 and MIF could be potential tissue biomarkers for OSCC.
Citation Format: Kai-Ping Chang, Jau-Song Yu. Low-molecular-mass secretome profiling identifies prognostic biomarkers for oral cavity squamous 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 481.