bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4724: Novel and selective inhibitors of histone deacetylases (HDAC) 1 and 2 synergize with DNA methyltransferase inhibitor azacitidine in acute myeloid leukemia (AML)
Authors: Min Chengyin , Quayle Steven N. , Huang Pengyu , Shearstone Jeffrey R. , Jones Simon S. , Yang Min 
Published: July 2016

Abstract
AML is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain generally poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and the DNA methyltransferase inhibitor VIDAZA™ (azacitidine) is approved by European Medicines Agency for the treatment of elderly patients with AML. Numerous clinical studies are ongoing to investigate the benefit of combining azacitidine with other investigational agents in AML.
HDAC inhibitors are promising agents for the treatment of AML. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have suggested beneficial clinical activity in AML. However, the toxicity profiles of non-selective HDAC inhibitors in the combination settings limit the clinical benefit. In this work, we describe the preclinical development of highly selective HDAC inhibitors, which are hypothesized to have improved safety profiles than non-selective HDAC inhibitors, for combination therapy in AML. We demonstrate that selective HDAC1/2 inhibitors are highly effective and efficacious both as single agents and in combination with azacitidine in preclinical models of AML, including established AML cell lines, bone marrow samples freshly derived from AML patients and in vivo xenograft models of human AML. At the molecular level, gene expression profiling, DNA methylation mapping and chromatin immunoprecipitation analysis were performed on AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the drug combination. Molecular signatures and genes involved in myeloid cell differentiation, apoptosis and cell cycle arrest were identified as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.
Citation Format: Chengyin Min, Steven N. Quayle, Pengyu Huang, Jeffrey R. Shearstone, Simon S. Jones, Min Yang. Novel and selective inhibitors of histone deacetylases (HDAC) 1 and 2 synergize with DNA methyltransferase inhibitor azacitidine in acute myeloid leukemia (AML). [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 4724.
Abstract 4983: Aminoflavone acts as an immunomodulator of tumor growth in a breast cancer mouse model
Authors: Callero Mariana Alejandra , Rodriguez Cristina Elisa , Sólimo Aldana , Bal de Kier Joffé Elisa , Loaiza Pérez. Andrea 
Published: July 2016

Abstract
Aminoflavone (AFP464, NSC 710464), an antitumor agent which recently entered phase II clinical trials, acts against estrogen-positive breast cancer (ER+). AFP464, which has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway, decreased tumor growth rate in an estrogen dependent, tamoxifen-sensitive mammary cancer murine model (M05) syngeneic in BALB/c developed in our animal facility. Considering that AhR has recently emerged as a physiological regulator of the innate and adaptive immune responses, it is our aim to investigate whether AFP464 modulates the immune response in our mouse model. Cytometric analyses of splenic cells obtained from AFP464-treated and control animals, at three different times after treatment (13, 21 and 41 days), revealed that MDSCs were lower in animals treated with AFP464 than in the vehicle control group. On the contrary (On the other hand) no differences in macrophages, NK, CD8+ T, and CD4+ T cells were observed between these two groups. We also found a diminished quantity of MDSCs in the inflammatory infiltrate, isolated from tumors treated with AFP464. According to these results, we also observed a higher cytotoxic activity of splenic cells from the AFP464-treated group compared with the control one (13 days: 1,50 ± 0,12 vs 0,74 ± 0,18; 21 days: 2,4 ± 0,3 vs 1,16 ± 0,2; 41 days: 2,97 ± 0,2. vs 1,07 ± 0,2 p &lt; 0,05). After an adoptive transfer of splenic cells to mice bearing M05 tumors, we observed that tumors were significantly smaller in mice that received splenic cells from AFP464-treated mice compared with controls (p &lt; 0,05). Finally, we also investigated the effects of AFP464 on metalloproteinase, arginase and iNOS activities in peritoneal macrophages. We found a time-dependent modulation: at 13 day after treatment AFP464 induces an anti-tumor M1 profile, which was gradually reverted to a pro-tumoral M2 profile, at 41 days after treatment. These data suggest that AFP464 modulates the immune response in order to collaborate with its anti-tumor activity and places the immune system as a novel target for this anti-cancer agent to strengthen the rationale for its inclusion in breast cancer treatment regimens.
Citation Format: Mariana Alejandra Callero, Cristina Elisa Rodriguez, Aldana Sólimo, Elisa Bal de Kier Joffé, Andrea Loaiza Pérez. Aminoflavone acts as an immunomodulator of tumor growth in a breast cancer mouse 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 4983.
Abstract 4994: SEA-CD40: from bench to bedside
Authors: Gardai Shyra J. , Neff-LaFord Haley , Epp Angela , Yang Jing , Manley Thomas , Law Che-Leung 
Published: July 2016

Abstract
SEA-CD40 is a non-fucosylated, humanized IgG1 monoclonal antibody directed against human CD40, a co-stimulatory receptor of the TNF receptor superfamily. The consequence of enhanced SEA-CD40/FcγRIIIa binding is potent immune stimulatory activity. CD40 receptor ligation induces multiple pathways; to pave the road for identification of a specific activity signature in the clinical setting, in vitro preclinical assays were developed to monitor the immune modulatory activity of SEA-CD40. Human PBMCs stimulated with increasing concentrations of SEA-CD40 were assessed for immune changes including cytokine production, cellular activation, and modulation of cellular subsets. SEA-CD40 PBMC stimulation elicited a unique set of cytokines including MIP-1β, MCP-1, and IL-8. In addition to inducing cytokines, specific immune cell changes were also observed including up-regulation of stimulatory molecules on monocyte/ macrophages, activation of NK cells, and changes in cellular subsets such as deletion of B-cells. While some of these changes were common across the other CD40 therapeutic antibodies being tested in the clinic, SEA-CD40-specific changes were identified. These changes included a reduction in the immune dampening cytokine IL-10, induction of Th1 CXCR3 positive cells, and reduction of T-regulatory cells, all potentially contributing to an antitumor immune response.
The specific in vitro SEA-CD40 signature was also observed in vivo in cynomolgus monkeys. SEA-CD40 treatment induced the same signature cytokines observed in vitro and elicited the same cellular changes including depletion of B-cells, and activation of CD8+ T-cells. A CD40 receptor occupancy assay was also created to correlate receptor engagement with activity. Interestingly, while SEA-CD40 is rapidly cleared from plasma, it is detectable on the surface of antigen-presenting cells for up to 3 weeks.
The initial starting dose for SEA-CD40 clinical trials was calculated using the minimal anticipated biological effect level (MABEL). SEA-CD40 cytokine induction was the most sensitive preclinical marker of biologic activity and was, therefore, used for MABEL dose calculation. In the ongoing phase 1 First-In-Human clinical trial, this preclinical SEA-CD40 activity signature is being monitored in adult patients with advanced solid tumors (study NCT02376699). Establishing a clear immune biomarker strategy from pre-clinical research to clinical trials is vital for tracking the activity of our immuno-oncology drugs in patients and for identifying a safe and efficacious regimen.
Citation Format: Shyra J. Gardai, Haley Neff-LaFord, Angela Epp, Jing Yang, Thomas Manley, Che-Leung Law. SEA-CD40: from bench to bedside. [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 4994.
Abstract 5011: Strong FGFR3 staining is a marker for FGFR3 fusions and poor prognosis in diffuse gliomas
Authors: Granberg Kirsi J. , Annala Matti , Lehtinen Birgitta , Kesseli Juha , Haapasalo Joonas , Yli-Harja Olli , Visakorpi Tapio , Haapasalo Hannu , Nykter Matti , Zhang Wei 
Published: July 2016

Abstract
Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled coil 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well to FGFR inhibitors. As high FGFR3 expression has been detected in fusion positive tumors, we sought to determine the clinical significance of FGFR3 protein expression level and its potential to indicate FGFR3 fusions. We thus performed FGFR3 IHC on tissue microarrays containing 676 grade II-IV astrocytoma and 116 grade II-III oligodendroglial tumor specimens. Selected cases were further analyzed using targeted sequencing. Moderate-to-strong FGFR3 staining was detected in all tumor grades, was more common in females, and associated with poor survival. Targeted sequencing identified FGFR3-TACC3 fusions and an FGFR3-CAMK2A fusion in 10 of 12 strongly stained cases (staining specificity 86%), whereas no fusions were found in 12 negatively-to-moderately stained cases (staining sensitivity 100%). Fusion-positive cases were predominantly female and negative for IDH, TP53, and EGFR/PDGFRA/MET alterations. Importantly, FGFR3 staining revealed intratumoral heterogeneity, with subclonal negative staining in a subpopulation of fusion-positive cases. Taken together, strong FGFR3 protein expression is indicative of FGFR3 fusions and may serve as a cost-effective predictive marker for FGFR-inhibitor-based treatment regimens.
Citation Format: Kirsi J. Granberg, Matti Annala, Birgitta Lehtinen, Juha Kesseli, Joonas Haapasalo, Olli Yli-Harja, Tapio Visakorpi, Hannu Haapasalo, Matti Nykter, Wei Zhang. Strong FGFR3 staining is a marker for FGFR3 fusions and poor prognosis in diffuse gliomas. [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 5011.
Abstract 59: Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer
Authors: lee doyeon , Yu SungSook , Jung Dawoon E.Jung1 , Lee YeoSong , Choi Beom Ku , Lee Yong Chan 
Published: July 2016

Abstract
Helicobacter pylori (H.pylori) infection of the gastric mucosa is strongly associated with chronic gastritis, peptic ulcer disease and gastric cancer. Individuals infected with H.pylori possessing CagA protein produce more reactive oxygen species (ROS) and increase the risk of developing gastric cancer. Sirtuins are NAD+ dependent deacetylases that regulate cellular metabolism in response to stress. Recently, mitochondrial sirtuin, SIRT3, is known to be a tumor suppressor via its ability to suppress ROS and regulate hypoxia inducible factor 1α (HIF-1α). However, it has not been investigated whether increased ROS production by H.pylori is regulated by SIRT3 via HIF-1α regulation and is mediated through intracellular CagA. We aimed to investigate the correlation between SIRT3, ROS and HIF-1α in H.pylori infected gastric epithelial cells. In this study, we showed that SIRT3 deficient AGS cells exhibited augmented HIF-1α protein stabilization and transcriptional activity in hypoxic condition. We also found that H.pylori CagA downregulated SIRT3 activity and induced ROS production through HIF-1α stabilization, similar to hypoxic condition in gastric epithelial cells. Overexpression of SIRT3 inhibited the stabilization of HIF-1α protein and attenuated the increase in HIF-1α transcriptional activity in hypoxia. Moreover, H.pylori CagA attenuated HIF-1α stability and transcriptional activity in SIRT3 overexpressed gastric epithelial cells. Taken together, these findings provide a valuable insight into the potential role of SIRT3 in the development of gastric cancer by regulating the HIF-1α protein.
Citation Format: doyeon lee, SungSook Yu, Dawoon E.Jung1 Jung, YeoSong Lee, Beom Ku Choi, Yong Chan Lee. Regulation of SIRT3 signal related metabolic reprogramming in gastric 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 59.
Abstract 689: Downregulation of TIMP2 via HIF-1á/miR-210/HIF-3á regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma
Authors: Kai Alan KL , Chan Lo Kong , Lo Regina CL , Lee Joyce , Wong Carmen CL , Wong Jack CM , Ng. Irene OL 
Published: July 2016

Abstract
Cancer metastasis is a multi-step process that involves a series of tumor-stromal interaction, including extracellular matrix (ECM) remodeling which requires a concerted action of multiple proteolytic enzymes and their endogenous inhibitors. This study investigated the role of tissue inhibitor of metalloproteinases 2 (TIMP2) in the context of hepatocellular carcinoma (HCC) metastasis. We found that TIMP2 was the most significantly downregulated member among the TIMP family in human HCCs. Moreover, TIMP2 underexpression was frequent (41.1%; 23/56) in human HCCs as compared to the corresponding non-tumorous livers and was significantly associated with direct liver invasion into the adjacent liver parenchyma and poorer survival outcomes of the HCC patients. Furthermore, stable silencing of TIMP2 in HCC cell lines enhanced the cell invasive ability and ECM degradation associated with formation of invadopodia-like feature, suggesting that TIMP2 is a negative regulator of HCC metastasis. Furthermore, using orthotopic tumor xenograft model, we demonstrated that ectopic expression of TIMP2 open reading frame in the highly metastatic HCC cell line MHCC-97L not only significantly reduced the incidence of tumor microsatellite formation and venous invasion in the primary hepatic tumor xenografts, but also pulmonary metastasis, suggesting that both extrahepatic and intrahepatic metastasis in HCC was suppressed by TIMP2 expression. Mechanistically, TIMP2 suppression in a hypoxic environment was induced through a regulatory feedback circuit consisting of HIF-1á, miR-210 and HIF-3á. Taken altogether, our findings established that TIMP2 was frequently downregulated in human HCCs and its downregulation was associated with aggressive behavior and poorer patients’ outcome. Its suppression was under the regulation of a novel feedback circuit consisting of HIF-1á/ miR-210/ HIF-3á. Overall, our study has provided solid in vitro and in vivo evidence that TIMP2 is an important regulator of ECM degradation and HCC metastasis. These findings demonstrated that perturbation of the dynamic HIF-1a signaling circuit by miR-210 inhibitor abolished TIMP2 downregulation and suppressed HCC cell invasion. They also support the notion that targeting against HIF-1á signaling is a promising direction to tackle the hypoxic responses in HCC elicited by transarterial chemo-embolization (TACE) treatment to HCC patients.
Citation Format: Alan KL Kai, Lo Kong Chan, Regina CL Lo, Joyce Lee, Carmen CL Wong, Jack CM Wong, Irene OL Ng. Downregulation of TIMP2 via HIF-1á/miR-210/HIF-3á regulatory feedback circuit enhances cancer metastasis in hepatocellular carcinoma. [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 689.
Abstract 727: TSLP expression and high serum TSLP level indicate a poor prognosis in gastric cancer patients
Authors: Watanabe Joji , Saito Hiroaki , Miyatani Kozo , Ikeguchi Masahide , Umekita Yoshihisa , Otani Shinji , Tsujitani Shunichi 
Published: July 2016

Abstract
Purpose: Thymic stromal lymphopoietin (TSLP) plays an important role in promoting tumor survival, by manipulating the immune response and angiogenesis. However, the clinical significance of TSLP in gastric cancer is unclear.
Method: Immunohistochemistry was used to investigate TSLP expression in non-cancerous gastric mucosa and gastric cancer tissue from patients with gastric cancer. Serum TSLP levels were measured using an enzyme-linked immunosorbent assay.
Results: Tumors with TSLP expression were significantly larger than those without TSLP expression. TSLP expression was observed more frequently in advanced (T2/T3/T4) than in early (T1) gastric cancer and in stage 3/4 than in stage 1/2. Lymph node metastasis, liver metastasis, positive peritoneal lavage cytology, lymphatic
invasion, and vascular invasion occurred significantly more often in TSLP-expressing than in non-expressing tumors. The prognosis of patients with TSLP-positive tumors was significantly worse than that of patients with TSLP-negative tumors. Patients with high serum TSLP concentrations also had a significantly worse prognosis than those with low concentrations. Multivariate analysis identified serum TSLP level as an independent prognostic indicator.
Conclusion: TSLP is closely related to the progression of gastric cancer and may predict
survival in these patients.
Citation Format: Joji Watanabe, Hiroaki Saito, Kozo Miyatani, Masahide Ikeguchi, Yoshihisa Umekita, Shinji Otani, Shunichi Tsujitani. TSLP expression and high serum TSLP level indicate a poor prognosis in gastric cancer patients. [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 727.
Abstract CT134: Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma
Authors: Algazi Alain , Tsai Katy K. , Takamura Kathryn T. , Chen Lawrence , Twitty Chris , Dwyer Mary , Greaney Samantha , Diep Tu , Pierce Robert H. , Le Mai H. , Fong Lawrence , Daud Adil 
Published: July 2016

Abstract
Background: Intratumoral electroporation of plasmid IL-12 (IT-pIL12-EP) induces tumor infiltrating lymphocytes (TILs) and anti-tumor immunity in melanoma as described in previous Phase 1 and 2 clinical trials. PD-1 and PD-L1 antibodies induce durable tumor responses in advanced melanoma, however responses to these agents are far less common in tumors lacking significant numbers of TILs. Therefore, in this retrospective study, patients were evaluated for response to anti-PD-1/PD-L1 therapies post IT-pIL12-EP.
Methods: A multi-center, Phase 2 trial of IT-pIL12-EP was conducted in patients with stage III/IV melanoma. Upon disease progression or treatment discontinuation with IT-pIL12-EP, many patients received subsequent PD-1/PD-L1 inhibitors. Patients with documented follow up history and evaluable for anti-PD-1/PD-L1 response were included in this analysis.
Results: We evaluated 34 patients enrolled and treated with IT-pIL12-EP monotherapy at a single center, of which, 14 patients went on to receive a systemic PD-1/PD-L1 inhibitor and were evaluable for PD-1/PD-L1 best overall response (BOR). The PD-1/PD-L1-associated BOR was 9/14 (64%) with CR in 5 patients (36%), PR in 4 (29%), SD in 2 (14%), and PD in 3 (21%). Eight of these evaluable patients received a systemic PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP. Of these 8 patients, a BOR of 75% was observed (50% CR and 25% PR).
Conclusion: Patients who received IT-pIL12-EP and later went on to receive a PD-1/PD-L1 inhibitor demonstrated a high PD-1/PD-L1-associated response rate (64% CR+PR). Interestingly, patients who received a PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP had a BOR of 75% (CR+PR). These data suggest that IT-pIL12-EP may prime for responses to PD-1 blockade. Patient tumor samples are being evaluated for TIL status and gene expression analysis to determine the mechanism of IT-pIL12-EP priming. A prospective clinical trial combining IT-pIL12-EP and pembrolizumab in advanced melanoma is ongoing at the University of California San Francisco.
NCT01502293
Citation Format: Alain Algazi, Katy K. Tsai, Kathryn T. Takamura, Lawrence Chen, Chris Twitty, Mary Dwyer, Samantha Greaney, Tu Diep, Robert H. Pierce, Mai H. Le, Lawrence Fong, Adil Daud. Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma. [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 CT134.
Abstract LB-068: Classification of cancer by synthesis of rare non-coding mutations within recurrent epigenetic and protein networks
Authors: Zhang Wei , Ideker Trey ,   the Pan-Cancer Analysis of Whole Genomes Working Group on Regulatory drivers and Pathways/Networks
Published: July 2016

Abstract
Cancers are mutationally heterogeneous, resulting in multiple subtypes with different clinical outcomes and responses to treatment. Newly available data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) working group have revealed vast numbers of mutations located in non-coding regions of the human genome. However, few of these mutations are recurrent and their functions are poorly characterized. Here, we synthesize all mutations identified in a patient, both coding and non-coding, in the context of prior knowledge of epigenetic architecture and molecular networks. Non-coding mutations are selected using a functional segmentation of the genome defined by the ENCODE, Roadmap, and FANTOM consortia; these are then aggregated with coding mutations using enhancer-gene (eQTL, HiC, Roadmap, linkage) and gene-gene functional interactions relevant to human cancer. This approach enables stratification of 756 patients from 22 cancer types into biologically and clinically informative subtypes, based on highly recurrent alteration of networks mediating cell adhesion, DNA damage checkpoint and apoptosis, HLA class I, PI3K signaling, telomere maintenance, or p53 signaling. Non-coding mutations (e.g. to enhancers of IKBKB, IL1A, and MALT1) are unified with coding mutations (e.g. in BTRC, ATM, and the PPAR subunits) within common networks, providing valuable prognostic power beyond the baseline survival rate of the tissue. We find that most of the relevant non-coding elements are affected in only one patient, with the recurrent signal becoming clear only after aggregation within epigenetic networks.
Citation Format: Wei Zhang, Trey Ideker, the Pan-Cancer Analysis of Whole Genomes Working Group on Regulatory drivers and Pathways/Networks. Classification of cancer by synthesis of rare non-coding mutations within recurrent epigenetic and protein networks. [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 LB-068.