bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 316: FTY720 enhances the efficacy of paclitaxel and of carboplatin in drug-resistant ovarian cancer cells
Authors: Kreitzburg Kelly M. , Alvarez Ronald D. , Landen Charles N. , Yoon Karina J. 
Published: July 2016

Abstract
Objectives: Our long-term goal is to develop effective therapies for ovarian cancer by targeting molecules that contribute to drug resistance in this tumor type. Preliminary RNA-seq data were generated using a patient-derived xenograft model. These data identified the sphingosine-1-phosphate (S1P) signaling pathway as one of the pathways most affected by carboplatin and paclitaxel, the current standards of care for ovarian cancer. We then examined whether a synthetic analog of sphingosine, FTY720, enhanced the cytotoxicity of platinum and taxane resistant ovarian cancer cell lines.
Methods: To assess the efficacy of FTY720 + carboplatin and of FTY720 + paclitaxel, we exposed three pairs of parental and drug resistant human ovarian cancer cell lines to each combination. The cell lines used were: SKOV3-ip1 and SKOV3-TR (taxane resistant), A2780 and A2780-CP20 (platinum resistant), and HeyA8 and HeyA8-MDR (taxane-platinum resistant). We used alamarBlue cell proliferation assays to determine the efficacy of FTY720 as a single agent or in combination with paclitaxel or carboplatin, and immunoblots to assess the expression of proteins involved in the S1P pathway.
Results: FTY720 as a single agent decreased cell viability in a dose-dependent manner in all three pairs of cell lines, with IC50 values ranging from 5 to 8 μM. When cells were exposed to the IC50 of FTY720 + a range of concentrations of carboplatin or paclitaxel, FTY720 had little effect in any of the three parental cell lines and in SKOV3-TR cells. Interestingly, however, FTY720 decreased the IC50 of carboplatin 15- to 16-fold and the IC50 of paclitaxel 20- to 90- fold in A2780-CP20 and HeyA8-MDR cells, respectively. We also observed that FTY720 altered the expression of sphingosine kinase2, S1P lyase, and acid ceramidase, each of which contributes to the ceramide-sphingosine-S1P rheostat that tightly regulates expression of S1P pathway proteins.
Conclusions: Our data show that FTY720 sensitized drug resistant ovarian cancer cell lines A2780-CP20 and HeyA8-MDR to carboplatin and to paclitaxel 15- to 90-fold. The data suggest that the S1P pathway may contribute to carboplatin and paclitaxel resistance in this cell type. We propose that proteins of the S1P pathway merit further study as effective molecular targets in drug resistant ovarian cancer cells.
Citation Format: Kelly M. Kreitzburg, Ronald D. Alvarez, Charles N. Landen, Karina J. Yoon. FTY720 enhances the efficacy of paclitaxel and of carboplatin in drug-resistant ovarian cancer 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 316.
Abstract 3181: Expression changes of the chromatin modifier PBRM1 in human renal cell carcinomas in relation to histopathological features
Authors: Krause Hans , Högner Anica , Jandrig Burkhard , Kilic Ergin , Kempkensteffen Carsten 
Published: July 2016

Abstract
Recent next-generation sequencing studies of clear cell renal cell carcinoma (ccRCC) have identified point mutations in chromatin-modifying genes, among them PBRM1 which is now the second most frequently mutated gene in RCCs (in up to 41% ccRCCs cases) and belongs to the m1 TCGA (The Cancer Genome Atlas) subset. The occasional presence of PBRM1 mutations in the absence of VHL mutations indicates, that PBRM1 might be another driver tumor suppressor gene in ccRCCs. We were interested in examining PBRM1 expression at mRNA and protein levels and correlated these findings to histopathological features of RCC patients.
Relative gene expression (RGE) data were obtained by Q-PCR from matched tumor and adjacent normal fresh frozen ccRCC tissues from 57 patients who underwent radical nephrectomy at our clinic. Papillary (pRCC) as well as chromophobic cases (chRCC) were added to analyze the expression of splice variants of PBRM1. Comparative Western blot analyses as well as semi-quantitative immuno-histochemical staining (IHC) for PBRM1 and VHL were performed on all ccRCC cases.
In 78.9% of cases (45/57) PBRM1 mRNA was downregulated at least 1.5-fold, 7% (4/57) showed PBRM1 upregulation, and 14% (8/57) displayed no obvious expression changes between tumor and corresponding tumor tissue. Interestingly, 21 of 45 ccRCCs tumor tissues expressed splice variant 4 more abundantly when compared to normal tissue, whereas the normal tissue preferentially expressed splice variant 1 that includes an additional exon. Remarkably, this differential expression picture is completely reversed in pRCC and chRCC cases.
The majority of 57 ccRCCs displayed weak nuclear PBRM1 staining (52.6%), whereas 31.6% showed moderate and 15.8% strong staining. However, we were not able to demonstrate a significant correlation of IHC expression levels, neither to tumor staging nor to Fuhrman grading.
The observed high frequency of decreased expression of the chromatin-remodeling gene PBRM1 on mRNA (78.9%) and protein levels (52.6%), respectively, as wells as a high mutation rate (about 15% in our data set) indicate a substantial role of PBRM1 in the tumorigenesis of ccRCCs. Preferences in the expression of different PBRM1 splice variants warrant further investigation with regard to renal cell carcinoma development.
Citation Format: Hans Krause, Anica Högner, Burkhard Jandrig, Ergin Kilic, Carsten Kempkensteffen. Expression changes of the chromatin modifier PBRM1 in human renal cell carcinomas in relation to histopathological features. [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 3181.
Abstract 3183: Delivery of point-of-care management to patients with gynecologic malignancies using comprehensive genomic profiling
Authors: Rodriguez-Rodriguez Lorna , Hirshfield Kim M. , Rojas Veronica , Ali Siraj , DiPaola Robert S. , Gibbon Darlene , Isani Sara , Leiser Aliza , Riedlinger Gregory M. , Ganesan Shridar 
Published: July 2016

Abstract
INTRODUCTION: Gynecologic cancers were estimated to occur in 98,280 women in 2015 in the United States and result in 30,440 deaths (Siegel 2015). The most common forms of gynecologic cancers occur in the ovary and uterine corpus (Siegel, 2015). Various reasons for poor outcome in these cancers include the late stage of the disease at the time of diagnosis and therapy resistance. We sought to elucidate alternate treatment avenues based on the genomic profiles of recalcitrant or rare gynecologic tumors. In the process, we aim to determine both the clinical utility and the feasibility of using comprehensive genomic profiling (CGP) during clinical care to identify clinically relevant tumor genomic alterations for these patients while enabling point-of-care management.
METHODS: As part of our ongoing prospective clinical trial, we report on the initial 69 patients with gynecologic cancers that were refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic mutations and alterations were reviewed by members of an expert, multidisciplinary institutional molecular tumor board (MTB). Consensus recommendations by the MTB were provided to the treating physician on genomically targeted, clinically relevant, FDA-approved, on- and off-label therapies and clinical trials. The outcomes were assessed.
RESULTS: Study outcomes were available for 64 patients. On average, patients had 4.97 genomic alterations per tumor (range 1-46), while the time from the testing laboratory report to the formulation of recommendations by the MTB was approximately 3-4 weeks. Targeted
treatment options were recommended by the MTB for 93% of patients; 39% of these patients had the MTB-based recommendations implemented by the treating physician. A response or clinical benefit was seen in 56% of the patients receiving MTB-based targeted therapy.
CONCLUSION: These data suggest that alternatives to standard therapies for recalcitrant gynecologic cancers can be found though CGP and subsequent analysis from members of an expert, multidisciplinary institutional MTB. The formulation of clinical recommendations by an MTB based on tumor genomic profiling results is a feasible option. Further research is needed to understand how this approach shapes clinical decision making.
Citation Format: Lorna Rodriguez-Rodriguez, Kim M. Hirshfield, Veronica Rojas, Siraj Ali, Robert S. DiPaola, Darlene Gibbon, Sara Isani, Aliza Leiser, Gregory M. Riedlinger, Shridar Ganesan. Delivery of point-of-care management to patients with gynecologic malignancies using comprehensive genomic profiling. [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 3183.
Abstract 3184: Genomic analyses reveal two distinct biologic entities of endometrial endometrioid carcinoma
Authors: Sugiyama Yuko , Fukui Nobuyuki , Gotoh Osamu , Hasumi Katsuhiko , Takazawa Yutaka , Noda Tetsuo , Mori Seiichi 
Published: July 2016

Abstract
Endometrial carcinoma (EC) is classified into two types: type 1 (endometrioid type) and type 2 (non-endometrioid type). Type 1 endometrioid adenocarcinoma (EA) has been generally considered a single disease entity and was developed from endometrial hyperplasia as a precursor lesion. Recently we identified two distinct subgroups in type 1 EA; groups 1 and 2 as tumors with and without endometrial hyperplasia, respectively. The purpose of this study is to identify genes involved those differentially expressed by groups 1 and 2 EA. Genomic analyses including transcriptome and exome sequencing and immunohistochemistry were performed. For the validation, these data were projected to the TCGA (The Cancer Genome Atlas Research Network) data. In the results of transcriptome, group 1 and 2 EAs identified differential regulation of multiple genes and pathways. As an example, estrogen receptor (ER) related pathways were up-regulated in group 1 EA. Immunohistochemical analyses further confirmed overexpression of ER and PgR in the protein level. In the result of exome sequencing, mutation was observed more frequently in group 2 and sixteen driver genes were more frequently mutated in group 2.
Citation Format: Yuko Sugiyama, Nobuyuki Fukui, Osamu Gotoh, Katsuhiko Hasumi, Yutaka Takazawa, Tetsuo Noda, Seiichi Mori. Genomic analyses reveal two distinct biologic entities of endometrial endometrioid 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 3184.
Abstract 3188: Targeted semiconductor sequencing of 409 cancer-related genes for somatic mutations and copy number variations in multiple myeloma
Authors: Ikeda Hiroshi , Sasaki Yasushi , Ishiguro Kazuya , Ishida Tadao , Aoki Yuka , Tokino Takashi 
Published: July 2016

Abstract
Background:
2016's NCCN guideline recommended that induction therapy used conventional chemotherapy such as proteasome inhibitors and Imids in MM. Overall survival is improving by these Novel agents. However, we don't know how to choose these new agents. In the future, we can use next generation sequencer as a tool of drug choosing system. So we reviewed newly diagnosed 11 patients with MM who had received novel agents in our institution.The comprehensive analysis of genetic alterations in tumor by next generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients.
Method:
DNA was extracted from magnetic bead-enriched bone marrow CD138-positive malignant plasma cells from 11 cases of MM, and CD138-negative cells were used as matched non-tumor cells. Forty nanograms of DNA were used for multiplex PCR amplification with an Ion Ampliseq Comprehensive Cancer Panel that offers targeted coverage of all exons in 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers. (covered regions: 95.4% of total). We sequenced 15,992 regions which obtained more than 1.5 megabases of target sequence.
Result:
Each sample underwent on average 8.3 million sequencing reads after quality filtering. The mean read depths were 539x, and &gt;95% of targeted bases were represented by at least 20 reads. The average number of non-synonymous mutations detected per patient was 5.8 (range 0-11). We also detected copy number variations in which segments of the genome can be duplicated or deleted from sequencing data. We found several genetic alterations that may have been associated with the poor prognosis and poor response to chemotherapy of MM patients. Pathway assessment has shown that somatic aberrations within MM genomes are mainly involved in several important pathways, including cell cycle regulation, RTK-MAPK-PI3K and NF-kB.
Conclusion:
We performed targeted next-generation sequencing for rapid (2 days), standardized, and cost-effective gene analysis of malignant plasma cells from patients with MM. We can use targeted next-generation sequencing as tool of drug choosing system.
Citation Format: Hiroshi Ikeda, Yasushi Sasaki, Kazuya Ishiguro, Tadao Ishida, Yuka Aoki, Takashi Tokino. Targeted semiconductor sequencing of 409 cancer-related genes for somatic mutations and copy number variations in multiple myeloma. [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 3188.
Abstract 32: Inhibition of cancer cell growth by combined treatment with lactate dehydrogenase (LDHA) inhibitors and either phenformin or inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3)
Authors: Lea Michael A. , Guzman Yolanda , desBordes. Charles 
Published: July 2016

Abstract
The tendency for enhanced glycolysis in cancer cells presents a target for chemotherapy. In previous studies we observed that proliferation of colon and bladder cancer cells can be inhibited by treatment with either phenformin or an inhibitor of PFKFB3 namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). In the present work we have examined the action of two inhibitors that are effective at lower concentrations than 3PO, namely 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP) and 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15). The LDHA inhibitors that we chose to study in increasing order of IC50s were methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2) &lt; isosafrole &lt; oxamate. A synergistic anti-cancer effect of phenformin and oxamate has been reported. In the present work with colon and bladder cancer cells, additive but not synergistic growth inhibitory effects were seen with the LDHA inhibitors of which NHI-2 was effective at the lowest concentrations. Growth inhibition with PQP and PFK15 was compared in colon (Caco-2 and HT29) and bladder cancer cells (5637, HT1376, RT4, SW780, T24, TCCSUP and UM-UC-3). Apart from RT4 cells where the effects were similar, the effects were somewhat greater with PFK15 than with PQP and for both compounds the actions were seen at lower concentrations than in previous studies with 3PO. Actions on medium acidification and glucose uptake are more readily observed in the most rapidly growing cell lines. Effects of phenformin on medium pH and glucose concentration were decreased by the PFKFB3 and LDHA inhibitors that were examined. In accord with our previous studies on inhibitors of glycolysis, the increased medium acidification and glucose uptake caused by phenformin could be blocked by combined treatment with PFKFB3 or LDHA inhibitors. At the same time additive growth inhibitory effects were observed. The results supported the concept that combined treatment with phenformin and inhibitors of glycolysis can cause additive inhibition of cell proliferation while mitigating the lactic acidosis caused by phenformin as a single agent.
Citation Format: Michael A. Lea, Yolanda Guzman, Charles desBordes. Inhibition of cancer cell growth by combined treatment with lactate dehydrogenase (LDHA) inhibitors and either phenformin or inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). [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 32.
Abstract 3202: Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity
Authors: Schirmer David , Klar Richard , Schmidt Oxana , Wohlleber Dirk , Uckert Wolfgang , Thiel Uwe , Bohne Felix , Busch Dirk H. , Krackhardt Angela M. , Burdach Stefan , Richter Günther H. 
Published: July 2016

Abstract
Background: Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology targetable tumor associated antigens (TAA) are identified and exploited for engineered T cell therapy. Here, the specific recognition and lytic potential of transgenic, allo-restricted CD8+ T cells directed against the ES-associated antigen STEAP1 was examined.
Methods: Following repetitive STEAP1130 peptide-driven stimulations with HLA-A*02:01+ dendritic cells, allo-restricted HLA-A*02:01- CD8+ T cells were sorted with HLA-A*02:01/peptide multimers and expanded by limiting dilution. After functional analysis of suitable T cell clones via ELISpot, flow cytometry and xCELLigence assay, TCR α- and β-chains were identified. They were cloned into retroviral vectors, codon optimized, transfected into HLA-A*02:01- primary T cell populations and tested again for specificity and lytic capacity in vitro and in a Rag2-/-γc-/- mouse model.
Results: Initially generated and transgenic T cells specifically recognized STEAP1130-pulsed or transfected cells in the context of HLA-A*02:01 with minimal cross-reactivity as determined by specific IFNγ release. They lysed cells and inhibited growth of HLA-A*02:01+ ES lines more effectively than HLA-A*02:01- ES lines. In vivo tumor growth was inhibited more effective with transgenic STEAP1130-specific T cells than with unspecific T cells.
Conclusion: Our results identify TCRs capable of recognizing and inhibiting growth of STEAP1 expressing HLA-A*02:01+ ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1 expressing tumors.
Citation Format: David Schirmer, Richard Klar, Oxana Schmidt, Dirk Wohlleber, Wolfgang Uckert, Uwe Thiel, Felix Bohne, Dirk H. Busch, Angela M. Krackhardt, Stefan Burdach, Günther H. Richter. Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity. [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 3202.
Abstract 3206: Programmed death receptor-1/programmed death receptor ligand-1 blockade improves priming of antitumor effector T cells after cytotoxic therapies
Authors: Takahashi Miho , Watanabe Satoshi , Sato Ko , Tanaka Tomohiro , Saida Yu , Baba Junko , Ohtsubo Aya , Sato Miyuki , Kondo Rie , Okajima Masaaki , Tanaka Junta , Kagamu Hiroshi , Yoshizawa Hirohisa , Kikuchi Toshiaki 
Published: July 2016

Abstract
Cytotoxic lymphodepletion therapies, such as chemotherapy and radiotherapy, have been established to augment antitumor immunity. Naïve T cells elicit effector-like phenotypes and functions during recovery from lymphopenia. We and others have repeatedly demonstrated that transfer of naïve T cells into lymphopenic-tumor bearing mice delayed tumor growth. This enhancement of naïve T cells is required an activation through T-cell receptor (TCR).
Programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) blockade therapy has been demonstrated to augment antitumor immunity. Previous studies have shown that PD-1/PD-L1 blockade therapy stimulates or restores the function of antitumor T cells in the effector phase. Because engagement of programmed death receptor-1 (PD-1) by ligand suppresses TCR signaling and inhibits T cell activation and function, there is a possibility that PD-1 regulates activation of T cells during recovery from lymphopenia after cytotoxic therapies.
In the current study, we transferred naïve T cells into tumor-bearing mice following whole-body irradiation for lymphodepletion. These mice were further treated with anti-PD-1 antibodies. PD-1/PD-L1 blockade therapy after lymphodepletion significantly suppressed tumor progression. Next, we tested several kinds of cytotoxic agents to induce lymphopenia in mice. We found that the kind of cytotoxic agents affected the augmentation of antitumor efficacies of PD-1/PD-L1 blockade. Analyses of tumor-draining lymph-nodes (TDLNs) revealed that the number of tumor-specific effector T cells was significantly increased in mice treated with anti-PD-1 antibodies. By contrast, the number of effector T cells in spleens was not increased by PD-1/PD-L1 blockade therapy. These results indicate that PD-1 regulates a priming of antitumor effector T cells in TDLNs after cytotoxic lymphodepletion therapies. PD-1/PD-L1 blockade therapy is able to enhance antitumor T cell responses not only in the effector phase but also in the priming phase.
Citation Format: Miho Takahashi, Satoshi Watanabe, Ko Sato, Tomohiro Tanaka, Yu Saida, Junko Baba, Aya Ohtsubo, Miyuki Sato, Rie Kondo, Masaaki Okajima, Junta Tanaka, Hiroshi Kagamu, Hirohisa Yoshizawa, Toshiaki Kikuchi. Programmed death receptor-1/programmed death receptor ligand-1 blockade improves priming of antitumor effector T cells after cytotoxic therapies. [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 3206.