tbuckley/cabot-search huggingface dataset:
Abstract 751: Characterization of STAT3 activation in human prostate cancer
Authors: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Naomi Ando, Kazuko Sakai, Koichi Sugimoto, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2017)

Abstract Signal transducers and activators of transcription (STATs) were initially associated with cytokine signal transduction pathways but are now also recognized as key modulators of key survival processes in in various cancers. Activation of STAT3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/ STAT3 signaling pathway. Interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors. Activated IL-6 has also been shown to be elevated in the sera from patients with metastatic prostate cancer, and persistent activation of STAT3 is a common feature. To better characterize the potential role of JAK/STAT3 as a therapeutic target for advanced prostate cancer, we examined expression patterns of activated STAT3 in 111 cases of localized prostate cancer from patients who underwent radical prostatectomy. Association studies were conducted with clinicopathological characteristics and biochemical recurrence. We also analyzed the expression of IL-6/KAK/STAT3 genes from RNA-sequencing data form the Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data set and its association to long-term outcomes. Immunohistochemical analysis revealed that 11.7%, 42.3% and 45.9% of patients had high, moderate or low/negative expression of phosphorylated-STAT3 (Tyr705). Cancerous glands tended to have higher STAT3 expression compared to paired normal adjacent tissue, P=0.088. No correlations were observed between STAT3 expression and clinicopathological parameters. Patients with moderate-high p-STAT3 expression tended to experience shorter times to biochemical recurrence (median time, 15 months) compared to patients with low/negative STAT3 activity, (median time to recurrence not reached, P=0.064). Cluster analysis suggested a trend for decreased disease-free survival for patients with high IL-6/KAK/STAT3 gene expression signature. Our data suggests an association between STAT3 signaling and prostate cancer recurrence and provides clinical evidence to support JAK/STAT3 as a potential therapeutic target for patients with advanced prostate cancer. Citation Format: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Naomi Ando, Kazuko Sakai, Koichi Sugimoto, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Characterization of STAT3 activation in human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 751. doi:10.1158/1538-7445.AM2017-751
Gastric peroral endoscopic myotomy for gastroparesis, after botulinum toxin injection
Authors: Monica Saumoy, Najib Nassani, Joaquin Ortiz, Viviana Parra, Amy Tyberg, Michel Kahaleh
Journal: Endoscopy (2017)

A 45-year-old woman had refractory Epstein–Barr virus-associated gastroparesis. Despite lifestyle modification and medication therapy, the patient had recurrent hospitalizations for gastroparesis. Management also included four previous sessions of endoscopic botulinum toxin injection. Despite transient symptomatic improvement, the patient’s symptoms had recurred. She was not a candidate for surgical implantation of a gastric pacemaker, so she was referred for gastric peroral endoscopic myotomy (G-POEM).
Abstract 2165: Deletion of survivin sensitize human hepatocellular carcinoma cells to low dose of doxorubicin and induce apoptosis
Authors: Joseph George, Nobuhiko Hayashi, Takashi Saito, Kazuaki Ozaki, Nobuyuki Toshikuni, Mutsumi Tsuchishima, Mikihiro Tsutsumi
Journal: Cancer Research (2017)

Abstract Background and Aims: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and patients with advanced HCC face a dismal prognosis due to lack of effective therapy. Survivin, a member of the family of inhibitor of apoptosis proteins, is highly upregulated in HCC as well as in experimentally induced intrahepatic tumors. Doxorubicin, the only known chemotherapeutic agent for HCC, is cardiotoxic in addition to several well known side effects. Methods: Survivin gene deletion was established in HepG2, Hep3B, and PLC/PRF/5 human HCC cells using CRISPR/Cas9 system. All the three HCC cells in culture were treated with doxorubicin at various concentrations before and after survivin gene knockout upto 72 hr. TUNEL assay and FACS analysis were performed to demonstrate the induction of apoptosis after doxorubicin treatment. Western blotting was carried out for cleaved fragments of caspase-9 and caspase-3 as well as major apoptotic executioner molecules. Results: Cell viability studies depicted around 20% cell death at 24 h, 50% at 48 h, and 80% at 72 h after treatment with doxorubicin at 1 µM (final concentration in the media). Among the three cell lines studied, Hep3B cells were more susceptible to doxorubicin compared to HepG2 and PLC/PRF/5 cells. After deletion of survivin gene, the dosage of doxorubicin could reduce to five fold (200 nM, final concentration in the media) with the same cytotoxic effect before the knockout of survivin gene. HCC cells treated with reduced doses of doxorubicin depicted induction of apoptosis that was proved with TUNEL assay and FACS analysis as wells as increased levels of cleaved caspases and major apoptotic executioner molecules. Conclusions: Our studies demonstrated that blocking of survivin molecule with effective methods would be a successful approach to treat primary hepatic tumors with low and safe doses of doxorubicin and other anticancer agents. Note: This abstract was not presented at the meeting. Citation Format: Joseph George, Nobuhiko Hayashi, Takashi Saito, Kazuaki Ozaki, Nobuyuki Toshikuni, Mutsumi Tsuchishima, Mikihiro Tsutsumi. Deletion of survivin sensitize human hepatocellular carcinoma cells to low dose of doxorubicin and induce apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2165. doi:10.1158/1538-7445.AM2017-2165
Abstract 1804: Identification of novel NM23 inhibitors as potential anti-angiogenic agents
Authors: Senny Nordmeier, Jon Evasovic, Suzann Duan, Ryan Wuebbles, Dean J. Burkin, Iain L. Buxton
Journal: Cancer Research (2017)

Abstract Exogenous nucleoside diphosphate kinase (eNDPK or NM23) has been shown to promote endothelial cell proliferation and migration and tumor-mediated angiogenesis. This is facilitated by its transphosphorylase activity, in which a gamma terminal phosphate group from a triphosphate nucleoside is transferred to a diphosphate nucleoside, resulting in elevated ATP levels. Increased levels of ATP in the tumor microenvironment can activate purinergic receptors (P2Y1) on adjacent endothelial cells to promote angiogenesis, independent of VEGF stimulation. Triple negative human breast cancer (MDA-MB-231) cells have been shown to elaborate exosomes that contain NM23. These exosomes have implications in targeting specific tissues/cells to promote angiogenesis and tumorigenesis. Our lab has shown that inhibition of eNDPK and the P2Y1 receptor reduces endothelial cell tubulogenesis (Rumjahn, et al., 2007) and breast cancer metastasis (Yokdang, et al., 2015). Therefore, targeted inhibition of eNDPK may have implications as a treatment for early tumor-mediated angiogenesis. For this study, we utilized a transphosphorylation activity assay to perform a drug screen on compounds from the Prestwick chemical library. Recombinant NDPK-B was added to FDA-approved drug compounds along with ADP and UTP substrates. Subsequent ATP generation was detected with a luciferase luciferin reaction. Decreased luminescence signal/inhibition of NDPK was compared to ellagic acid control, a known inhibitor of NDPK. From our initial screen, we identified eight potential compounds that inhibited NDPK at comparable levels to ellagic acid. These eight compounds were further examined to determine the dose response curve. We found that Chicago Sky Blue 6B inhibited NDPK at an IC50 value of 1.88µM. The results from this study demonstrate a drug screening method to discover alternative small molecule inhibitors of NDPK as a potential treatment of angiogenesis and breast cancer metastasis. Citation Format: Senny Nordmeier, Jon Evasovic, Suzann Duan, Ryan Wuebbles, Dean J. Burkin, Iain L. Buxton. Identification of novel NM23 inhibitors as potential anti-angiogenic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1804. doi:10.1158/1538-7445.AM2017-1804
Abstract 4863: Aurora-A kinase: a nuclear driver of metastasis
Authors: Kristina Marinak, Anna Kiseleva, Yuriy Loskutov, Matthew Smolkin, Elena Pugacheva
Journal: Cancer Research (2017)

Abstract Aurora-A Kinase (AURKA) is a serine/threonine kinase that is critical for mitosis. AURKA is overexpressed in 96% of human cancers, including breast cancer. It has been previously shown that AURKA localizes to the nucleus in breast cancer metastases and especially in metastases of Triple Negative Breast Cancer (TNBC). Our objective is to define the role of nuclear AURKA in breast cancer metastasis in TNBC. Here we report that TNBC cells vary in amount of nuclear AURKA and this potentially correlates with their metastatic capabilities. Based on our preliminary findings we hypothesized that nuclear AURKA promotes cell survival and resistance to apoptosis in the metastatic niche. To test this hypothesis we created TNBC cell lines with CRISPR/Cas9 based deletion of endogenous AURKA. We also constructed exogenous AURKA specifically targeted to the nucleus by addition of a nuclear localization signal (NLS) or cytoplasm via addition of a nuclear exclusion signal (NES), respectively. To allow for in vitro and in vivo rescue experiments with exogenous NES or NLS AURKA in sgAURKA expressing TNBC cells, we introduced several silent mutations to avoid sgAURKA targeting. In our pilot orthotopic xenograft study with MDA-MB-231-luc2-Cas9 (TNBC) cells expressing sgAURKA with WT AURKA, NLS-AURKA or AURKA-NES shows a trend of increased metastatic colonization in the AURKA-NLS group. Overall, our results indicate that the amount of nuclear AURKA is increased in metastatic breast cancer cell lines and metastases of TNBC, but the mechanism of this translocation is currently unknown. Elucidation of this mechanism is critical for development of new therapeutical strategies for control and eradication of metastatic disease. Citation Format: Kristina Marinak, Anna Kiseleva, Yuriy Loskutov, Matthew Smolkin, Elena Pugacheva. Aurora-A kinase: a nuclear driver of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4863. doi:10.1158/1538-7445.AM2017-4863
Abstract 4657: LOX and ZFPM2 as novel diagnostic biomarkers for malignant pleural mesothelioma
Authors: Minkyu Kim, Hyun-Won Kim, Soon-Hee Jung, Sung Soo Oh, Yangsik Jeong, Jong-Whan Choi
Journal: Cancer Research (2017)

Abstract Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer being developed on outlayer of lung tissues and caused by mostly occupational exposure to asbestos. Poor prognosis needs to develop therapeutic drug as well as early diagnostic biomarker. Currently, mesothelin (MSLN), osteopontin (OPN), and fibulin 3 (FBLN3) have been reported as potential diagnostic biomarkers for MPM. In this study, we first performed bioinformatics analysis for public database to find diagnostic biomarkers for MPM. From the analysis using Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO) databases, included were 7 genes involving LOX, LOXL1, LOXL2, ZFPM2, THBS2, SULF1, CDH11 identified as potential diagnostic biomarkers. These genes showed a similar diagnostic ability to FBLN3 or MSLN as MPM biomarker candidates. Further molecular approach using quantitative real-time polymerase chain reaction (QPCR) confirmed the higher mRNA expression of these candidates in MPM cell lines and patient samples. Moreover, two particular genes, LOX and ZFPM, showed MPM specific patterns of mRNA expression that were further confirmed in protein level by western blot assay. Together with biological approach, biostatistical analysis of receiver operating characteristic (ROC) analysis using the GEO database revealed significantly higher diagnostic potential of LOX and ZFPM2 genes compared to the FBLN3, one of the best diagnostic biomarkers currently reported. From this study, we believe these genes together with FBLN3 and MSLN would become novel potential biomarker candidates for MPM diagnosis. Citation Format: Minkyu Kim, Hyun-Won Kim, Soon-Hee Jung, Sung Soo Oh, Yangsik Jeong, Jong-Whan Choi. LOX and ZFPM2 as novel diagnostic biomarkers for malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4657. doi:10.1158/1538-7445.AM2017-4657
Abstract 834: Formation of DNA double-strand breaks in colon tumors after targeted alpha therapy with 211At-mAb
Authors: Sophie E. Eriksson, Erika Elgström, Sture Lindegren, Tom Bäck
Journal: Cancer Research (2017)

Abstract Introduction: Targeted alpha therapy has shown promising results in preclinical and clinical studies. Alpha particle irradiation gives a high fraction of DNA double-strand breaks (DSB), as shown in vitro, resulting in a high probability of cell death. We have previously examined the therapeutic effects of 211At on solid colon carcinoma tumors (diameter approximately 1 cm), with tolerable activities (5 MBq/animals) resulting in non-palpable tumors within one week p.i. The aim of the present study was to investigate the formation of DNA DSB during tumor regression after radioimmunotherapy with 211At-mAb in a syngeneic rat colon carcinoma model. Methods: 18 rats bearing solid colon tumors (1 cm in diameter) between peritoneum and the abdominal muscle were injected intravenously with 5 MBq/animal 211At-BR96. Tumors were excised and paraffin-embedded after 10 min, 2 h, 8 h, 18 h, 24 h, and 48 h p.i. (3 tumors per time point). 53BP1 was stained by immunohistochemistry and used as a marker for DNA DSB. Untreated tumors were used as controls (n=9). DNA DSB were counted in central and peripheral tumor areas selected at random. Results: A few DNA DSB were detected in untreated tumors. Already 10 min p.i., the number of DNA DSB had increased slightly in peripheral tumor tissue. The number peaked 8 h p.i., when the number of DNA DSB had increased 50 times in the tumor periphery and 24 times in the tumor center. The number of DNA DSB then declined, but the difference between center and periphery remained, as expected considering the intratumoral distribution of radioimmunoconjugate. This correlates with the 211At half-life of 7.2 h. Conclusion: DNA DSB are formed early after injection of 211At-mAb and follows the intratumoral distribution of mAbs. Citation Format: Sophie E. Eriksson, Erika Elgström, Sture Lindegren, Tom Bäck. Formation of DNA double-strand breaks in colon tumors after targeted alpha therapy with 211At-mAb [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 834. doi:10.1158/1538-7445.AM2017-834
Abstract 1313: Characterization of germline susceptibility to male breast cancer
Authors: Eleni Perrakis, Sarah Maguire, Katarzyna Tomczyk, Anthony Swerdlow, Nick Orr
Journal: Cancer Research (2017)

Abstract Male breast cancer (MBC) accounts for approximately 1% of all breast cancer cases. Family history is an established risk factor for MBC and 10% of cases have germline BRCA2 mutations. We recently demonstrated that common germline polymorphisms contribute to MBC predisposition and that there is overlap between genetic susceptibility loci for MBC and female breast cancer (FBC). Here we report a comprehensive evaluation of all 107 known FBC predisposition loci in an association analysis of 1,032 MBC cases and 2,795 population matched controls. A total of 21 FBC predisposition single nucleotide polymorphisms (SNPs) showed evidence of association with risk of MBC. For approximately a third of these SNPs, the risk estimates were significantly larger in MBC than FBC. The magnitude of effects observed suggest that common susceptibility variants may be of value for risk stratification in men who have a high absolute risk of breast cancer such as BRCA2 mutation carriers. Although our data suggests that MBC predisposition shares many features in common with FBC, there are striking differences. Surprisingly, given the predominance of hormone receptor positive tumors in MBC, we observed no evidence of association between SNPs at FGFR2 and MBC risk suggesting that the estrogen receptor status of MBC tumors does not explain the observed SNP associations. In summary, the data presented in this abstract significantly advance our understanding of genetic factors that contribute to MBC predisposition and further underscore the growing consensus that male breast cancer is not simply analogous to hormone receptor positive female breast cancer. Citation Format: Eleni Perrakis, Sarah Maguire, Katarzyna Tomczyk, Anthony Swerdlow, Nick Orr. Characterization of germline susceptibility to male breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1313. doi:10.1158/1538-7445.AM2017-1313
Abstract 4796: Chronic exposure to nitric oxide drives human breast epithelial cells to malignant-like features
Authors: Yuk Sing Robert Cheng, Stephen K. Anderson, Daniel W. McVicar, Daivd A. Wink, Lisa A. Ridnour
Journal: Cancer Research (2017)

Abstract The small endogenous signaling molecule, nitric oxide (NO) influences numerous physiological conditions including cancers. We have previously shown that different steady state NO levels activate pro-tumor signaling cascades. In this study, we explored the effect(s) of chronic NO exposure on breast epithelial cells as defined by changes in genomic stability, RNA and protein expression, and mostly importantly altered cell phenotype. Human breast epithelial cells (MCF10A) were chronically exposed to various concentrations of the NO donor DETA/NO for a three weeks. Distinct patterns of genomic alteration in the target genes (TP53, KRAS &amp; PIK3CA) of exposed cells as compared to the background mutations were observed. In addition, quantitative real time PCR revealed increased expression of cancer stem cell (CSC) markers including NANOG, CD44, CXCR4 and OCT4 at 300 μM DETA/NO exposure. While altered cell morphology was observed in cells chronically exposed to 300-500 μM DETA/NO, increased motility occurred in cells cultured in 100 μM DETA/NO. Strikingly, these 100 μM NO-exposed cells grew in serum-free media; selected clonal populations as well as pooled cells formed colonies in soft agar that were disorganized and resembled cancer-like-clusters. In conclusion, these results implicate a precise tuning of microenvironmental NO levels that shift non-transformed breast epithelial cells toward cancerous phenotypes. The elucidation of underlying mechanisms may lend a new perspective regarding therapeutic approaches that redirect the cellular response(s) of tumor cells. Citation Format: Yuk Sing Robert Cheng, Stephen K. Anderson, Daniel W. McVicar, Daivd A. Wink, Lisa A. Ridnour. Chronic exposure to nitric oxide drives human breast epithelial cells to malignant-like features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4796. doi:10.1158/1538-7445.AM2017-4796
Abstract 947: CXCR4 in combination with immune check point inhibition in ovarian cancer mouse model demonstrates potential for novel therapeutic strategies
Authors: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros
Journal: Cancer Research (2017)

Abstract Chemokine CXCL12 and its receptor CXCR4 are the most highly expressed chemokine axis in serous ovarian cancer. CXCR4 promotes tumor growth, angiogenesis, and metastasis. High CXCR4 expression is associated with poor survival, making it an attractive therapeutic target. The objective of this study was to establish an immune competent murine ovarian cancer model with high CXCR4 expression and to test single agent CXCR4 blockade and combination therapy to optimize emerging treatment strategies for future clinical trials. CXCR4 expression was evaluated by flow cytometry in ID8, ID8-VEGF, IE9-MP1, BR5, BR5-Akt, BR5-C2k, and BR5-Kras mouse ovarian cancer cell lines as well as IE9-MP1 tumor samples. Subsequently an exploratory study was undertaken utilizing the ID8 immune competent mouse model to assess the efficacy of AMD3100, the only commercially available CXCR4 inhibitor, alone and in combination with bevacizumab and anti-PD-1. Immune analysis of circulating lymphocytes by flow cytometry was performed during treatment to monitor changes of immune cell subsets. Surface expression of CXCR4 receptor was minimal in ID8 (1.6%), ID8-VEGF (0.9%), IE9-MP1 (1.8%), BR5 (0.9%), BR5-Akt (1.2%), BR5-C2k (2.3%), and BR5-Kras (1.1%), however intracellular staining revealed widespread CXCR4 expression in ID8 (99.6%), ID8-VEGF (99.7%) BR5 (96.7%), BR5-Akt (94.3%), BR5-C2k (98.2%), and BR5-Kras (98.7%) cell lines. Using the ID8 intraperitoneal ovarian cancer mouse model in C57BL/6J mice, treatment with immunotherapy significantly increased cell surface expression of CXCR4 from 2% in the control group to 79.6-91.8% in the treatment group. Treatment with AMD3100 as a single agent showed no improvement in survival over control. However, AMD3100 in combination with anti-PD-1 therapy significantly improved survival. The addition of bevacizumab demonstrated no further survival benefit and bevacizumab as a single agent showed no improvement in survival over control, either alone or in combination with anti-PD-1. Analysis of circulating lymphocytes revealed a trend toward higher CD4 to CD8 ratio in mice who were treated with anti-PD1 therapy. Targeting the CXCL12-CXCR4 axis in combination with other immunotherapies such as immune checkpoint inhibitors is a novel therapeutic strategy which may provide benefit over single-agent immunotherapy and warrant investigation in a clinical trial. Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. CXCR4 in combination with immune check point inhibition in ovarian cancer mouse model demonstrates potential for novel therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 947. doi:10.1158/1538-7445.AM2017-947