bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1706: Whole exome sequencing of pre and post treatment diffuse large B cell lymphoma reveals the mutation spectrum of the relapse/refractory patient population
Authors: Greenawalt Danielle , Byth Kate , Lai Zhongwu , Johnson Justin , Ahmed Ambar , Dougherty Brian , Thress Kenneth , Zinda Michael , Liang Winnie S. , Carpten John , Fawell Stephen , Barrett J. Carl 
Published: August 2015

Abstract
Our current understanding of the mutation spectrum of relapse/refractory patients is limited. Several published studies describing the mutational landscape of Diffuse Large B cell Lymphoma (DLBCL) have focused, by design, on diagnostic (pre-treatment) biopsies alone, while re-biopsy of patients who are refractory to first line therapy or who relapse on treatment is not standard of care in DLBCL. We have performed whole exome sequencing on 47 post treatment DLBCL core needle biopsies, 8 with matched diagnostic biopsies. Samples were obtained during a phase II trial prior to the start of treatment with the BCR targeted agent fostamatinib (1,2). Patients had progressed following therapy with an anthracycline-based regimen such as R-CHOP and had a median of 3 prior therapies (range 1-8). We compared the whole exome somatic variant and copy number calls from the post treatment and matched pairs to 2 cohorts of primary DLBCL (n = 112) analyzed with the same mutation caller (3,4). The average mutation rate between the pre and post treatment samples (n = 250, 282 respectively) and the paired diagnostic and post treatment biopsies were similar. However, we found that the mutation spectrum between the paired biopsies differed. Known DLBCL hotspot mutations such as MYD88 L265P remained consistent between pre and post treatment biopsies, however novel mutations in known DLBCL targets were found to emerge in the post treatment biopsies.
1. Veldman-Jones, M. et al. Reproducible, quantitative and flexible molecular sub-typing of clinical DLBCL samples using the NanoString nCounter system. Clin Cancer Res (2014)
2. Flinn I, B.N., Blum KA, et al. A Phase II Trial to Evaluate the Efficacy of Fostamatinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). American Society of Hematology (San Francisco, 2014).
3. Zhang, J. et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 110, 1398-403 (2013).
4. Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43, 830-7 (2011).
Citation Format: Danielle Greenawalt, Kate Byth, Zhongwu Lai, Justin Johnson, Ambar Ahmed, Brian Dougherty, Kenneth Thress, Michael Zinda, Winnie S. Liang, John Carpten, Stephen Fawell, J. Carl Barrett. Whole exome sequencing of pre and post treatment diffuse large B cell lymphoma reveals the mutation spectrum of the relapse/refractory patient population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1706. doi:10.1158/1538-7445.AM2015-1706
Abstract 1720: HO-3867, a selective inhibitor of stat3, suppress ovarian tumor growth and metastasis in human tissue culture and in an orthotopic mouse model
Authors: Naidu Shan , Saini Uksha , ElNaggar Adam C. , Bid Hemant K. , Wanner Ross , Bixel Kristin , Suarez Adrian A. , Bolyard Chelsea , Kaur Balveen , Goodfellow Paul J. , Kuppusamy Periannan , Cohn David , Selvendiran Karuppaiyah 
Published: August 2015

Abstract
The lack of an efficient pre-clinical model predicting a drug's clinical response before it enters into clinical trials is a major reason behind the limited success or complete failure of most of the traditional anti-cancer compounds. In this study, we evaluate our novel, safe and selective STAT3 inhibitor HO-3867 for its anti-cancer efficacy/bio-availability using a pre-clinical relevant, orthotopic ovarian tumor model and ex-vivo human tumor tissue culture. Treatment with HO-3867 (100PPM) significantly suppressed ovarian tumor growth and metastasis when compared to the standard Cisplatin (4mg/kg). A substantial amount of HO-3867 was detected in the ovarian tumor tissues and quantified using EPR spectroscopy. Markers specific to cell proliferation (Ki-67, Cyclin D1), angiogenesis (VEGF and Kinase array) and apoptosis (caspase-3 activity) were significantly altered by treatment with HO-3867. In vivo histopathological evaluation of internal organs collected from treated tumor mice revealed no evidence of toxicity specific to HO-3867. Normal and malignant tissues were collected and TUNEL/8-OHdG staining revealed selective induction of apoptosis limited to neoplastic cells and concomitant increase in reactive oxygen species within the orthotopic tumor. Suppression of STAT3 and its downstream target proteins (cell proliferative, anti-apoptotic and angiogenic) was confirmed with proteomic array. HO-3867 treated samples had significantly reduced vessel formation (∼4 times) as compared to the untreated control as is evident by in vivo Matrigel assay. HO-3867 was also found to have cytotoxic effects in ex vivo culture of freshly collected human tumor samples, including patients with chemotherapy resistant form of the disease. Overall, these results highlight the clinical anti-cancer potential of HO-3867 using a relevant preclinical orthotopic ovarian tumor model, and provide a rationale for the inclusion of ex vivo patient tumor slice culture in oncologic drug development processes.
Citation Format: Shan Naidu, Uksha Saini, Adam C. ElNaggar, Hemant K. Bid, Ross Wanner, Kristin Bixel, Adrian A. Suarez, Chelsea Bolyard, Balveen Kaur, Paul J. Goodfellow, Periannan Kuppusamy, David Cohn, Karuppaiyah Selvendiran. HO-3867, a selective inhibitor of stat3, suppress ovarian tumor growth and metastasis in human tissue culture and in an orthotopic mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1720. doi:10.1158/1538-7445.AM2015-1720
Abstract 173: SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells
Authors: Koumangoye Rainelli B. , Andl Thomas , Taubenslag Kenneth J. , Zilberman Steven T. , Taylor Chase , Andl Claudia D. 
Published: August 2015

Abstract
Tumor metastasis is responsible for 90% of cancer-related deaths. A strong link between microRNA dysregulation and human cancers has recently been established. However, the molecular mechanisms through which microRNAs regulate metastasis and cancer progression remain unclear. We analyzed the reciprocal expression regulation of miR-31 and SOX4 in esophageal squamous and adenocarcinoma cell lines by qRT-PCR and Western Blotting using overexpression and shRNA knock-down approaches. Here we report that SOX4 promotes esophageal tumor cell proliferation and invasion by silencing miR-31 via activation and stabilization of a co-repressor complex with EZH2 and HDAC3. We demonstrate that miR-31 is significantly decreased in invasive esophageal cancer cells compared to non-invasive cell lines, while upregulation of miR-31 inhibits growth, migration and invasion of esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) cell lines. miR-31, in turn, targets SOX4 for degradation by directly binding to its 3′-UTR. Additionally, miR-31 regulates EZH2 and HDAC3 indirectly. SOX4, EZH2 and HDAC3 levels inversely correlate with miR-31 expression in ESCC cell lines. Ectopic expression of miR-31 in ESCC and EAC cell lines leads to down regulation of SOX4, EZH2 and HDAC3. Conversely, pharmacologic and genetic inhibition of SOX4 and EZH2 restore miR-31 expression. We show that SOX4, EZH2 and HDAC3 form a co-repressor complex that binds to the miR-31 promoter, repressing miR-31 through an epigenetic mark by H3K27me3 and by histone acetylation. Clinically, when compared to normal adjacent tissues, esophageal tumor samples show upregulation of SOX4, EZH2, and HDAC3, and EZH2 expression is significantly increased in metastatic ESCC tissues. Thus, we identified a novel molecular mechanism by which the SOX4, EZH2 and miR-31 circuit promotes tumor progression and potential therapeutic targets for invasive esophageal carcinomas.
Citation Format: Rainelli B. Koumangoye, Thomas Andl, Kenneth J. Taubenslag, Steven T. Zilberman, Chase Taylor, Claudia D. Andl. SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 173. doi:10.1158/1538-7445.AM2015-173
Abstract 1741: GRP78 / BiP / HSPA5 expression and those of other chaperone proteins is rapidly degraded by OSU-03012 and Viagra exposure: Implications for anti-cancer and anti-pathogen therapies
Authors: Booth Laurence A. , Roberts Jane L. , Dent Paul 
Published: August 2015

Abstract
We examined the interaction between the non-coxib OSU-03012 with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone GRP78/BiP/HSPA5 in the response of cells. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill tumor cells including stem-like and anoikis resistant cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of growth factor receptors and plasma membrane drug efflux pumps; and caused a more rapid degradation of GRP78 and of other important chaperone proteins e.g. HSP27, HSP40, HSP60, HSP70 and HSP90. Decreased expression of receptors and pumps was dependent upon enhanced PERK-eIF2 signaling and blocked by GRP78 over-expression. The combination of OSU-03012/sildenafil synergized with sorafenib to kill tumor cells. GRP78 is also a protein required for human virus reproduction. Pre-treatment of mammalian cells with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Cytomegalovirus and Influenza viruses. OSU-03012/sildenafil decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola / Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Bacteria express a GRP78 homologue and phosphodiesterases, and treatment of multi-antibiotic resistant E. coli and N. gonorrhoeae with OSU-03012/PDE5 inhibitor combinations was bactericidal and restored antibiotic sensitivity. Thus modulation of GRP78 function may be of therapeutic use in multiple human pathologies.
Citation Format: Laurence A. Booth, Jane L. Roberts, Paul Dent. GRP78 / BiP / HSPA5 expression and those of other chaperone proteins is rapidly degraded by OSU-03012 and Viagra exposure: Implications for anti-cancer and anti-pathogen therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1741. doi:10.1158/1538-7445.AM2015-1741
Abstract 1743: Pharmacological sequestration of Skp1 causes degradation of oncogenic E3 ligases and mitotic blockade
Authors: Zhou Guangbiao , Liu Yong-Qiang , Liu Jinsong 
Published: August 2015

Abstract
Skp1 is an essential adaptor protein of the Skp1-Cul1-F-box protein complex and is able to stabilize the conformation of some ubiquitin E3 ligases. However, the role Skp1 plays during tumorigenesis remains unclear and Skp1-targeting agent is lacking. Here we showed that Skp1 was overexpressed in 33/56 (58.9%) non-small cell lung cancers, and elevated Skp1 was associated with poor prognosis. By structure-based high-throughput virtual screening, we found some Skp1-targeting compounds including 6-O-angeloylplenolin (6-OAP). 6-OAP could bind to Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and proteolysis of oncogenic E3 ligases NIPA, Skp2, and β-TRCP. Consequently, substrates of these E3 ligases Cyclin B1, P27 and E-Cadherin accumulated within the cells and caused prometaphase arrest. 6-OAP exhibited potent anti-lung cancer activity in two murine models and showed low adverse effect. These results indicate that Skp1 is critical to lung cancer pathogenesis, and targeting Skp1 can inactivate crucial oncogenic E3 ligases and exhibits significant therapeutic potentials.
Citation Format: Guangbiao Zhou, Yong-Qiang Liu, Jinsong Liu. Pharmacological sequestration of Skp1 causes degradation of oncogenic E3 ligases and mitotic blockade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1743. doi:10.1158/1538-7445.AM2015-1743
Abstract 1745: NPY1 receptor specific peptide-drug-conjugates as novel treatment for metastatic breast cancer
Authors: Weber Lutz , Rennert Robert 
Published: August 2015

Abstract
The NPY1 receptor is a known marker for breast cancer that was characterized first at the university hospital Bern by the group of Reubi. In healthy breast tissue the NPY2 receptor (NPY2R) can be found, expression of which is switched to the NPY1R in tumor tissues (Reubi et al., Cancer Res. 2001, 61, 4636-4641). Particularly high NPY1R densities were also found in tumor biopsies of patients suffering from Ewing's sarcoma, which is a rare, difficult to treat juvenile bone cancer (Körner et al., Clin. Cancer Res. 2008, 14, 5043-5049.). Our own results verify these literature reports, shown on a panel of patient biopsies where nearly 50% of the tumors strongly overexpress the NPY1R, whereas NPY2R could not be detected.
OntoChem has developed peptide-drug-conjugates (“CytoPep”) that are selective agonists of the NPY1 receptor. As drugs we have used tubulin binding cytolysins and maytansines. CytoPep shall be developed as novel approach to treat Ewing's sarcoma and NPY1R expressing breast cancer.
We will present data on in vitro and in vivo pharmacology of these PDCs. IN particular efficacy is directly correlated with NPY1R expression levels in cells. We will also demonstrate internalization studies, showing a fast and selective internalization into NPY1R expressing cells. These in vitro data will be compared with corresponding data from ADCs such as for example trastuzumab emtansine, that show a considerably slower internalization and efficacy.
Citation Format: Lutz Weber, Robert Rennert. NPY1 receptor specific peptide-drug-conjugates as novel treatment for metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1745. doi:10.1158/1538-7445.AM2015-1745
Abstract 1753: XIAP maintains the characteristics of cancer stem cells and is a therapeutic target in nasopharyngeal carcinoma
Authors: ji jiao , Deng Rong , Chen Wen-Dan , Feng Gong-Kan , Zhu Xiao-Feng , Yang Da-Jun 
Published: August 2015

Abstract
Nasopharyngeal carcinoma (NPC) is a common malignancy in South China. Cancer stem cells (CSCs) are thought as the key players in the resistance to chemo- or radio-therapy and are response for tumor recurrence and metastasis, while their ability to escape from the apoptosis pathway may render them the resistant property to the therapies. We show that XIAP is overexpressed in the NPC cell line S18, which have the higher SP populations and CD44+ populations and the stronger abilities of sphere-formation and metastasis. Importantly, XIAP knockdown decreases SP and CD44+ populations, prevents sphere-formation and reduces the ability of invasion and migration. What more, loss of XIAP enhances the sensitivity of cells to conventional chemotherapy drugs CDDP and 5-FU. The primary xenograft tumor formation in vivo found there is a dramatic reduction in tumor formation in the XIAP KD group. They all indicate that XIAP plays an important role in nasopharyngeal cancer stem cell. Further studies show that XIAP limits MAPK signaling and thereby restricts differentiation and maintains the characteristics of cancer stem cells. We designed and synthesized a novel Smac mimetic compound APG-1387 that promotes the rapid degradation of cIAP1/2 and XIAP, and it exerts an antitumor effect on nasopharyngeal carcinoma cancer stem cells. Further studies show that APG-1387 enhances the chemosensitivity and promotes apoptosis in combination with CDDP and 5-FU of NPC in vitro and vivo.
Citation Format: jiao ji, Rong Deng, Wen-Dan Chen, Gong-Kan Feng, Xiao-Feng Zhu, Da-Jun Yang. XIAP maintains the characteristics of cancer stem cells and is a therapeutic target in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2015-1753
Abstract 1769: Rottlerin induces ER stress-mediated cell death in pancreatic stellate cells
Authors: Su Hsin-Yuan , Waldron Richard , Gong Raymond , Pandol Stephen , Lugea Aurelia 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate under 5%. Whereas activated pancreatic stellate cells (PaSC) are important players in PDAC stroma, simultaneously targeting both cancer and stromal cells can be beneficial for cancer therapy. We previously reported that the phytochemical rottlerin dose-dependently reduces PaSC viability through dysregulation of autophagy and induction of apoptosis, and attenuates tumor progression in PDAC experimental models. Interestingly, both rottlerin and metformin have been shown to affect mitochondrial function, and metformin has been demonstrated to induce AMPK-dependent, CHOP-mediated cell death. Here we further studied the mechanisms underlying cell death and autophagy in rottlerin-treated mouse PaSC. Rottlerin rapidly depolarized mitochondrial membrane, increased oxygen consumption and decreased cellular ATP levels and the expression of the mitochondrial transmembrane protein TOM20, suggesting mitochondrial damage. Rottlerin dysregulated autophagy as indicated by rapid and prolonged increasing in LC3I-LC3II conversion and p62/SQSTM1 accumulation. However, rottlerin-induced LC3II did not further change in the presence of inhibitors of autophagic flux, suggesting that rottlerin blocks autophagy progression in PaSC. In addition, rottlerin induced marked AMPK activation and inhibited mTOR signaling. In contrast to metformin, AMPKα1/2 knockdown had no effect on rottlerin-induced inhibition of mTOR signaling and cell viability. Furthermore, rottlerin induced ER stress as manifested by persistent activation of the PERK pathway and upregulation of proapoptotic transcription factor CHOP. Importantly, rottlerin-induced apoptosis was greatly reduced in PaSC isolated from CHOP null mice. In summary, these data indicate that rottlerin reduces PaSC viability through impairing mitochondrial function, inhibiting mTOR signaling and inducing prolonged ER stress. Specifically, CHOP induction plays an important role in determining cell-fate in mitochondria-targeting agents, such as rottlerin and metformin.
Citation Format: Hsin-Yuan Su, Richard Waldron, Raymond Gong, Stephen Pandol, Aurelia Lugea. Rottlerin induces ER stress-mediated cell death in pancreatic stellate cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1769. doi:10.1158/1538-7445.AM2015-1769
Abstract 1770: A role of nicotinamide phosphoribosyltransferase in growth of KRAS mutant non-small cell lung cancer
Authors: Okumura Shunsuke , Sasaki Takaaki , Ohsaki Yoshinobu 
Published: August 2015

Abstract
Background:
KRAS mutations are frequently found in non-small cell lung cancer (NSCLC). The KRAS mutations could be predictive of resistance to targeted therapy like epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or a prognostic factor in NSCLC. No successful targeted therapy currently exists to treat patients with KRAS mutant NSCLC, and novel therapeutic strategies are needed to prolong survival in patients with KRAS mutant NSCLC. Nicotinamide phosphoribosyltransferase (nampt) is a rate-limiting enzyme in NAD+ salvage, and we previously reported that nampt is a potent therapeutic target in NSCLC. Based on the analysis result of GEO database, we found that expression of nampt is associated with RAS-MAPK signaling pathway in NSCLC, and we therefore, conducted an in vitro study to evaluate a role of nampt in growth of KRAS mutant NSCLC.
Methods: We used a panel of KRAS mutant NSCLC cell lines (A427, A549, H157, H23, H1792, H2009, H358, H441, Calu6, Calu1). The cells were treated with a nampt inhibitor, FK866, and acid phosphatase (APH) assay (Thermo SCIENTIFIC) was used to evaluate cell viability of the KRAS mutant cells. Changes in expression of MAPK signaling pathway and BCL2 family proteins (antibodies from Cell Signaling and Santa Cruz) were evaluated by western blot. Apoptosis of the cells treated with FK866 was detected using an Annexin V FITC apoptosis detection kit (BD Biosciences). FACS analysis was performed using a BD FACSAria II cytometer (BD Bioscience). Autophagic proteolysis was studied by Cyto-ID autophagy detection kit (Cosmo Bio), and the expression of the fluorescent signal was visualized by a FV1000 confocal microscope (OLYMPUS JAPAN).
Results:
We found that the sensitivity to FK866 was different among the KRAS mutant cell lines, and for instance, A427 cells were sensitive while H157 cells were resistant. FK866 suppressed growth of KRAS mutant NSCLC and decreased expression of p-ERK expression in the cell line sensitive to FK866. We will report alteration of apoptosis and autophagy in the KRAS mutant NSCLC treated with FK866.
Conclusion:
Nampt could be a potent therapeutic target in KRAS mutant NSCLC.
Citation Format: Shunsuke Okumura, Takaaki Sasaki, Yoshinobu Ohsaki. A role of nicotinamide phosphoribosyltransferase in growth of KRAS mutant non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1770. doi:10.1158/1538-7445.AM2015-1770