bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 92: Comparative expression analysis of somatostatin receptor subtypes in human neuroendocrine tumors using two sets of new monoclonal antibodies.
Authors: Lambertini Chiara , Barzaghi-Rinaudo Patrizia , D'Amato Lisa , Schulz Stefan , Nuciforo Paolo , Schmid Herbert A. 
Published: August 2014

Abstract
The expression and reliable detection of somatostatin receptor subtypes (SSTR1-5) is a prerequisite for the successful use of somatostatin analogues in neuroendocrine tumors (NET). Two sets of monoclonal antibodies (mAbs) against human SSTR1, 2A, 3 and 5 have recently been developed by two independent laboratories using rabbit and mouse hybridomas. Our aim was to evaluate the usefulness of both sets of mAbs for detection of SSTRs in NET samples as they are routinely collected in clinical practice. Mouse and rabbit mAbs were characterized in SSTR1, 2, 3 and 5-transfected HEK293 cells and human archival pancreatic tissue and NET samples. Comparative analysis of mAbs was also conducted by immunostaining of a tissue microarray composed of 75 cores of NET. Immunohistochemical analysis of HEK293 cells showed that both rabbit and mouse mAbs specifically detect their cognate receptor subtype, with mild cytoplasmic cross-reactivity observed for rabbit mAbs. Both sets of mAbs labeled normal pancreatic islets and showed similar patterns of immunoreactivity in NET controls. Direct comparison of mAb sets using a NET tissue microarray revealed a strong correlation between rabbit and mouse mAbs against SSTR1 and 5, and moderate correlation for SSTR3. The rabbit mAb against SSTR2A showed higher affinity for its cognate receptor than the corresponding mouse mAb, resulting in more reliable detection of this SSTR. In conclusion, mAbs from both sets are reliable tools for the detection of SSTR1, 3 and 5, whereas the rabbit mAb against SSTR2A is recommended for use in routine clinical testing due to its superior binding affinity.
Citation Format: Chiara Lambertini, Patrizia Barzaghi-Rinaudo, Lisa D'Amato, Stefan Schulz, Paolo Nuciforo, Herbert A. Schmid. Comparative expression analysis of somatostatin receptor subtypes in human neuroendocrine tumors using two sets of new monoclonal antibodies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 92. doi:10.1158/1538-7445.AM2013-92
Abstract 926: The angiotensin IV analog Norleual acts as a hepatocyte growth factor/c-Met inhibitor in pancreatic cancer cells.
Authors: Kawas Leen H. , Harris Phillip , Church Kevin , Wright John W. , Harding Joseph W. 
Published: August 2014

Abstract
The primary purpose of this study was to demonstrate that the hepatocyte growth factor (HGF) antagonist Norleual is capable of attenuating the cellular responses of pancreatic cancer cells to HGF. The angiotensin IV analog Norleual [Nle-Tyr-Ile-ψ-(CH2-NH2)3-4-His-Pro-Phe] exhibits structural homology with the hinge (linker) region of HGF and acts to block HGF dimerization, a process required for its activation. Norleual competitively inhibited the binding of a H3-Hinge peptide sequence to the HGF, and binds directly to HGF with a Ki = 3.6x10-12M. Predictably, Norleual is able to block the cellular responses due to HGF activation in multiple cell types at concentrations in the picomolar range including HGF/c-Met sensitive pancreatic cancer cells. Norleual's ability to inhibit the growth and survival of pancreatic cancer cells was evaluated using viability testing and cell sorting tags to identify living, dead and apoptotic cells. HGF/c-Met activation increases the invasive potential of the pancreatic cancer cells, which provides a mechanistic basis for the ability of c-Met to support pancreatic tumor metastasis. In this regard Norleual as an HGF antagonist was able to block the migration and invasion of pancreatic cancer cells through collagen gels in a transwell chamber. Over-activation of the growth factor system HGF/c-Met is a critical contributor to pancreatic cancer's ability to disseminate rapidly and its refractoriness to standard chemotherapy. Norleual, which is a representative of a “first-in-class” group of molecules that blocks the activation step of HGF, represent a novel therapeutic approach to the treatment of pancreatic cancer.
Citation Format: Leen H. Kawas, Phillip Harris, Kevin Church, John W. Wright, Joseph W. Harding. The angiotensin IV analog Norleual acts as a hepatocyte growth factor/c-Met inhibitor in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 926. doi:10.1158/1538-7445.AM2013-926
Abstract 937: Dissection of KRAS-driven survival signaling networks via phosphoproteomics in lung cancer cells.
Authors: Kim Jae-Young , Welsh Eric A. , Fang Bin , Oguz Umut , Li Jiannong , Kinose Fumi , Bronk Crystina , Beg Amer A. , Chen Ann , Eschrich Steven , Koomen John , Haura Eric B. 
Published: August 2014

Abstract
KRAS mutation accounts for development of approximately 30% of lung adenocarcinoma yet therapeutic options remain limited. We report our efforts to explore downstream signaling proteins driven by KRAS, including TANK-binding kinase 1 (TBK1), through a mass spectrometry based phosphoproteomics approach. We hypothesized that such a search would identify key survival proteins as well as uncover potential adaptive resistance mechanisms. We identified proteins whose phosphorylation is regulated TBK1 using SILAC and mass spectrometry following RNAi-mediated TBK1 knockdown. A cohesive network view of the underlying results centered major effects on Polo-like Kinase 1 (PLK1) and decreased phosphorylation of its targets implicating TBK1 as involved in mitosis. TBK1 activity was induced especially in late G1 and M phase, and loss of TBK1 sensitized lung cancer cells to a mitotic stressor. Surprisingly, we found that TBK1 knockdown increased phosphorylation of oncogenic kinases, including EGFR, Met, and ERK1/2. We screened multiple tyrosine kinase inhibitors in combination with TBK1 loss and found the pro-apoptotic effect of TBK1 loss was enhanced by dasatinib, a Src-family kinase inhibitor, providing a mechanistic basis for rational combinatorial therapies involving TBK1. Moving upstream, we analyzed global phosphoproteome change after KRAS knockdown and identified unexpected role of KRAS involved in CDK1 regulation as well as potential adaptive resistant mechanisms that can protect cells against KRAS loss. Finally, we have started exploring changes in the programmed kinome in KRAS mutated lung cancer cells following exposure to MEK inhibitors using activity based protein profiling. Initial experiments have characterized phenotypic effects of two MEK inhibitors in a subset of KRAS mutated lung cancer cells and preliminary studies have identified increased levels of some kinases following MEK inhibition. Collectively, we expect this kinome and phosphoproteomic network based approach will provide better insights into survival signaling mechanism maintaining survival of KRAS mutant lung cancer cell as well as novel therapeutic strategies for this cancer subtype. Updated work will be presented. Supported by the SPORE in Lung Cancer (P50-CA119997)
Citation Format: Jae-Young Kim, Eric A. Welsh, Bin Fang, Umut Oguz, Jiannong Li, Fumi Kinose, Crystina Bronk, Amer A. Beg, Ann Chen, Steven Eschrich, John Koomen, Eric B. Haura. Dissection of KRAS-driven survival signaling networks via phosphoproteomics in lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 937. doi:10.1158/1538-7445.AM2013-937
Abstract 942: Decreasing the AKT feedback loop with arsenic trioxide enhances mTORi anti-tumor effects.
Authors: Guilbert Cynthia , Annis Matthew G. , Siegel Peter , Miller Wilson H. , Mann Koren K. 
Published: August 2014

Abstract
Inhibitors of the mammalian target of rapamycin (mTORi) have exciting clinical activity in renal cell carcinoma, breast cancer, and some hematologic malignancies. However, the potential benefits of mTOR inhibition may be limited by a feedback mechanism that results in AKT activation. While mTORi can block important growth promoting events downstream from TORC1, an increased activation of AKT may inhibit apoptotic signals. Increased AKT activity resulting from mTOR inhibition is a result of increased growth factor/MAPK signaling or alternatively, via the second mTOR complex, TORC2. We have previously shown that arsenic trioxide (ATO) inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and mTORi may circumvent the AKT feedback loop and increase the anti-tumor effects of these drugs. Using a panel of breast cancer cell lines, we find that ATO, at clinically achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus in some, but not all, cell lines. MCF-7, MDA-MB-468, and SKBR3, but not T47D cells, exhibit a decrease in cell number that correlates with an increase in the percentage of cells arrested in the G0/G1 phase of the cell cycle. In all these cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in MCF-7, MDA-MB-468, and SKBR3 cell lines. Treatment with mTORi also results in activated ERK signaling, which is decreased with ATO co-treatment in MCF7, MDA-MB-468, and SKBR3. These data indicate that, when effective, ATO decreases phospho-AKT and ERK concomitantly. We next tested the toxicity and efficacy of rapamcyin plus ATO combination therapy in a MDA-MB-468 xenograft model. The combination was well-tolerated, and rapamycin did not increase ATO-induced liver enzyme levels. In contrast, the combination was significantly more effective at inhibiting tumor growth. The increased anti-tumor effects corresponded with ATO decreasing the rapamycin-induced phospho-Akt, phospho-ERK, and phospho-4EBP1 within the tumor. Therefore, we propose that adding ATO to mTORi treatment may overcome the negative feedback loop by decreasing MAPK and activated AKT in addition to the downstream targets of mTOR/TORC1.
Citation Format: Cynthia Guilbert, Matthew G. Annis, Peter Siegel, Wilson H. Miller, Koren K. Mann. Decreasing the AKT feedback loop with arsenic trioxide enhances mTORi anti-tumor effects. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 942. doi:10.1158/1538-7445.AM2013-942
Abstract 944: The effect of endogenous peroxidase activity on cell culture-based drug activity screening.
Authors: Bakhsheshian Joshua , Kwit Alexandra D.T. , Brimacombe Kyle R. , Hall Matthew D. , Gottesman Michael M. 
Published: August 2014

Abstract
Reactive oxygen species (ROS) are known to play an intrinsic role in mediating the cancer cell killing of many commonly employed anticancer agents. In many cases this is due to direct production of ROS via interaction with cellular components. This evidence is based partly on observations that ROS-scavenging agents such as N-acetylcysteine or catalase reverse killing in cancer cells. Catalase enzymatically degrades hydrogen peroxide (H2O2) into dioxygen and water. We examined the effect of catalase (5,000 U/mL) supplemented in growth media on the efficacy of ∼800 cytotoxic small molecules. Strong reversal of toxicity was found for 34 compounds with diverse mechanisms, including tubilin-interacting drugs. This implies that cytotoxins may have diminished efficacy in vivo due to the high activity of catalase in blood (∼100,000 U/mL). Surprisingly, we found that assays conducted with supplementation of catalase in media at levels greater than &gt;20,000 U/mL, intended to replicate the endogenous environment, were highly toxic to cells. This phenomenon has been replicated in a number of cell lines from various tissue origins. One implication of this funding is that cancer cell lines require baseline ROS levels for cell survival proliferation, consistent with the cancer ROS addiction theory. Given that cell culture medium lacks peroxidase activity we conclude that the precise cell culture environment is a critical determinant of the results obtained when screening drugs for toxicity to cancer cells.
Citation Format: Joshua Bakhsheshian, Alexandra D.T. Kwit, Kyle R. Brimacombe, Matthew D. Hall, Michael M. Gottesman. The effect of endogenous peroxidase activity on cell culture-based drug activity screening. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 944. doi:10.1158/1538-7445.AM2013-944
Abstract 954: Multidrug resistance transcriptome analysis highlights compounds that sensitize resistant hepatocellular carcinoma through increased histone acetylation.
Authors: Gillet Jean-Pierre , Andersen Jesper B. , Madigan James P. , Varma Sudhir , Wu Chung-Pu , Calcagno Anna M. , Ambudkar Suresh V. , Thorgeirsson Snorri S. , Gottesman Michael M. 
Published: August 2014

Abstract
No effective systemic therapy exists for patients with advanced hepatocellular carcinoma (HCC). Surgery is the mainstay treatment for patients with early stage HCC tumors. Either resection or transplantation is advocated if the HCC is within the Milan criteria. Nonsurgical treatments including percutaneous ethanol injection, radiofrequency ablation, and transcatheter arterial chemoembolization (TACE) are used as adjuvant therapy to surgery but also to treat unresectable HCC. Although a meta-analysis showed a beneficial survival effect for patients with intermediate HCC treated by TACE using doxorubicin and cisplatin, the survival benefit of systemic chemotherapy for the treatment of liver cancer is marginal at best. Although Sorafenib, a multi-tyrosine kinase inhibitor, is becoming established as the first line of therapy for advanced HCC, it was recently shown to be a substrate of ABCB1 and ABCG2, two major transporters involved in multidrug resistance (MDR) and expressed in hepatocytes. In this study, the MDR transcriptome was analyzed in a cohort of 38 patients using TaqMan-based qRT-PCR, with the aim of finding ways to sensitize this intrinsically MDR cancer. The study reveals a 45-gene signature, validated using an independent cohort of 53 patients, that predicts overall survival (OS). We used the Connectivity Map tool, designed to reveal connections among drugs, genes, and pathological states, to identify three compounds that converted the gene expression profile of HCC cell lines from one matching patients with poor OS to one with good OS. These compounds increased histone acetylation, resulting in the sensitization of tumor cells to conventional chemotherapy including cisplatin, sorafenib and 5-FU. This work provides new treatment strategies based on gene expression profiling and connectivity data for a disease for which no effective systemic treatments exist. More importantly, the current study reveals a new strategy to sensitize any type of refractory cancer to chemotherapy.
Citation Format: Jean-Pierre Gillet, Jesper B. Andersen, James P. Madigan, Sudhir Varma, Chung-Pu Wu, Anna M. Calcagno, Suresh V. Ambudkar, Snorri S. Thorgeirsson, Michael M. Gottesman. Multidrug resistance transcriptome analysis highlights compounds that sensitize resistant hepatocellular carcinoma through increased histone acetylation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 954. doi:10.1158/1538-7445.AM2013-954
Abstract 962: Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model.
Authors: Kumar Sushil , Mokhtari Reza Bayat , Islam Syed , Yeger Herman , Baruchel Sylvain 
Published: August 2014

Abstract
Background: We have previously observed that the combination of daily oral Low Dose Metronomic (LDM) Topotecan (TP) and Pazopanib (PZ) significantly delayed the tumor growth and enhanced the survival in neuroblastoma (NB) mouse models (Kumar et al, 2011). However, this combination (TP+PZ) did not stop tumor growth and the animals eventually died due to disease during the course of therapy. Therefore, we planned to investigate the factors contributing to resistance to this antiangiogenic therapy in NB mouse model.
Objectives: To investigate the effect of prolonged TP+PZ therapy on angiogenesis by testing the effect of therapy at different durations in NB mice xenograft model.
Methods: Mice bearing subcutaneous SK-N-BE(2) NB xenografts were treated with either of the four regimens, daily, orally: vehicle (untreated), PZ (150 mg pazopanib), TP (1.0 mg/Kg topotecan), TP+PZ (combination of topotecan and pazopanib, same doses as single agents). Durations of treatment planned for each regimen were 28 days, 56 days and 80 days. Animals were sacrificed after these durations or upon end point, whichever was earlier. The criteria for end point are tumor sizes exceeding 2.0 cms in diameter or animals showing signs of morbidity.
Results: The animals in control, PZ, TP reached the end point after 23d, 28d and 46d respectively. TP+PZ halted the tumor growth for up to 40 days, after which gradual growth was observed. The mean tumor diameters in the third TP+PZ group reached 1.8 cms at the day 80. CD31 immunofluorescence revealed that all the three durations of TP+PZ significantly lowered microvessel densities compared to the control (P= 0.02, 0.04 and 0.009 respectively for 28, 56 and 80 days respectively). However the ratio of CD31 to α- smooth muscle actin (pericyte marker) stained areas were significantly higher in animals treated with TP+PZ for 56 and 80days, compared to control (P=0.0006; 56d and 0.004; 80d) indicating higher pericyte coverage. TP+PZ (28d) showed signs of necrosis and cell cycle arrest (Ki67 staining), which were not observed in later durations (56 and 80 days) with TP+PZ. Long-term TP+PZ therapy also increased the levels of HIF-1 alpha, VEGF and Oct-4 within the tumor tissue.
Conclusion: This study indicates that even though prolonged TP+PZ therapy demonstrates sustained antiangiogenic activity, it encounters resistance in NB, potentially mediated by pericyte coverage. Long-term TP+PZ therapy may also increase tumor stemness.
Citation Format: Sushil Kumar, Reza Bayat Mokhtari, Syed Islam, Herman Yeger, Sylvain Baruchel. Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 962. doi:10.1158/1538-7445.AM2013-962
Abstract 965: Establishment of a Sunitinib resistant cell line from ccRCC by long term drug application.
Authors: Unteregger Gerhard , Krein Simone , Weiland Anne , Stoeckle Michael , Junker Kerstin 
Published: August 2014

Abstract
Introduction: Sunitinib (SUN) acts as a multitargeted tyrosine kinase inhibitor (TKI) in the treatment of advanced renal cell carcinoma. It addresses predominantly the neo-angiogenic pathway by inhibition of proliferation and induction of apoptosis. But in clinical practice patients fail therapy. To elucidate the mechanism behind the failure of SUN we started to investigate the efficacy of SUN in long term cell culture studies using permanent cell lines representing ccRCC.
Material and Methods: CAKI-1/2, A-498 and 786-O cell lines, normal fibroblasts and HUVEC were subjected to different concentrations of SUN for up to 5 days. Efficacy of SUN was monitored by quantification of viability (WST-1), apoptosis (CDD+), necrosis (LDH+) and proliferation (BrdU). Under long term SUN-treatment growth behavior was assessed by cell counting spanning a cultivation period of several weeks. miRNA profiling was performed by microarray analysis at different point within this schedule.
Results: ccRCC cell lines offer a decrease in viability down to 40-60% at 2-5μM/L SUN dependent on cell-type and cell concentration as a result of f proliferation-inhibition. Endothelial cells and fibroblasts react more sensitive showing a growth inhibition between 80-90% compared to untreated controls. Long term application of SUN to these ccRCC-cells results in SUN-insensitive cell clones offering no inhibition of proliferation at 2-5μM/l drug. Specific miRNA expression changes were identified in insensitive cells.
Conclusion: Drug resistance by a long term SUN treatment provides cell lines to study the molecular mechanisms underlying this phenomenon. We have shown that resistance is associated with miRNA alterations. 3D-combination of these cell lines together with endothelial cells and fibroblasts offer a powerful tissue-like model to develop new therapeutic schedules to overcome the failure of actual treatment.
Citation Format: Gerhard Unteregger, Simone Krein, Anne Weiland, Michael Stoeckle, Kerstin Junker. Establishment of a Sunitinib resistant cell line from ccRCC by long term drug application. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 965. doi:10.1158/1538-7445.AM2013-965