bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2113: Arsenic hexoxide inhibits NF-κB activity through, at least in part, suppression of IκBα phosphorylation in MCF-7 human breast cancer cells.
Authors: Lee Won Sup , Kim Min Jeong , Jung Ji-Hyun , Yun Jeong Won , Lu Jing Nan , Yi Sang mi , Kim Hye Jung , Chang Seong-Hwan , Kim GonSup , Hong Soon Chan , Hwa Woo song 
Published: August 2014

Abstract
Arsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980’s. Evidence suggests that the anti-cancer effects of As4O6 are different from those of As2O3. Nuclear factor-κB (NF-κB) is a well-known transcription factor involved in cell proliferation, invasion and metastasis. Here, we investigated the effects of As4O6 on NF-κB activity, NF-κB-regulated gene expressions, and NF-κB-mediated cellular responses. As4O6 suppressed NF-κB activation induced by TNF-α, and the some of the downstream NF-κB-regulated proteins involved in caner proliferation, metastasis and anti-apoptosis. As4O6 also suppressed IκB phosphorylation in a time-dependent manner, suggesting the suppression of NF-κB results from at least in part by inhibiting IκB degradation. We also confirmed the anti-NF-κB activity of As4O6 with synergism with TNF-α at the molecular levels. This study demonstrates that As4O6 inhibits NF-κB activation and NF-κB regulated proteins at least in part through the inhibition of IκB phosphorylation. [This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare & Family Affairs, Republic of Korea. (0820050), and National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (20120002631).]
Keywords: Arsenic hexoxide, Nuclear factor-κB, IκB, cancer
Citation Format: Won Sup Lee, Min Jeong Kim, Ji-Hyun Jung, Jeong Won Yun, Jing Nan Lu, Sang mi Yi, Hye Jung Kim, Seong-Hwan Chang, GonSup Kim, Soon Chan Hong, Woo song Hwa. Arsenic hexoxide inhibits NF-κB activity through, at least in part, suppression of IκBα phosphorylation in MCF-7 human breast 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 2113. doi:10.1158/1538-7445.AM2013-2113
Abstract 2131: Functional assays to define agonists and antagonists of sigma-2 receptors.
Authors: Mach Robert H. , Zeng Chenbo , Rothfuss Justin M. , Zhang Jun , Vangveravong Suwanna , Chu Wenhua , Tu Zhude , Li Shihong 
Published: August 2014

Abstract
The sigma receptor was originally defined pharmacologically as the specific binding site for a group of compounds named as sigma ligands. The sigma-2 receptor has been identified as a biomarker in proliferating tumors. It regulates cell growth and is an emerging target for cancer diagnosis and therapeutics. Up to date numerous sigma-2 selective ligands have been developed. However, there is no well-established functional assay for defining agonist/antagonist for sigma-2 receptors. Many sigma-2 ligands with diverse structures have been shown to induce cytotoxicity in a variety of cancer cells by triggering caspase-independent and caspase-dependent apoptosis. Therefore, in the current study, we propose to use cell viability and caspase 3 activity, a hallmark of apoptosis, as functional assays to define agonist/antagonist for sigma-2 receptors. Three classes of sigma-2 ligands developed in our laboratory were tested in these two assays in two tumor cell lines: mouse breast cancer cell line EMT6 and human melanoma cell line MDA-MB435. Based on the ratios of the EC50 values of our sigma-2 ligands to the EC50 of siramesine, we categorized the azabicyclononane analogs as agonists (e.g. SV 119) or partial agonists (e.g. WC 26 and SV 95), and benzamide analogs as non-canonical antagonists (e.g. RHM-1) since they do not trigger cell death, and they do not block sigma-2 agonist-induced cell death. SV 95 partially blocked SV 119-induced cytotoxicity. The establishment of functional assays for defining agonist/antagonist will facilitate functional characterization of sigma-2 ligands and sigma-2 receptors.
Citation Format: Robert H. Mach, Chenbo Zeng, Justin M. Rothfuss, Jun Zhang, Suwanna Vangveravong, Wenhua Chu, Zhude Tu, Shihong Li. Functional assays to define agonists and antagonists of sigma-2 receptors. [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 2131. doi:10.1158/1538-7445.AM2013-2131
Abstract 2140: Oral antiangiogenic therapy suppresses xenograft growth and is well tolerated in rats.
Authors: Benny Ofra , Bazinet Lauren , D'Amato Robert 
Published: August 2014

Abstract
Lodamin, the oral formulation of TNP-470, a methionine aminopeptidase 2 (MetAp2) inhibitor, was previously shown to significantly inhibit angiogenesis and suppress the progression of fast growing murine tumors. Lodamins’ unique structure as a polymer micelle composed of poly(ethylene-glycol)-poly(lactic)acid (PEG-PLA) conjugate of TNP-470 is pharmacologically advantageous over the non-conjugated form. It shows better stability, oral availability, solubility in water and importantly, has an improved safety profile (Benny O. Folkman J et al, Nat Biotech, 2008). We now report the successful large scale synthesis of Lodamin, yielding pure and active product composed of mPEG-PLA-TNP-470 conjugate without residual free drug as confirmed by NMR and LC-MS/MS. The safety profile of Lodamin was studied in an acute high dose rat study (4 fold higher than therapeutic dose). Lodamin was administered at 10mg/kg or 60mg/kg via oral gavage while control rats were given vehicle only. After 7 days of daily treatment, no changes in body weight or behavior were observed compared to the control group. On day 8 post treatment, gross pathology of all rats was examined. This data showed Lodamin treatment had no adverse effect on tissue morphology. Lodamin is a potent antiangiogenic drug in numerous in vivo murine models including the corneal micropocket assay, matrigel assay, Delayed-Type Hypersensitivity (DTH) reaction and the choroidal neovascularization (CNV) model (Benny O. Folkman J et al, Nat Biotech, 2008, Benny O. D'Amato R et al, Plos One 2010). We now show that in addition to its dramatic anti-cancer effects on Lewis lung carcinoma and B16F10 melanoma murine tumors, Lodamin suppresses human tumors induced in nude mice. The volume of subcutaneous (s.c) human glioblastoma (U87MG) xenografts were reduced by 70% after 30 days, and 71% after 45 days when administered by gavage or in drinking water, respectively. Human breast tumor (MDA-MB231, s.c) growth was inhibited by 62% after 47 days of administration, and Human hepatocarcinoma (HepG2, s.c) tumor growth was inhibited by 60% after only 12 days. Taken together we have established Lodamin as a potent antiangiogenic drug which retains TNP-470 activity without TNP-470-associated side effects. Lodamin is a safe and efficacious drug in our animal models and hopefully will be reintroduced for the treatment of cancer in patients.
Citation Format: Ofra Benny, Lauren Bazinet, Robert D'Amato. Oral antiangiogenic therapy suppresses xenograft growth and is well tolerated in rats. [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 2140. doi:10.1158/1538-7445.AM2013-2140
Abstract 2148: Novel therapy of liver metastases of cancer using Abraxane loaded into Multi-Stage Nanovector.
Authors: Tanei Tomonori , Ferrari Mauro , Godin Biana , Yokoi Kenji 
Published: August 2014

Abstract
Purpose; To investigate whether the Abraxane loaded within Multi-Stage Nanovector (MSV) system (MSV-ABX) is more effective in therapy of liver metastases of breast and colorectal cancer as compared to Abraxane (ABX).
Experimental Design; MTT assay was performed to evaluate sensitivity of 4T1, murine breast cancer cells and CT26, murine colon cancer cells to ABX or MSV-ABX in vitro. Experimental liver metastases were produced by intra-splenic injection of 4T1 or CT26 cells in Balb/C mice. The mice bearing liver metastases were treated with intravenous injection of (1) control (PBS), (2) ABX or (3) MSV-ABX. Then the mice were sacrificed and liver weight was measured to evaluate the therapeutic efficacy. To evaluate the biological the effects of therapeutics, we performed histological and immunohistochemical analysis of the tumor specimens. Apoptosis of 4T1 and CT26 tumor cells were evaluated by TUNEL staining, and proliferation of the tumor cells were stained using antibody to Ki67. Tumor diameter was measured in H&E stained sections.
Results; There was no significant difference in the sensitivity of 4T1 and CT26 cancer cells to ABX and MSV-ABX, in vitro. All the mice injected with 4T1 or CT26 cells developed multiple liver metastases. The liver weight was significantly lower in the mice treated with MSV-ABX as compared to those in the other groups. The tumor diameters in the liver were significantly smaller in the mice treated with MSV-ABX as compared to those in the other two groups. Immunofluorescent analysis revealed that MSV-ABX inhibited proliferation and increased apoptosis of 4T1 and CT26 tumor cells in the liver significantly more than ABX.
Conclusions; These studies demonstrate that MSV-ABX is more effective than ABX in therapy of the liver metastasis of breast and colorectal cancer in our mouse models. These data can be translated into the clinic for planning novel clinical trials using MSV-ABX.
Citation Format: Tomonori Tanei, Mauro Ferrari, Biana Godin, Kenji Yokoi. Novel therapy of liver metastases of cancer using Abraxane loaded into Multi-Stage Nanovector. [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 2148. doi:10.1158/1538-7445.AM2013-2148
Abstract 2155: Achieving complete response to locoregional disease without toxicity using temperature-sensitive liposomes and ultrasound-mediated hyperthermia.
Authors: Kheirolomoom Azadeh , Lai Chun-Yen , TAM Sarah M. , Even Lisa M. , Ingham Elizabeth S. , Fite Brett Z. , Watson Katherine D. , Ferrara Katherine W. 
Published: August 2014

Abstract
By stabilizing doxorubicin within temperature-sensitive liposomes and repeating delivery twice per week for four weeks, extended survival and complete response were obtained in syngeneic murine breast tumors. Further, with the stabilized formulation, cardiac toxicity and leukopenia were not detected. Liposomes composed of DPPC:MPPC:DSPE-PEG2k, 86:10:4 were prepared in the presence of copper(II) gluconate and triethanolamine and extruded with 100 nm membrane filters. Cu-liposomes were loaded with Dox at 0.2 mg-drug/mg-lipid with 100% loading. We studied the efficacy of CuDox liposomes (CuDox-LTSLs) using the highly invasive neu deletion (NDL) tumor. Treatment began when the tumor diameter reached 4 mm. The fluorescence of circulating doxorubicin in blood was quenched after the digestion of liposomes with Triton X-100, indicating that the circulating drug remained associated with copper. Dox fluorescence was restored upon reducing the pH using a citrate-saline buffer.
Over the 28 days of the study, CuDox-LTSLs were administrated intravenously two times per week at a therapeutic level of 6 mg-drug/kg-body weight. The entire tumor was insonified with a peak ultrasound pressure of 1.1 MPa at a frequency of 1.5 MHz at 42°C for 5 min prior to and 20 min post drug injection. A total of 30 mice were studied, including groups spanning drug treatment with ultrasound, ultrasound, drug treatment and no treatment. Although a single dose administration of CuDox-LTSLs combined with insonation of the entire tumor suppressed the tumor growth, complete response was achieved only upon repeated treatment over a period of 28 days. At 30 days after the last administered dose, none of the mice from the other groups survive; however, 100% of mice treated with ultrasound combined with CuDox-LTSLs survive and the remaining tumor is undetectable. In conclusion, repeated treatment of stabilized temperature sensitive doxorubicin liposomes is highly effective in the treatment of aggressive murine tumors.
Acknowledgement: NIHR01CA134659 and NIHR01CA103828
Citation Format: Azadeh Kheirolomoom, Chun-Yen Lai, Sarah M. TAM, Lisa M. Even, Elizabeth S. Ingham, Brett Z. Fite, Katherine D. Watson, Katherine W. Ferrara. Achieving complete response to locoregional disease without toxicity using temperature-sensitive liposomes and ultrasound-mediated hyperthermia. [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 2155. doi:10.1158/1538-7445.AM2013-2155
Abstract 2156: Targeting polo-like kinase 1 with novel inhibitors of the polo-box domain.
Authors: Baxter Merissa , Craig Sandra , McInnes Campbell , Wyatt Michael D. 
Published: August 2014

Abstract
Polo-like Kinase 1 (PLK1) is a central player in cell cycle regulation and mitotic progression. Observations that PLK1 is over-expressed in many cancer types have led to efforts to target this protein therapeutically. Several ATP-binding site inhibitors of PLK1 have advanced to clinical trials, but these compounds inhibit at least three of the four known mammalian PLKs to varying degrees. This is problematic because, for example, PLK3 acts as a tumor suppressor and has opposing functions to PLK1. Moreover, a recent study identified a single point mutation near the ATP binding site that renders PLK1 resistant to several structurally unrelated ATP-based inhibitors, while retaining kinase activity. The Polo-box domain (PBD) of each PLK is a phospho-peptide binding motif that determines substrate recognition and subcellular localization. Our approach is to target the PBD of PLK1 to achieve desired PLK1 selectivity and improve efficacy. We recently reported a structure-activity relationship for a series of fragment-ligated inhibitory peptides (FLIPs) designed to be selective for the PBD of PLK1 (Mol. Cancer Ther., 2012, 11, 1683-1692). Our most potent compound in that class possessed a binding affinity to the PLK1 PBD (IC50 value of 8.6 μM), and insignificant levels of PLK3 binding up to 600 μM, which represents at least a 100-fold selectivity. The compound was able to induce cellular phenotypes consistent with a PLK1 knockdown, including aberrant mitoses and induction of apoptosis. Here, we report the development of new FLIP analogues with improved potency in binding to the PLK1 PBD. Specifically, we have designed, synthesized, and tested new benzoic acid capping groups to exploit a hydrophobic cleft in the PBD binding site. This newer generation of compounds possess binding affinities to the PLK1 PBD with IC50 values below 1 μM. Studies are in progress to determine PLK1 selectivity and activity in cells. Future studies will explore the ability of PBD-targeted compounds to circumvent resistance to ATP-based compounds.
Citation Format: Merissa Baxter, Sandra Craig, Campbell McInnes, Michael D. Wyatt. Targeting polo-like kinase 1 with novel inhibitors of the polo-box domain. [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 2156. doi:10.1158/1538-7445.AM2013-2156
Abstract 2167: Strengthening anti-cancer effects on non-small cell lung carcinoma by dual blockage of MET and EGFR in a context-dependent manner.
Authors: Zhang Yu-Wen , Staal Ben , Essenburg Curt , Lewis Steven , Kaufman Dafna , Vande Woude George F. 
Published: August 2014

Abstract
Non-small cell lung carcinoma (NSCLC) accounts for more than 80% of lung cancer, the leading cause of death among all cancer casualties. The MET receptor tyrosine kinase (RTK) is often co-expressed with EGFR in the NSCLC cells, and is an important alternative resistant mechanism for escaping EGFR-targeted therapy. To assess the benefit of dual blockage of MET and EGFR for NSCLC therapy, we investigated the activities of these two RTK pathways in several NSCLC cell lines carrying distinct cellular contexts, and determined their responses to SGX523 and erlotinib, the small molecule kinase inhibitors of MET and EGFR, respectively. Here, we showed that MET can cross-activate EGFR in MET-amplified or overexpressing cells via hetero-receptor dimerization, and the MET-dependent phosphorylation of EGFR can be abolished by SGX523 but not by erlotinib. More importantly, combined inhibition of MET and EGFR in vitro results in a maximal suppression of downstream ERK and AKT activation and of cell proliferation when their ligands (HGF and EGF) are present. Furthermore, we demonstrated that SGX523 and erlotinib combination strengthens anti-cancer activity in vivo in a cellular context-dependent manner. The combination led to regression of MET-amplified H1993 tumors by enhancing suppression of proliferation and inducing apoptosis, whereas significantly reduced MET-non-amplified H1373 tumor growths by suppression of proliferation without inducing apoptosis. Although SGX523 alone was sufficient to achieve near complete regression of MET-addicted EBC-1 tumors, its combination with erlotinib strongly inhibited viability of a population of SGX523-insensitive cells emerging from SGX523-treated EBC-1 tumor relapse. Our data suggest that dual blockage of MET and EGFR can enhance anti-cancer effects on NSCLC in a context-dependent manner, and provide a strong rationale and mechanisms for combining MET and EGFR inhibitors for NSCLC therapy.
Citation Format: Yu-Wen Zhang, Ben Staal, Curt Essenburg, Steven Lewis, Dafna Kaufman, George F. Vande Woude. Strengthening anti-cancer effects on non-small cell lung carcinoma by dual blockage of MET and EGFR in a context-dependent manner. [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 2167. doi:10.1158/1538-7445.AM2013-2167
Abstract 2201: The molecular signature of tumor cells that are sensitives to a new tight binder NAMPT inhibitor.
Authors: Hilairet Sandrine , Arigon Jerome , Nardi Frederico , Jegham Samir , Peleraux Annick , Cosnier Sylvie , Floutard Regine , Jbilo Omar , August Paul , Shomali Maysoun , Autelitano Francois , Arrebola Rosalia , Reiling Stephan , Pollard Jack , Adrian Francisco , Sager Jason , Lengauer Christoph , Dorsh Marion , Garcia-Echeverria Carlos , Bouaboula Monsif 
Published: August 2014

Abstract
SAR154782 is a tight binder, low reversible NAMPT inhibitor that has been identified by a phenotypic screen and chemogenomic approaches. This class of NAMPT inhibitor induces a profound and time dependent modulation of tumor metabolism which in turn induces the reprogrammation of tumor cell transcriptome. The transcriptional profile revealed that different metabolic and oncogenic signaling pathways are modulated by SAR154782. In order to define the context of tumor cell sensitivity to NAMPT inhibition, the effects of this compound on tumor cell growth and viability have been assessed against a panel of about 240 cell lines from different tissue origin. Based on the difference of tumor cell lines sensitivity to NAMPT inhibitor, a panel of 60 genes that are differentially expressed in the sensitive versus non-sensitive cell lines has been identified. Interestingly, the low expression of NAMPT concomitant with the high expression of Sirtuin1 and PARP1 are the main outstanding features in the panel of genes identified for the most sensitive cell lines. This finding is in agreement with high NAD turnover. The relevance of the preceding biomarkers to determine the potential cancer target population that could benefit upon treatment with a NAMPT inhibitor has been investigated in in vivo settings by evaluating the antitumor activity of an advanced new class of NAMPT inhibitors in several mouse tumor xenografts and human primary tumor models.
The results obtained from these studies highlighted the modulation upon NAMPT inhibition of important tumor growth pathways and revealed for the first time a potential molecular signature of tumor sensitivity and support further investigation into use of the signature for patient stratification in the clinical setting
Citation Format: Sandrine Hilairet, Jerome Arigon, Frederico Nardi, Samir Jegham, Annick Peleraux, Sylvie Cosnier, Regine Floutard, Omar Jbilo, Paul August, Maysoun Shomali, Francois Autelitano, Rosalia Arrebola, Stephan Reiling, Jack Pollard, Francisco Adrian, Jason Sager, Christoph Lengauer, Marion Dorsh, Carlos Garcia-Echeverria, Monsif Bouaboula. The molecular signature of tumor cells that are sensitives to a new tight binder NAMPT inhibitor. [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 2201. doi:10.1158/1538-7445.AM2013-2201
Abstract 2202: Classification of DPYD variations using an isogenic system of expression.
Authors: Offer Steven M. , Wegner Natalie J. , Fossum Croix , Diasio Robert D. 
Published: August 2014

Abstract
The pyrimidine analog 5-fluorouracil (5-FU) was developed in the 1950s and remains one of the most widely used chemotherapy drugs in use today. A significant portion of patients who receive 5-FU suffer severe adverse toxicities, and, in extreme cases, death. Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) rapidly degrades 85% of administered 5-FU, and as such, limits the amount of drug available for conversion into active metabolites. Genetic variations in DPYD have been suggested to increase the risk of 5-FU toxicity. Large-scale sequencing efforts have identified nearly 100 missense and nonsense DPYD variations, however only a handful of alleles have been studied for their association with 5-FU toxicity. Most studies have focused on a single allele (DPYD*2A), which only accounts for a small fraction of DPD deficiencies. Further complicating the interpretation of DPYD alleles, many individuals carry multiple variations within the DPYD gene. The purpose of this study was to identify missense variants that affect the enzyme function of DPD using a mammalian isogenic system of expression. Expression vectors encoding missense DPYD variations were generated by site directed mutagenesis and the expressed protein assayed for enzyme activity. Cells expressing selected variants were also teasted for sensitivity to 5-FU using a novel implementation of electrical impedance based realtime cellular analysis. The results of functional studies are compared to in silico predictions used to classify variants as deleterious or benign. An appreciable fraction of DPD variants showed enzyme activity that was significantly lower than that of wildtype protein. Within the deficient group of variants, a gradient of activities was noted, prompting the grouping of variants as mildly, moderately, and severely impaired. In addition to loss-of-function variations, a few hyperactive DPYD alleles were identified. This novel class of DPYD variants may be protective against 5-FU toxicity at the cost of treatment efficacy. The further evaluation of hyperactive alleles in clinical studies will be necessary to determine their impact on patient outcomes. Overall these data will facilitate the development of predictive tests for 5-FU toxicity by allowing researchers to prioritize variations for association studies.
Citation Format: Steven M. Offer, Natalie J. Wegner, Croix Fossum, Robert D. Diasio. Classification of DPYD variations using an isogenic system of expression. [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 2202. doi:10.1158/1538-7445.AM2013-2202