bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2581: Indolequinone mechanism-based inhibitors of quinone reductases: Structural basis for selective inhibition of NQO2 relative to NQO1
Authors: Yan Chao , Dufour Marine , Siegel David , Reigan Philip , Gomez Joe , Shieh Biehuoy , Moody Christopher J. , Ross David 
Published: June 2012

Abstract
There are two quinone reductases that occur in mammalian systems NAD(P)H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) and NRH:quinone oxidoreductase 2 (NQO2, EC 1.10.99.2). NQO1 has been shown to be up-regulated in many types of human solid cancer; whereas NQO2 has been shown to be highly expressed in leukemias. In order to explore their potential as therapeutic targets, we have developed potent and selective mechanism-based inhibitors for both enzymes centered on the indolequinone pharmacophore. Previously, we characterized ES936 (5-methoxy-1,2-dimethyl-3-(4-nitrophenoxy)methylindole-4,7-dione) as an efficient mechanism-based inhibitor of NQO1 and we have now developed a series of indolequinones as mechanism-based inhibitors of NQO2. Substitution of the 5-methoxy group in ES936 with an aminoalkylamino side chain generated potent mechanism-based inhibitors of NQO2 that did not efficiently inhibit NQO1. NQO2 inhibition was observed with compounds with 5’-aminoalkyl chains that varied from 3 to 8 carbons in length, with maximal inhibition observed with compounds that possessed 5’-chain lengths of between 3 to 5 carbons. Compounds with substitutions at the 6-position were not efficient mechanism-based inhibitors of NQO2. As previously observed for a series of NQO1 mechanism-based inhibitors, structural requirements for efficient inhibition of NQO2 also included a substituent at the 3-position capable of leaving to generate a reactive iminium electrophile following enzymatic reduction. Selected indolequinones were tested for NQO2 inhibition using the human leukemia cell line K562 and were found to inhibit NQO2 activity in K562 cells at nanomolar concentrations while not affecting NQO1 activity. Computational-based molecular modeling simulations demonstrated the substantial difference between the active site of NQO1 and NQO2 and ESI-LC/MS provided possible explanations for selective enzyme inhibition. These indolequinones represent the first mechanism based inhibitors of NQO2 to be characterized.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2581. doi:10.1158/1538-7445.AM2011-2581
Abstract 2584: eNOS as a therapeutic target in pancreatic cancer
Authors: Barrientos Katharine S. , Lampson Benjamin L. , Kendall Stephan D. , Counter Christopher M. 
Published: June 2012

Abstract
Pancreatic cancer has a very high mortality rate, and frontline therapy has not changed in over a decade indicating a need for novel therapeutics. In this regard, endothelial Nitric Oxide Synthase (eNOS) has emerged as a new target due to recent studies demonstrating elevated expression in human pancreatic cancers, and inhibition of pancreatic tumor growth with eNOS knockdown or knockout in xenograft and genetically engineered mouse models. By pharmacologically testing eNOS inhibition, we found that a non-selective NOS inhibitor, L-NG-Nitroarginine methyl ester (L-NAME), inhibited tumor growth of human pancreatic cancer cell lines and extended survival in the aggressive Pdx-1-CreTg/+;LSL-KRASG12D/+;LSL-Trp5R172H/+ (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC) by ∼30 days. This extended survival is particularly significant given that the current frontline therapy, gemcitabine, does not provide these mice with a similar survival advantage. While general inhibitors such as L-NAME are attractive molecules to explore, evidence has shown that targeting all three NOS enzymes can have undesirable off-target effects. As eNOS has been identified as the NOS family member required for pancreatic tumorigenesis, and there currently are no selective eNOS inhibitors, we have created and optimized a cell-based system to identify potent and selective compounds for eNOS inhibition. This assay uses a mammalian baculovirus expression system to distinguish the activity of eNOS, nNOS, and iNOS via measurement of the stable bi-products of nitric oxide synthesis, and has been tested with a variety of published NOS inhibitors including L-NAME, the iNOS specific inhibitor 1400W, and the nNOS specific inhibitor L-NPA. The assay is suitable for high throughput screening of small molecule libraries to identify novel eNOS inhibitors that, when paired with gemcitabine, may represent a novel combination therapy for pancreatic cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2584. doi:10.1158/1538-7445.AM2011-2584
Abstract 259: Novel peptide directed targeting of EWS-FLI1 impairs tumor cell growth
Authors: Erkizan Hayriye V. , Scher Lauren M. , Gamble Ellen , Barber-Rotenberg Julie , Uren Aykut , Toretsky Jeffrey 
Published: June 2012

Abstract
Introduction: Patients with Ewing's Sarcoma require improved therapy. EWS-FLI1 fusion protein provides a unique targeting opportunity. In the quest for protein partners, we identified a novel peptide sequence that binds to EWS-FLI1 using phage display. We hypothesize that by identifying peptides, and their cognate proteins, we can modulate the function of EWS-FLI1 to improve therapies for ESFT patients. Methods: Secreted peptide-alkaline phosphatase conjugates were used in ELISA for resolving binding regions. Cytotoxicity experiments were analyzed with MTT or WST reduction. Cell cycle analysis were performed using flow cytometry. Results: A phage display experiment to identify EWS-FLI1 peptides resulted in 96 phage clones that demonstrated binding to EWS-FLI1 by ELISA. Those 96 phage clones resulted in sequences that yielded twenty-seven unique peptides. Peptide A1 is one of 27 unique peptides that was commercially synthesized fused to penetratin (16aa) to facilitate intracellular transport. The cytotoxicity of A1 peptide was evaluated in TC32 and TC71 (EWS-FLI1, type I), A4573 (EWS-FLI1, type III), JN-DSRCT (desmoplastic small round blue cell tumor containing EWS-WT1), and SKNAS (a neuroblastoma cell line lacking EWS-FLI1 rearrangement). The IC50 level for A1 is between 5 -15 μM in cell lines bearing EWS fusion proteins. However, it is more than 50 μM in cells without the rearrangement. A1-alkaline phosphatase (A1-AP) conjugates were prepared with alanine substitutions throughout the peptide. Wild-type non-conjugated A1 competed away the interaction between the EWS-FLI1 and A1-AP, confirming its ability to bind to EWS-FLI1. Mutations in A1 demonstrated that the lysine residues are critical for binding to EWS-FLI1. The minimal interacting amino acids were validated using shortened and mutated versions of A1 in both ELISA and cell growth assays, including soft agar. A1 peptide blocked cell cycle progression of synchronized ESFT cells and caused accumulation at S phase. A1 peptide also inhibited EWS-FLI1 dependent transcription. Discussion: The A1 peptide directly binds to the EWS-FLI1 oncoprotein and leads to cell death in cells with either the EWS-FLI1 or EWS-WT1 fusion proteins. While A1 was discovered based on binding to EWS-FLI1; toxicity in JN-DSRCT studies suggest that the A1 peptide may have potency to EWS bearing fusion proteins. These findings present a novel method of targeting EWS rearranged oncoproteins and could lead to novel therapies
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 259. doi:10.1158/1538-7445.AM2011-259
Abstract 2592: Therapeutic testing of a novel inhibitor GAP-107B8 on ovarian cancer cells
Authors: Yan Fu J. , Garson Kenneth , Chabot Jaclyn M. , Vanderhyden Barbara C. 
Published: June 2012

Abstract
Background: Ovarian cancer is the most fatal gynaecologic disease in the western world. In 2010 in the United States, an estimated 21,880 women will develop ovarian cancer and an estimated 13,850 women will succumb to this disease. Current treatments are limited to surgery and chemotherapy, but the disease often recurs highlighting the need for novel cancer therapeutics. We are currently evaluating the efficacy of a novel therapeutic, GAP-107B8 (PharmaGap Inc, Ottawa) using in vitro and in vivo models. GAP-107B8 was designed as a protein kinase C (PKC) inhibitor. The PKC family of serine/threonine kinases are involved in cellular proliferation, differentiation, apoptosis and cell polarity. One PKC isoform, PKC iota, has recently been identified as a human oncogene and has been shown to be overexpressed in epithelial ovarian cancers and is thus a potential therapeutic target for ovarian cancer. Objectives: 1) To test the novel inhibitor GAP-107B8 on ovarian cancer cell lines to determine its effects on cell proliferation, cell cycle progression and apoptosis; and 2) To determine the therapeutic potential of GAP-107B8 in xenograft models of two different ovarian cancer cell lines. Methods: Three ovarian cancer cell lines were treated with three different concentrations of GAP-107B8 and screened using high throughput assays to measure the proliferation of cells in adherent cultures. Apoptosis was measured by TUNEL staining, PARP cleavage and cell cycle analysis. Tumor burden was assessed in mice receiving subcutaneous implants of two ovarian cancer cell lines, followed by daily intra-tumoral injections of GAP-107B8. Results: GAP-107B8 caused a significant reduction in cell proliferation in 3 ovarian cancer cell lines tested (86% to 95%; p&lt;0.001), including a cell line resistant to standard chemotherapy. In vivo, intra-tumoral treatment with GAP-107B8 resulted in a 45% reduction in average tumor size in the A2780cp-derived tumours (n=6/group, p&lt;0.01) and 75% in the HEY-derived tumors (n=3/group, p&lt;0.001). Cell killing may be mediated by apoptosis based on the observation of TUNEL staining 30 hours after treatment of cells in vitro with GAP-107B8. Apoptosis was confirmed by flow cytometry and PARP cleavage. GAP-107B8 also inhibited progression of cells through the cell cycle by blocking or delaying progression of cells through G2/M into the G1 phase.
Conclusion: The novel inhibitor GAP-107B8 displays good efficacy in vitro in suppressing the proliferation of ovarian cancer cell lines. Cytotoxicity may be manifested in perturbations of the cell cyle and induction of apoptosis. Finally, GAP-107B8 showed therapeutic efficacy in ovarian cancer xenograft models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2592. doi:10.1158/1538-7445.AM2011-2592
Abstract 2597: PLA2G7 associates with aggressive prostate cancer in vivo and regulates prostate cancer cell migration and adhesion in vitro
Authors: Vainio Paula , Hilvo Mika , Vesterinen Tiina , Gupta Santosh , Härmä Ville , Nees Matthias , Turunen Juha P. , Lundin Johan , Rannikko Antti , Orešič Matej , Kallioniemi Olli , Iljin Kristiina 
Published: June 2012

Abstract
There is an urgent need for more efficient and more targeted methods of prostate cancer treatment. We have previously shown PLA2G7 (also known as lipoprotein-associated phospholipase A2, Lp-PLA2) to be a possible biomarker and drug target especially in ERG positive prostate cancers by combining gene expression data from prostate cancer tissues in vivo and functional RNAi studies in vitro. To further study the potential of PLA2G7 in prostate cancer management immunohistochemical staining of 119 clinical prostate cancer samples and 112 adjacent normal prostate samples were performed. In addition, a global lipidomic, eicosanoid and gene expression analysis was utilized to study the effect of PLA2G7 silencing in ERG oncogene positive prostate cancer cells. The results emphasized high expression of PLA2G7 in 66 % of the cancer samples, whereas less than 4 % of the adjacent normal tissues showed positive staining. Furthermore, PLA2G7 expression significantly correlated with high Gleason score. PLA2G7 silencing in vitro induced a reduction in the amount of lysophosphatidyl choline and leukotriene E4, as well as in the expression of multiple genes and signaling pathways involved in cell adhesion and motility. In accordance, knock-down of PLA2G7 in 3D prostate cancer cell culture model lead to decreased invasion to extracellular matrix. Interestingly, PLA2G7 silencing also reduced the expression of ALDH1A1, a marker for malignant prostate stem cells and predictor of poor prostate cancer outcome. In conclusion, these novel findings suggest an oncogenic role for PLA2G7 in aggressive prostate cancers and support the rationale for PLA2G7 targeted therapy in these cancers. A novel PLA2G7 inhibitor is currently under clinical evaluation for cardiovascular diseases, presenting thus an interesting opportunity for drug repositioning to other indications, such as prostate cancer. In addition, lipid-lowering statins are known to lower PLA2G7 mass and activity, therefore PLA2G7 may also represent a target of lipid-lowering therapy in reducing the risk of aggressive prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2597. doi:10.1158/1538-7445.AM2011-2597
Abstract 2601: ROCK1 as a potential therapeutic target in pancreatic cancer
Authors: Whatcott Clifford , Watanabe Aprill , Demirjian Joseph , Barrett Michael , Hostetter Galen , Hoff Daniel Von , Han Haiyong 
Published: June 2012

Abstract
ROCK1, or Rho-associated coiled coil-containing protein kinase 1, is a multifunctional member of the AGC (protein kinase A/G/C) kinase family that has been implicated in the modulation of stress-fiber assembly, cell-cell adhesion, cell contraction, apoptosis, cytokinesis, and in the migration and invasion of multiple cell types. Increased ROCK1 expression has been observed in a number of pathological conditions, including cancer. We identified a low frequency (4/34) amplification of the ROCK1 gene locus at chromosome 18q11.1 in pancreatic ductal adenocarcinoma (PDA) patient tissue samples by aCGH analysis. We therefore hypothesized that ROCK1 might play an important role in pancreatic cancer progression, and may serve as a suitable target in pancreatic cancer treatment. Consistent with findings in other tumor types, we observed increased expression of ROCK1 in pancreatic epithelial cells relative to the surrounding stromal cells, or adjacent normal pancreatic ductal cells, in an immunohistochemical (IHC) analysis of a pancreatic cancer tissue array. In our study, 76% (53/70) of tumor samples exhibited 2+ or greater (scale 0-3+) in staining intensity by IHC analysis, versus 40% (19/47) of adjacent normal tissue samples (P&lt;0.0001). This same increased expression of ROCK1 in cancer cells was also observed in a coculture model of human PDA cells and primary myofibroblast cells derived from PDA tissues. Inhibition of ROCK kinase activity by small molecule inhibitors (Fasudil and Y27632) demonstrated moderate (IC50s range from 2-30 μM) inhibition of PDA cell proliferation. An increased sensitivity to ROCK1 inhibition was observed in PDA myofibroblasts, which corresponded with a decreased expression of Collagen I. These results suggest that ROCK1 may play a role in pancreatic cancer, both in the proliferation of tumor epithelial cells, as well as the development of the stromal compartment. Based on these findings we feel that ROCK1 is a potential therapeutic target in both the tumor and stromal cells in pancreatic cancer, and may provide an effective means to enhance current treatment regimens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2601. doi:10.1158/1538-7445.AM2011-2601
Abstract 2604: PENAO: A novel tumor metabolism inhibitor for glioblastoma
Authors: Chung Sylvia A. , Dilda Pierre J. , Ramsay Emma E. , Teo Charlie , Hogg Philip J. , McDonald Kerrie L. 
Published: June 2012

Abstract
Despite undeniable progress in the care and the treatment of primary brain tumors, for most patients diagnosed with glioblastoma (GBM) there is no realistic possibility of cure or even long term survival. Inherent resistance to conventional chemotherapy and irradiation are characteristic of GBM. Testing of new potential anti-tumorigenic drugs is needed. PENAO, (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a mitochondrial toxin that inactivates inner-membrane adenine nucleotide translocase (ANT) resulting in proliferation arrest and apoptosis of tumor and tumor-supporting cells. The cytostatic efficacy of PENAO was tested on a panel of five commercial and primary GBM cell lines that differed in tumorigenicity, drug resistance, invasion and DNA repair. PENAO demonstrated an impressive anti-proliferative activity compared to carboplatin and temozolomide, drugs commonly used to treat GBM patients. The half maximal inhibitory concentration (IC50) values for PENAO were all in the low micromolar range. The increase in anti-proliferative activity for PENAO compared to carboplatin ranged from 6 to 200-fold. PENAO is a substrate for the multidrug resistant associated proteins 1 and 2 and inhibition of this transporter enhanced PENAO anti-proliferative activity from 2 to 8-fold. In conclusion, PENAO is a potent inhibitor of GBM cell line proliferation. This activity was superior to that observed with standard chemotherapeutics and warrants further in vivo investigations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2604. doi:10.1158/1538-7445.AM2011-2604
Abstract 2612: Effective targeting triple negative breast cancer cells by a novel oral heat shock protein 90 inhibitor PF-4942847
Authors: Mehta Pramod P. , Whalen Pamela , Kung Pei-Pei , Yamazaki Shinji , Gehring Michael R. , Yin Min-Jean 
Published: June 2012

Abstract
Triple negative breast cancer (TNBC) patients have poor prognosis and survival that the development of new targeted therapies for TNBC is strongly demanded. Genes associated with high proliferation and aggressive tumor progression, such as PI3K/PTEN aberration, EGFR overexpression, and cell cycle upregulation, play important roles in triple negative breast cancer. The molecular chaperone heat shock protein 90 (Hsp90) is required for the conformational maturation and stability of a variety of key signaling proteins, such as EGFR, AKT, Raf, p53, and cdk4, in addition to many others. Therefore, an Hsp90 inhibitor may present therapeutic benefits on TNBC via the inhibition of EGFR, AKT/PI3K pathway, and cell cycle progression. In this study, we describe a novel oral Hsp90 inhibitor, PF-4942847, which induces apoptosis and cell cycle block, as well as inhibits cell proliferation in TNBC cells through protein degradation in EGFR, cMet, AKT, and pERK. PF-4942847 exhibits excellent oral bioavailability in mice and effectively induces Hsp90 client protein degradation in MDA-MB-231 xenograft tumors, and subsequently abolishes the in vivo tumor growth of MDA-MB-231 in the xenograft model. Moreover, correlation of AKT degradation and Hsp70 induction in host peripheral blood lymphocytes (PBLs) and xenograft tumors was determined and reveals a differential target modulation dynamic between Hsp90 client proteins in different tissue compartments. These data implicate AKT degradation in PBLs as a possible biomarker of tumor progression for future clinical development. In summary, our results demonstrate PF-4942847 is a potent oral Hsp90 inhibitor and is a candidate for clinical development in triple negative breast cancer by collaboratively targeting multiple signaling pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2612. doi:10.1158/1538-7445.AM2011-2612
Abstract 2618: DNMT1 as a marker of differential sensitivities to epigenetic therapy of a Kras mutant and Kras wild type human non small cell lung cancer cell line
Authors: Du Zhenzong , Wrangle John , Pelosky Kristen , Harris James , Shin James , Vendetti Frank , Hulbert Alicia , Lee Beverley , Zahnow Cyntia , Ahuja Nita , Herman James , Baylin Stephen , Brock Malcolm 
Published: June 2012

Abstract
INTRODUCTION: Epigenetic therapy with a demethylating agent and an histone deacetylase inhibitor (HDACi) is now being pursued in hematological as well as solid tumor malignancies. Clinical responses have been varied with complete responses in some patients and no efficacy of the drugs in others. We investigated the effect of this therapy on two targets, DNA methyltransferase1 (DNMT1) and H3K4 modified histones, respectively.
METHODS: Two human lung adenocarcinoma cell lines, A549 (Kras mutant) and H838 (Kras wild type) were pre-exposed for 72 hours with daily treatment of 500nM azacitidine alone or 72 hours of daily 500nM azacitidine followed subsequently with 10 nM, 100nM, 1000nM entinostat at 96 hours. DNMT1 and H3K4 protein levels were assayed by Western blot analysis at various time points after treatment. Cells were also re-plated after treatment to assess differential growth characteristics.
RESULTS: In vitro growth of H838 cells is sensitive to azacitidine alone and in combination with entinostat whereas growth of the A549 cell line is only sensitive to azacitidine and entinostat in combination. Treatment with azacitidine, severely depleted DNMT1 protein expression in H838 cells both when given alone and in combination with most dose levels of entinostat. This decrease was transient and within 4 days, the protein was fully replenished. Azacitidine alone did not cause an appreciable decrease in DNMT1 protein expression of A549 cells but, when combined with increasing levels of entinostat, DNMT1 levels were significantly depleted and did not replenish for 7 days. Re-plating after treatment showed growth inhibition versus mock of all regimens containing azacitidine in the H838 cell line only whereas growth inhibition in the A549 cells was observed only in the combinatory therapy arms. Furthermore, in the A549 cell line, H3K4 protein levels (a marker of active gene expression) peaked at 7 days after treatment versus a peak in the first 24 hours in the H838 cell line.
CONCLUSIONS: Differing sensitivities to epigenetic therapy in lung adenocarcinoma cell lines may reflect underlying differences in molecular phenotypes. Large decreases in DNMT1 expression are associated with sensitivity to azacitidine. In a cell line insensitive to azacidine alone, the addition of entinostat may accentuate DNMT1 protein depletion and delay its reexpression. This effect on DNMT1 may render this latter cancer cell line more sensitive to epigenetic therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2618. doi:10.1158/1538-7445.AM2011-2618