bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C156: GRB7 is required for triple-negative breast cancer motility, invasion, and chemoresistance.
Authors: Giricz Orsi , Calvo Veronica , Pero Stephanie C. , Krag David N. , Sparano Joseph A. , Kenny Paraic A. 
Published: June 2012

Abstract
Triple-negative breast tumors lack expression of estrogen and progesterone receptors and HER2, rendering them non-responsive to the most effective targeted therapies in breast cancer. These tumors are typically more aggressive than other breast cancer subtypes and, consequently, have a poor prognosis. In a clinical trial of triple-negative breast cancer patients treated with anthracyclines and taxanes, we and others have recently determined that high levels of GRB7 are predictive of tumor recurrence (Sparano et al. J Clin Oncol 27(15s) 500). GRB7 is a cytoplasmic adaptor protein that interacts with receptor tyrosine kinases and integrins, transducing information to their downstream signaling cascades.
In this study, we have tested the hypothesis that triple-negative breast cancer cell lines are dependent on GRB7 for migration, invasion and colony formation in 3D culture. Using a highly specific peptide inhibitor (G7–18NATE), we found that the GRB7 inhibition significantly impaired each of these phenotypes in four triple-negative breast cancer cell lines: MDA-MB-468, MDA-MB-231, HCC70 and T4-2. In addition, we have tested whether GRB7 inhibition may sensitize these cell lines to the chemotherapies used in the initial clinical trial. Combination treatment with G7–18NATE and doxorubicin or docetaxel resulted in cooperative cell growth inhibition in each of the four cell lines. Co-treatment lowered the IC40 of both chemotherapeutic agents, and it proved to be synergistic in all cases (Combination Index values &lt;1)
These data implicate GRB7 as a key mediator of migration, invasion, colony growth and chemoresistance of triple-negative breast cancer cells and suggest that GRB7 itself, or GRB7-dependent pathways, may prove to be important therapeutic targets.
This work was supported in part by Susan G. Komen for the Cure (KG091136 and KG100888).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C156.
Abstract C157: Identification of activated receptor tyrosine kinases in colon cancer cell lines.
Authors: Lee Choong-kun , Lee Myung Eun , Hong Soojung , Kim Han Sang , Kim Hye Ryun , Shin Yoo Kun , Kim Tae Soo , Ahn Joong Bae , Chung Hyun Cheol , Rha Sun Young 
Published: June 2012

Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States and increasing rapidly in Asian countries. To improve colorectal cancer treatment, relevant molecular targets need to be identified. Receptor tyrosine kinases (RTKs) are multifunctional transmembrane proteins and important mediators of the signaling cascade, determining key roles in diverse biological processes such as proliferation, growth, differentiation, and apoptosis of cells. Recent advances in understanding of cellular signaling by RTKs have brought to light the potential of RTKs as anti-cancer targets. To determine if any of these RTKs are activated in colorectal cancer, we performed phospho-receptor tyrosine kinase array and evaluated its possibility as a therapeutic target. We examined activation pattern of RTKs in 10 colon cancer cell lines using Human Phospho-RTK Antibody Proteome Profiler Array (R&D Systems). Relative levels of tyrosine phosphorylation of RTKs among these cell lines were determined as a ratio relative to positive control's intensity in each membrane. TKI-258 (Novartis Inc.), a specific class III-V RTK inhibitor, was used to evaluate its anti-cancer effect. To confirm of anti-cancer effect of TKI-258 in vivo, xenograft model with LoVo cells was used. We found that various RTKs including fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) were highly activated in colon cancer cell lines. The RTK activity and related signaling molecules were decreased on TKI-258 treatment in a time-dependent manner. Also, TKI-258 treated cells showed significantly impaired anchorage-independent growth in soft agar colony formation assay as compared with the control cells. In vivo xenograft model, TKI-258 treated group showed anti-tumor growth effect compared with control group. These results suggested that various RTKs are highly activated in colorectal cancer, and these RTKs might be specific targets for colorectal cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C157.
Abstract C159: Identification of potential cancer drug targets using HT RNAi screening with pooled shRNA libraries.
Authors: Tedesco Donato , Bonneau Kyle , Makhanov Mikhail , Frangou Costas G. , Chenchik Alex 
Published: June 2012

Abstract
Genes modulating proliferation and survival in oncogenic cells have been identified using pooled lentiviral-based libraries expressing many thousands of shRNAs. Viability assays with human isogenic mammary epithelial cells (HMEC) and blood cancer cell lines transduced with these shRNA libraries targeting thousands of genes identified hundreds of essential genes for each panel of cells. Subsequent validation using single shRNA-expressing constructs showed that about 80% of the shRNAs identified in each complex library screen did in fact lead to cell death when transduced in cells. Analysis of the identified essential genes for known biological interactions revealed non-random clusters of interacting proteins that provide some insight into signaling pathways and protein networks specific to these cancers. Also, we have recently adapted the approach to combinatorially screen shRNA sequences targeting hundreds of genes to discover additive and synergistic combinations that generate a synthetic-lethal phenotype. Analysis of the lethal combinations indicates redundant, complementary, and compensatory responses in cancer cells. This presentation will provide an overview of the screening platform, our approach to shRNA library design, and results from the screens for cancer cell-specific lethal and synthetic-lethal genes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C159.
Abstract C164: Preclinical pharmacological characterization of GBR 401, a new monoclonal antibody directed against human CD19.
Authors: Hou Samuel , Blein Stanislas , Skegro Darko , Macoin Julie , Lissilaa Rami , Back Jonathan 
Published: June 2012

Abstract
GBR 401 is a humanized monoclonal antibody directed against domain 2 of human B-lymphocyte antigen CD19 and displays a number of mechanisms which can specifically target and kill B cells. Glenmark is developing this product as a B-cell depleting agent for B cell malignancies.
CD19 is the archetypal B cell marker and is used in the diagnosis of B cell lymphomas/ leukemias by the identification of abnormal B cell numbers and/or populations. Expression of CD19 is found in the majority of B cell lineage malignancies including, but not limited to non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia. Given its role as a signaling molecule, an antibody directed against CD19 might be predicted to affect the progression of lymphomas and leukemias.
GBR 401 is a humanized IgG1 which can specifically kill CD19 bearing cells with very efficient in vitro antibody-dependent cellular cytotoxicity (ADCC) and rapid-onset apoptosis-inducing abilities. It also can inhibit the proliferation of CD19+ tumor cells but has little to no complement dependent cytotoxicity (CDC), at least, in vitro. The in vivo anti-B cell activity of GBR 401 was evaluated using human peripheral blood mononuclear cell (huPBMC) graft models in SCID mice. GBR 401 significantly depleted human B cells in grafted mice at levels down to 0.1mg/kg compared to an isotype control. GBR 401 also produced approximately 50% depletion or EC50 at 0.02mg/kg. These in vitro and in vivo pharmacology data provide a rationale for the clinical testing of GBR 401 in patients with CD19+hematologic malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C164.
Abstract C168: Cancer-selective mitochondrial copper transport by elesclomol results in potent single agent efficacy in multiple tumor types.
Authors: Sang Jim , Nagai Masazumi , Zhang Chaohua , Smith Donald , Sequeira Manuel , Ogawa Luisa Shin , Ye Josephine , Liu Yuan , Inoue Takayo , Zhou Dan , Koya Keizo , Wada Yumiko 
Published: June 2012

Abstract
Elesclomol is a first-in-class investigational drug that exerts potent anticancer activity through the elevation of reactive oxygen species (ROS) levels and is currently under clinical evaluation as a novel anticancer therapeutic. We recently demonstrated that elesclomol preferentially binds extracellular copper (Cu) and selectively transports this metal ion to the mitochondria of tumor cells to promote mitochondrial ROS generation and subsequent apoptosis. Here we report that elesclomol-induced copper transport and apoptosis is tumor selective. Comparative analysis using human PBMCs and the promyelocytic tumor cell line HL-60 demonstrated increased Cu levels in the mitochondrial fraction of HL-60 cells following elesclomol-Cu treatment, but not in donor PBMCs. Further, elesclomol-Cu induces ROS in HL-60-derived mitochondria but not in those isolated from PBMCs. These results suggest that elesclomol-Cu selectively targets cancer cell mitochondria to ultimately produce critical elevations in oxidative stress. To evaluate increased exposure to elesclomol-Cu in vivo, elesclomol was administered continuously to tumor-bearing mice using an Alzet pump at a clinically relevant dose. Upon release, elesclomol immediately chelates copper from the blood to form an elesclomol-Cu complex, achieving 10-fold higher levels of elesclomol-Cu compared to those following bolus injection. Even with this increased formation of elesclomol-Cu in situ, no signs of toxicity have been observed. In five different tumor xenograft models tested, elesclomol consistently demonstrated marked single agent activity with significant tumor growth suppression, indicating that increased elesclomol-Cu levels result in selective and enhanced antitumor efficacy. These findings highlight a unique mechanism of action of elesclomol and support potential single agent activity of this compound in a variety of tumor types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C168.
Abstract C169: Inhibition of SREBPs by fatostatin reduces glioblastoma cell proliferation and viability.
Authors: Youssef Mary , Reinitz Felicia , Cloughesy Timothy , Mischel Paul , Guo Deliang 
Published: June 2012

Abstract
Glioblastoma (GBM) is the most common type of malignant brain tumor. Due to its aggressive invasion of the surrounding tissue, it is one of the most deadly cancers, with an average patient survival rate of 12–18 months after diagnosis despite surgery, radiation and chemotherapy, underscoring the urgent need to find new molecular targets and effective drugs. Recently, The Cancer Genome Atlas identified that the RTK/PI3K/Akt pathway, which can be initiated by epidermal growth factor receptor (EGFR), is activated in about 88% of GBM; this pathway has been recognized as a major driver in promoting malignant cancer cell growth in several cancers. In accordance with this, our group has demonstrated that aberrant EGFR/PI3K/Akt signaling promotes GBM cell growth through sterol regulatory element-binding protein 1 (SREBP-1) mediated fatty acid synthesis and cholesterol uptake, and identified SREBP-1 as a potential molecular target. The focus of our research is to evaluate inhibitors of lipid synthesis/uptake, and to assess their affect on GBM growth. Previously, the small molecular inhibitor fatostatin was shown to effectively inhibit cleavage and activation of SREBPs, suggesting that it can prevent EGFR induced lipid synthesis and uptake and reduce cancer cell viability. Indeed, GBM cells treated with fatostatin exhibited diminished cell proliferation and increased cell death in a dose-dependant manner. These data suggest that alteration of lipid and cholesterol homeostasis through pharmacological inhibitors can suppress glioblastoma growth, providing a new avenue for treating GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C169.
Abstract C171: TriplatinNC, a nucleolar-targeting platinum agent. Heparan sulfate-mediated cell entry, localization, and apoptosis.
Authors: Peterson Erica , Silva Heveline , Menon Vijay , Benedetti Brad , Kipping Ralph , Farrell Nicholas 
Published: June 2012

Abstract
TriplatinNC, a “non-covalent” derivative of the phase II clinical drug BBR3464, exhibits a distinct mode of DNA binding mediated through “phosphate clamps”, which display structural analogy to the “polyarginine” (arginine fork) DNA/RNA recognition motif. TriplatinNC shows an improved pharmacokinetic profile and increased cellular accumulation compared to BBR3464. Furthering the “polyarginine” analogy, the cellular accumulation of TriplatinNC, unlike cisplatin or oxaliplatin, is dependent upon the presence of cell surface glycosaminoglycans (GAGs), shown through comparison of platinum level accumulation in wild-type Chinese Hamster Ovary (CHO) cell lines to those lacking heparan sulfate (CHO-pgsD-677) or both heparan sulfate and chondroitin sulfate (CHO-pgsA-745). The cellular localization of TriplatinNC and cisplatin was visualized in confocal microscopy experiments utilizing the fluorescently-tagged derivatives, TriplatinNC-NBD or cisplatin-NBD. TriplatinNC, but not cisplatin, shows distinct localization to the nucleolar region of human colon and ovarian carcinoma cell lines, HCT116 and A2780, respectively. It was hypothesized that this pattern of localization, combined with nucleic acid affinity, would allow TriplatinNC to disrupt rRNA synthesis, the primary function within the nucleolus. Using 32P-metabolic labeling to monitor the rate of pre-rRNA transcript formation after cellular treatment, it was observed that both 47S pre-RNA and processed rRNAs, 32S, 28S, and 18S levels decreased dramatically compared to the untreated control in a dose-dependent manner. While the localization and abundance of nucleolar proteins, RNA pol I and UBTF, were unaffected by treatments with TriplatinNC at early timepoints, levels of the clinical relevant proliferative marker Ki-67, decreased markedly within one hour post-treatment. The morphological characteristics of apoptosis, including reduction in cell size, membrane blebbing, and cytosolic vacuolization, become visible 10hrs after drug treatment. This apoptotic process is not dependent on p53, as western blot analysis showed cleavage of procaspases 8, 9, and 3, followed by Parp-1 in HCT116 p53+/+ and p53−/− cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C171.
Abstract C175: JS-K, a nitric oxide-releasing anticancer prodrug with a broad spectrum of action.
Authors: Maciag Anna E. , Saavedra Joseph E. , Nandurdikar Rahul S. , Holland Ryan J. , Shami Paul J. , Anderson Lucy M. , Keefer Larry K. 
Published: June 2012

Abstract
Non-small cell lung cancer (NSCLC) is among the most common and deadly forms of human malignancies. Early detection is unusual and cures are limited to early stage disease. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent anticancer agent that has proven effective in several cancer models in vitro and in vivo, including NSCLC. Here we report mechanistic studies with JS-K and its homopiperazine analogue and structural modification of these into more stable prodrugs. Prodrugs of the JS-K class were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector, activating transcription factor 3 (ATF3). Treatment of the NSCLC cells with JS-K resulted in oxidative/nitrosative stress, which combined with the arylating properties of the compound was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization and cytochrome c release. Inactivation of MnSOD by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have anti-tumor activity. The data suggest that: 1) diazeniumdiolate-based NO-releasing prodrugs may have application as a therapy for lung cancer; 2) rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C175.
Abstract C176: Activity of novel indolequinone inhibitors of thioredoxin reductase 1 in pancreatic and colon cancers and in melanomas. Signaling mechanisms underlying antiproliferative activity.
Authors: Yan Chao , Inman Martyn , Thompson Christopher , Quackenbush Kevin , Reinemann Jaclyn , Chan Dan , Zhang Zhiyong , Messersmith Wells , Arcaroli John , Siegel David , Moody Christopher J. , Ross David 
Published: June 2012

Abstract
Novel indolequinones (including QG001, 5-methoxy-1-methyl-3-[(2,4,6-trifluorophenoxy)methyl]-1H-indole-4,7-dione and NJ824, 2-(hydroxymethyl)-5-methoxy-1-methyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione) demonstrated marked anti-proliferative activity in MIAPaCa-2 and BxPC-3 pancreatic cancer cells as well as in colon, melanoma and renal cell lines as indicated by testing in the NCI-60 cell line screen. In studies using MIAPaCa-2 and BxPC-3 cell lines we examined the mechanism of action of lead IQs and results demonstrated inhibition of the selenoprotein thioredoxin reductase 1 (TR1) and induction of apoptosis in pancreatic cell lines at doses approximating their IC50 values obtained from MTT growth inhibition assays. Other selenoproteins such as glutathione peroxidase were not inhibited and the depletion of cellular thiols was not observed following treatment with lead IQs indicating target selectivity. The mechanisms underlying IQ-induced apoptosis were investigated and lead IQs were found to induce oxidation of cellular thioredoxin subsequent to inhibition of thioredoxin reductase 1 and downstream activation of p38 and JNK leading to apoptosis. IQ-induced apoptosis could be inhibited by the use of p38 and JNK inhibitors in MIAPaCa-2 cells confirming the importance of this pathway. The role of ASK1 as an intermediary MAPKKK modulating signaling from oxidation of thioredoxin to activation of p38 and JNK was investigated in MIAPaCa-2 cells overexpressing ASK1 and lead IQs were found to induce ASK1 phosphorylation. Studies were extended to panels of eighteen human colorectal cancers and nineteen pancreatic cancer cell lines and lead IQs were found to exhibit marked growth inhibitory activity with IC50 values ranging from 0.05 to 0.5 micromolar. In vivo studies were performed in xenograft systems and lead IQs demonstrated significant growth inhibitory activity in both pancreatic and melanoma xenografts. These data demonstrate that this class of IQ has marked growth inhibitory activity in pancreatic, colon and melanoma tumors and are worthy of further translational evaluation as potential therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C176.
Abstract C178: Synergistic activity of SR16388 with microtubule inhibitors against multiple cancer cell lines.
Authors: Zhou Wei , Calaogan Joy , Sato Barbara , Sambucetti Lidia 
Published: June 2012

Abstract
Synergistic combinations of anti-cancer compounds can provide therapeutic benefits by producing better efficacy at potentially lower doses. SR16388, a novel steroidal compound that inhibits estrogen and estrogen-related receptors, has previously been shown to inhibit the proliferation and viability of diverse human cancer cell lines in vitro and to reduce the growth of several types of human xenograft tumors in mice, including, NSCLC and androgen-independent prostate cancer. We examined the two-drug combination effects of SR16388 in cell culture systems using a panel of approved cancer drugs with different mechanisms-of-action. Sixty cancer cell lines were treated with compounds alone or in combination for three days and CellTiter-Glo® Luminescent Cell Viability Assay (Promega Corp.) was used as the endpoint to measure cell viability. Combinations of SR16388 with anti-mitotic drugs Paclitaxel or Vincristine demonstrated synergistic effects on cell killing in multiple cell lines. These synergistic effects were further evaluated by calculating combination-index values using CalcuSyn software (Biosoft, Cambridge, UK)”. Studies are ongoing to elucidate the mechanisms that may lead the synergistic interaction of SR16388 and these antimitotic drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C178.