bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3681: Aspirin acetylates glucose 6 phosphate dehydrogenase and inhibits its activity in colon cancer cells.
Authors: Ai Guoqiang , Hagen Fred K. , Gunaje Jayarama B. 
Published: August 2014

Abstract
Epidemiological studies have demonstrated a significant correlation between regular aspirin use and reduced colon cancer incidence and mortality. Although a consensus is emerging on the view that aspirin has significant anti-cancer properties, it is not yet clear which pathways or molecular targets might be involved. We hypothesized that aspirin's anti-cancer effect may occur through acetylation of a panel of protein targets, including novel candidates with modulated functional activity, as a result of aspirin-mediated acetylation. In the present study, using anti-acetyl lysine antibody, we determined aspirin-mediated protein acetylation profiles in three different colon cancer cell lines namely HCT-116, HT-29 and GC3/c1, by treating cells with aspirin at different concentration, and analyzing them in Western Blot. We observed that in all cell lines tested, aspirin induced acetylation of multiple proteins in a concentration dependent fashion spanning a molecular weight range from 20 to 200 kDa. Aspirin's acetylation targets included the tumor suppressor protein p53, and glucose 6 phosphate dehydrogenase (G6PD), an enzyme in the pentose phosphate pathway. Mass spectrometry analysis of the recombinant G6PD, treated with aspirin in vitro, revealed acetylation of up to 14 distinct lysine residues, including lysine 235 at its active site. In vitro G6PD assay in lysates isolated from the cancer cell lines showed that aspirin caused a 70% decrease in the G6PD enzyme activity in HCT116 cells; however, the reduction in the enzyme activity was less in HT-29/GC3/c1 cells (up to 30%). Inhibition of G6PD activity leading to a reduction in ribonucleotide synthesis and cell proliferation may represent an important mechanism by which aspirin exerts its anticancer effects.
Citation Format: Guoqiang Ai, Fred K. Hagen, Jayarama B. Gunaje. Aspirin acetylates glucose 6 phosphate dehydrogenase and inhibits its activity in colon 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 3681. doi:10.1158/1538-7445.AM2013-3681
Abstract 3728: Anti-Notch1 antibody (OMP-52M51) impedes tumor growth and cancer stem cell frequency (CSC) in a chemo-refractory breast cancer xenograft model with an activating Notch1 mutation and screening for activated Notch1 across multiple solid tumor types.
Authors: Cancilla Belinda , Cain Jennifer , Wang Min , Beviglia Lucia , Shah Jalpa , Gurney Austin , Lewicki John , Esserman Laura , Hoey Tim , Kapoun Ann M. 
Published: August 2014

Abstract
The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated in many human cancers. Notch1 is also known to be activated by oncogenic mutations in tumors including T cell leukemia, chronic lymphocytic leukemia and non-small cell lung cancer. Here we report the discovery of similar mutations in breast cancer. We have developed a primary human xenograft model from a patient bearing an activating Notch1 mutation and have shown that blocking Notch signaling in this model with a novel anti-Notch1 antibody, OMP-52M51, impeded tumor growth and reduced cancer stem cell (CSC) frequency. OMP-52M51 is a humanized antibody that binds with high affinity and selectivity to human Notch1 and antagonizes Notch signaling.
Additionally, we sought to determine the frequency of Notch pathway activation across a large panel of human tumors (n&gt;600) by an immunohistochemistry assay that detects the activated form of Notch1 using a polyclonal antibody that specifically recognizes the Notch1 intracellular domain (ICD). Using this test and a rigorous H-score cut-off of 30, we found elevated Notch1 in 7-29% of the following cancers: chemo-resistant breast, gastric, cholangiocarcinoma, esophageal, hepatacellular carcinoma (HCC), and small cell lung cancer (SCLC).
The class of patients that showed the highest frequency of elevated Notch1.ICD was chemo-resistant breast cancer (∼30%). This frequency was significantly higher than in unselected breast cancer patients, suggesting that Notch1 signaling plays a significant role in breast cancer chemoresistance. Interestingly, the human xenograft model which showed sensitivity to OMP-52M51 was derived from a patient that failed to respond to pre-operative chemotherapy and developed metastatic disease following surgery. Thus, chemo-resistant breast cancer as well as the other tumors with high Notch1.ICD may represent important classes of patients who could benefit from anti-Notch1 therapy in the clinic.
Citation Format: Belinda Cancilla, Jennifer Cain, Min Wang, Lucia Beviglia, Jalpa Shah, Austin Gurney, John Lewicki, Laura Esserman, Tim Hoey, Ann M. Kapoun. Anti-Notch1 antibody (OMP-52M51) impedes tumor growth and cancer stem cell frequency (CSC) in a chemo-refractory breast cancer xenograft model with an activating Notch1 mutation and screening for activated Notch1 across multiple solid tumor types. [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 3728. doi:10.1158/1538-7445.AM2013-3728
Abstract 4000: Genistein-induced reduction of Wnt/beta-catenin pathway activity in colorectal cancer cell lines correlates with inhibition of proliferation and colony growth in soft agar .
Authors: Pintova Sofya , Planoutis Kestutis , Planutiene Marina , Holcombe Randall F. 
Published: August 2014

Abstract
Introduction. The majority of colorectal cancers (CRC) have mutationally-driven constitutive activation of the Wnt pathway. Despite this, tumor cells remain responsive to Wnt signals arising at the cell membrane through the interaction of extracellular Wnt ligands and cell surface frizzled receptors; the strength of the Wnt signal can be modified by Wnt pathway inhibitors (sFRP) in the tumor microenvironment. Genistein, a natural product from soy, is known to remove epigenetic blockage of sFRP promoters and decrease nuclear beta-catenin expression, a marker for Wnt pathway activation. In this study we have examined the effect of genistein on Wnt throughput in CRC cell lines and on proliferation in tissue culture and growth in soft agar.
Methods. Human CRC cell lines HT29, DLD1 and RKO were transfected with Wnt/beta-catenin reporter plasmids and treated with different concentrations of genistein. Pathway activity was measured using a super TOP-flash luminescence reporter construct. Proliferation was estimated with an MTT assay. A soft agar assay was utilized to define non-adherent colony formation.
Results. Genistein reduced proliferation of HT29 and DLD1 at 50uM, with an inhibitory P50 at 100uM. RKO cells were inhibited at lower concentrations. Inhibition of soft agar colony growth occurred at similar concentrations. Wnt/beta-catenin activity was significantly inhibited at 75uM for HT29 (p=0.025) and at 50uM for DLD1. The reduction in proliferation and colony growth correlated with reduced Wnt signaling, with the latter most strongly correlated (R2=0.81 vs. 0.47 for the former). Cells growing independently of anchorage were more sensitive to genistein treatment than those attached to the plastic : colony counts decreased for RKO 8-fold at 50 uM while proliferation on plastic decreased less than 4x; colony counts decreased for HT29 7-fold for at 100 uM while proliferation on plastic decreased less than 2x.
Conclusions. Genistein reduces Wnt/beta-catenin activity in CRC cell lines; this reduction correlates with cell proliferation in vitro and with soft agar colony growth. Cells growing in an anchorage-independent fashion appear more sensitive to genistein treatment. Further investigation into the mechanisms of this effect in CRC is ongoing. These data suggest that genistein may be a useful adjunctive therapy for patients with CRC.
Citation Format: Sofya Pintova, Kestutis Planoutis, Marina Planutiene, Randall F. Holcombe. Genistein-induced reduction of Wnt/beta-catenin pathway activity in colorectal cancer cell lines correlates with inhibition of proliferation and colony growth in soft agar . [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 4000. doi:10.1158/1538-7445.AM2013-4000
Abstract 427: c-Met reduces response to radiation in breast cancer.
Authors: Veenstra Cynthia , Pérez-Tenorio Gizeh , Fornander Tommy , Skoog Lambert , Nordenskjöld Bo , Stål Olle 
Published: August 2014

Abstract
The c-Met receptor promotes cell survival and proliferation by activating signalling pathways. c-Met is abundant in several cancers and in some cases it interferes with treatment response. In vitro, c-Met has been shown to be up-regulated and activated after radiation treatment, which renders the cells resistant to apoptosis and radiation. Therefore, it was hypothesised that high c-Met expression could influence response to radiation in breast cancer. In this study, it was aimed to determine the number of MET gene copies and c-Met protein expression in breast tumours. Tumours of 172 post-menopausal patients with primary breast cancer were analysed for MET using qPCR. Increased MET copy number (three or more copies) was found in 34% of the tumours. Five or more gene copies were found in 4.7% of the patients and indicated a significantly higher risk of developing distant metastasis. For the patients that received radiotherapy as the only postoperative treatment, the number of MET copies was associated with increased risk of distant metastasis. In terms of loco-regional recurrence, it was found that increased MET copy number was associated with worse response to postoperative radiation therapy compared with chemotherapy. c-Met protein analysis by immunohistochemistry in tumours of 208 pre-menopausal patients with primary breast cancer revealed that patients with low expression of c-Met responded better to radiotherapy compared with patients with a high c-Met expression. These results suggest that radiotherapy in combination with a Met inhibitor may be an option for patients with increased c-Met expression, to overcome radio-resistance.
Citation Format: Cynthia Veenstra, Gizeh Pérez-Tenorio, Tommy Fornander, Lambert Skoog, Bo Nordenskjöld, Olle Stål. c-Met reduces response to radiation in breast cancer. [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 427. doi:10.1158/1538-7445.AM2013-427
Abstract 4437: Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double strand breaks.
Authors: Shen Changxian , Oswald Duane , Phelps Doris , cam hakan , Pelloski Christopher E. , Pang Qishen , Houghton Peter J. 
Published: August 2014

Abstract
Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA damaging agents, however the molecular mechanism is not well understood. We found that a mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft to radiotherapy and sensitized rhabdomyosarcoma cells to interstrand crosslinker (ICL) melphalan. Sensitization correlated with drug-induced downregulation of a key component of the Fanconi anemia (FA) pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2 deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2-deficient cells demonstrated impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by re-introduction of wild type FANCD2. Pharmacological inhibition of PI3K-mTOR-Akt pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double strand breaks by sustaining FANCD2 and provide a novel mechanism of how the FA pathway modulates DNA damage response and repair.
Citation Format: Changxian Shen, Duane Oswald, Doris Phelps, hakan cam, Christopher E. Pelloski, Qishen Pang, Peter J. Houghton. Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double strand breaks. [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 4437. doi:10.1158/1538-7445.AM2013-4437
Abstract 4532: Fluorine-18- carboplatin derivative for imaging and therapeutic applications.
Authors: Dewkar Gajanan K. , Jose Purnima , Lamichhane Narottam , Thadigiri Celina , Sundaresan Gobalakrishnan , Farrell Nicholas , Zweit Jamal 
Published: August 2014

Abstract
DNA-damaging agents, such as cisplatin and other platinum drugs are the largest class of anti-cancer drugs. They are most important in the clinical use for the treatment of various cancers, although ovarian cancer cells often become resistant. Besides resistance, non-specific uptake in normal tissues and related toxicity is a dose limiting factor and affects their overall effectiveness. Knowledge of the drug concentration in the tumor as well as its overall concentration in the body of a patient will be helpful in accurately predicting the overall responsiveness of a patient to the drug. This type of knowledge can be accomplished by the development of a drug analog with positron emission tomography (PET) imaging capability, so that the accumulation of the drug in the tumor and normal organs can be tracked and quantified during the course of therapy to predict its effectiveness in a patient. Therefore, we developed a novel fluorinated carboplatin derivative, towards a hybrid agent for imaging and therapy. We synthesized 19F fluorinated carboplatin derivative using 2-(5-fluoro-pentyl)-2-methyl malonic acid by co-ordination with cis-platinum aqua complex. It was then used to treat various cell lines and compared with Cis-platin and Carboplatin at different concentrations ranging from 0.001 μM to 100 μM for 72 hrs and 96 hrs. LC50 values calculated from cell viability indicate that fluorinated carboplatin is a more potent drug than Carboplatin but less effective than Cisplatin.
Table 1: LC50 values of fluorinated carboplatin and known platinum drugs Cell line Cisplatin (μM) Carboplatin(μM) Fluorinated Carboplatin (μM) 72 hrs 96 hrs 72 hrs 96 hrs 72 hrs 96 hrs COLO 205 28.78 1.35 &gt;100 48.98 92.52 31.56 SK-OV-3 4.34 1.28 33.7 18.94 20.3 12.56 FaDu 2.77 &lt;2 34.72 11.26 21.54 8.55 A549 11.01 3.07 56.56 31.78 41.18 24.8 A498 13.35 3.42 152.83 39.34 57.25 18.5 LNCaP 19.2 7.18 113.51 63.4 80.09 46.06 RWPE-1 6.27 &lt;1 65.19 36.8 34.69 10.2 KB 3-1 4.13 2.04 59.82 26.08 22.76 13.46
We have also developed a microfluidic method to synthesize [18F]-2-(5-fluoro-pentyl)-2-methyl malonic acid, which will co-ordinate with cis-platinum aqua complex to yield 18F labeled carboplatin derivative. Our approach to synthesis various derivatives of 18F labeled fluorinated carboplatin will allow us to develop anticancer drugs with PET imaging capabilities.
Citation Format: Gajanan K. Dewkar, Purnima Jose, Narottam Lamichhane, Celina Thadigiri, Gobalakrishnan Sundaresan, Nicholas Farrell, Jamal Zweit. Fluorine-18- carboplatin derivative for imaging and therapeutic applications. [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 4532. doi:10.1158/1538-7445.AM2013-4532
Abstract 4755: Combination of PV-10 immuno-chemoablation and systemic anti-CTLA-4 antibody therapy in murine models of melanoma.
Authors: Wachter Eric A. , Blair Savannah , Singer Jamie , Dees Craig 
Published: August 2014

Abstract
Rose bengal disodium (PV-10) is an investigational small molecule ablative agent currently entering pivotal phase 3 clinical testing as a monotherapy for locoregional control of cutaneous metastatic melanoma. Upon intralesional (IL) administration, PV-10 localizes to the injected tumor tissues while clearing rapidly from healthy tissue. Tumor infiltration with PV-10 leads to rapid necrosis of the injected lesion, with complete resolution common within 2-8 weeks. In phase 2 testing in 80 patients with Stage IIIB-IV(M1c) melanoma, IL PV-10 elicited an objective response in injected tumors in 51% of patients (CR:25%, PR:26%) after 1-4 treatment cycles. In addition to this direct ablative effect on injected tumors, some patients achieved an objective response in their monitored untreated tumors (CR:26%, PR:7% in 42 subjects with monitored untreated lesions) in an apparent immune-mediated bystander response that highly correlated with successful ablation of their injected tumors. Treatment was generally well tolerated, with adverse events confined mainly to the injection site and no grade 4 or 5 adverse events associated with use of PV-10. Recent nonclinical testing in the B16-F10 murine melanoma tumor line has confirmed that PV-10 ablation induces tumor-specific immunity, resulting in marked suppression of synchronous lung metastases upon ablation of a flank tumor and tumor-specific IFN-γ production. In this study we assess potential benefit of combination of PV-10 immuno-chemoablation with the hamster anti-murine CTLA-4 antibody 9H10 in bilateral flank and lung metastasis models (B16-F10 melanoma in C57BL/6 mice). Results from these models will be reported and could support clinical development of combination therapy in advanced melanoma patients, such as stage IV patients with substantial tumor burden in locations inaccessible to PV-10 injection. The rapid reduction in tumor burden and tumor specific immunologic stimulation provided by PV-10 may complement the immune stimulation of anti-CTLA-4 antibodies such as ipilimumab without increased toxicity.
Citation Format: Eric A. Wachter, Savannah Blair, Jamie Singer, Craig Dees. Combination of PV-10 immuno-chemoablation and systemic anti-CTLA-4 antibody therapy in murine models of melanoma. [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 4755. doi:10.1158/1538-7445.AM2013-4755
Abstract 493: Antitumoral efficacy of therapeutic human anti-KIR antibody (BMS-986015/IPH2102) in a preclinical xenograft tumor model.
Authors: Sola Caroline , Chanuc Fabien , Thielens Ariane , Fuseri Nicolas , Palacios Isabelle , Blery Mathieu , André Pascale , Vivier Eric , Ugolini Sophie , Graziano Robert , Romagne François , Bonnafous Cécile 
Published: August 2014

Abstract
Natural Killer cells (NK cells) are lymphocytes able to recognize and kill tumors for which the expression of Major Histocompatibility Complex (MHC) class I molecules is altered. This “missing self” recognition is mediated in humans by the lack of engagement of MHC class I i.e. Human Leucocyte Antigens (HLA) molecules with NK cell inhibitory receptors that include Killer Immunoglobulin-like Receptors (KIR). Some tumors escape NK cell immune surveillance by increasing the expression of HLA molecules on their surface. Consequently, blocking interactions between KIR and HLA molecules constitutes an interesting therapeutic strategy. The anti-KIR2DL1/2/3-specific monoclonal antibody, BMS-986015/IPH2102, is a human IgG4 that is being developed for treating both hematologic malignancies and solid tumors.
In rodents, the MHC class I inhibitory system regulating NK cell activation is based on lectin-like family Ly49 but the KIR molecules are not expressed. The objective of this study was to develop a preclinical model to assess the efficacy of the drug candidate used in clinical trials, BMS-986015/IPH2102. Mice expressing the human NK inhibitory KIR2DL3, on the surface of NK cells were generated on a RAG-1deficient background (KIRtgRAG mice). The human B cell lymphoma cell line, 721.221, transduced with HLA-Cw3 molecule, a ligand of KIR2DL3, was intra-venously engrafted in these mice. The expression of HLA-C by tumor cells was sufficient to allow them to escape control of NK cells, leading to mice death in around 30 days. IPH2102 treatment increased mice survival in a dose dependent manner when injected at the same time as the tumor challenge. This protective effect was NK cell mediated and directly correlated with the duration of KIR saturation. Interestingly, BMS-986015/IPH2102 treatment also improved survival in therapeutic conditions i.e. when the antibody was injected 5 days after the tumor, also in a NK cell dependent manner.
In conclusion, this study showed efficacy of BMS-986015/IPH2102 as single agent in a HLA-Cw3-expressing tumor model and this xenogenic pre-clinical model will be an excellent tool to investigate the therapeutic benefits of combination treatments.
Citation Format: Caroline Sola, Fabien Chanuc, Ariane Thielens, Nicolas Fuseri, Isabelle Palacios, Mathieu Blery, Pascale André, Eric Vivier, Sophie Ugolini, Robert Graziano, François Romagne, Cécile Bonnafous. Antitumoral efficacy of therapeutic human anti-KIR antibody (BMS-986015/IPH2102) in a preclinical xenograft tumor 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 493. doi:10.1158/1538-7445.AM2013-493