bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5646: Allele-specific shRNA to Nanog family members inhibits 3-D growth of colorectal carcinoma through the intrinsic apoptotic pathway
Authors: Zhang Jingyu , Thorgeirsson Snorri S. , Jessup J. Milburn 
Published: August 2012

Abstract
Nanog and NanogP8 modulate stemness of human colorectal cancer (CRC) as measured by directly affecting spherogenicity, tumorigenicity and metastatic potential. As a result, we tested whether targeting NanogP8 (the dominant Nanog member expressed in human CRC lines and liver metastases) by specific lentiviral (LV) shRNA inhibits the growth of CRC in 3-D spheroids in suspension culture. We first designed allele-specific shRNAs to NanogP8 and Nanog, genes that differ only in 5 nucleotides in a 915 nt ORF, and demonstrated that the shRNA to NanogP8 (shNp8-1) and Nanog (shNG-1) specifically inhibited their target in PA-1, a human embryonal carcinoma line expressing only Nanog, or CX-1, a CRC that expresses predominantly NanogP8. When Clone A or CX-1 CRC cells transfected with Luc2 were cultured for 24 hours in suspension in serum-free medium (SFM), transduced with LV shNP8-1, shNG-1 or a control shRNA (shNeg) at a multiplicity of infection (MOI) 8 and cultured for another 72 hours in SFM, all of the LV vectors transduced 40 - 75% of the cells in 3-D constructs. shNp8-1 transduction significantly reduced the mass of cells and luciferase activity by 50%. Apoptosis was induced because CRC treated with shNp8-1 had significantly more annexin V+ cells than did shNEG or untreated parental cells. Previous work in our lab demonstrated that caspase 8 was important in anoikis - the apoptosis caused by suspension of cells whose growth generally requires adherence. Caspase 3, 8 and 9 activity was measured by fluorogenic substrates in Clone A and CX-1 cells at 4 days of suspension culture, 3 days after LV treatment. Caspase 3 activity was increased by shNp8-1 by 2.5 to 3-fold in both CX-1 and Clone A compared to untreated cells. shNp8-1 treatment increased Caspase 9 activity by ∼50% in both CRC lines compared to untreated cells whereas shNEG and shNG-1 transduction did not increase Caspase 9 activity significantly. Treatment with a Caspase 9 peptidomimetic blocked apoptosis and increased CX-1 survival significantly. When cells were harvested at the end of the 4 day apoptosis assay and replated in a standard colony forming assay, CX-1 cells transduced with shNp8-1 LV produced 33% fewer colonies than did the shNEG and shNG-1 controls. These results indicate that shNp8-1 transduction may activate apoptosis through a Caspase 9-dependent pathway and that this treatment may have long term effects that inhibit tumor regrowth after treatment. Supported by Center for Cancer Research funds and Department of Defense IDEA grant W81XWH-11-1-0327.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5646. doi:1538-7445.AM2012-5646
Abstract 5660: Vaccinia virus GLV-1h153 in combination with 131I-iodine shows increased efficiency in treating triple-negative breast cancer in vivo
Authors: Gholami Sepideh , Chen Chun-Hao , Lou Emil , Marano Andrew A. , Mojica Kelly M. , Chen Nanhai G. , Aguilar Richard J. , Belin Laurence J. , Longo Valerie A. , Zanzonico Pat , Szalay Aladar A. , Fong Yuman 
Published: August 2012

Abstract
BACKGROUND: Triple-negative breast cancers (TNBC) are aggressive tumors due to their inherent biology and the lack of receptors for hormonal/targeted therapy, namely estrogen, progesterone, and Her2/neu. The human sodium iodide symporter (hNIS) is a naturally occurring protein in some human breast and thyroid tissue which enables cells to concentrate iodine, including radioiodide. In this study, we investigated the therapeutic efficacy of a new oncolytic vaccinia virus, GLV-1h153 carrying the hNIS, in combination with radioiodine in a TNBC murine model. METHODS: GLV-1h153, a replication-competent vaccinia virus, was tested against the TNBC cell lines MDA-MB-231, MDA-MB-468, HCC-1937, and HCC-1143 at multiplicities of infections (MOI) of 0.1, 1.0, and 5. Cytotoxicity and viral replication were determined. Mammary fat pad tumors were generated in athymic nude mice with MDA-MB-231 cells. A subset of xenografts were infected with GLV-1h153 and ∼150 μCi of 124I-iodine was administered. Serial Focus 120 microPET were obtained for 131I dosimetry calculations. For the combination therapy study, 14 days after cell implantation, xenografts were treated with intratumoral injection of GLV-1h153 or PBS. One week after viral injection (day 21), xenografts were further randomized into 4 treatments groups: GLV-1h153 alone, GLV-1h153 and iodine (∼5 mCi of 131I), iodine alone, or PBS and followed for tumor growth. RESULTS: Greater than 90% cell kill was achieved in all cell lines within 5 days at an MOI of 5.0. GLV-1h153 replicated efficiently in all cell lines with a peak titer of 2.6 x107 viral plaque forming units per ml (&gt;1300-fold increase from the initial viral dose) by day 4 in cell line MDA-MB-468. Only infected tumors were identified via PET scanning compared to controls. In vivo, administration of systemic radioiodine in combination with GLV-1h153 resulted in greater tumor regression, 24 mm3 compared to 146 mm3 for the viral-treated group only (p&lt;0.05; days 21-40), a six-fold difference. CONCLUSION: GLV-1h153 infected, replicated in, and killed all TNBC cell lines effectively. This study is the first to our knowledege to demonstrate killing of TNBC by a novel vaccinia virus in combination with radioactive 131I-iodine in an in vivo xenograft model. Our results suggest that GLV-1h153 is a promising therapeutic agent in combination with 131I and merits further testing in the clinical setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5660. doi:1538-7445.AM2012-5660
Abstract 5671: Differential roles of caveolin-1 variants in cell death in breast cancer
Authors: Clarke Robert , Dobbin Zachary C. , Hickman F.Edward , Shajahan Ayesha N. 
Published: August 2012

Abstract
Paclitaxel, an anti-microtubule agent, is an effective chemotherapeutic drug in breast cancer. Nonetheless, resistance to paclitaxel remains a major clinical challenge. The need to better understand the resistant phenotype, and to find biomarkers that could predict tumor response to paclitaxel is urgent. In estrogen receptor α (ER+) breast cancer cells, phosphorylation of caveolin-1 (CAV1) on Y14 facilitates mitochondrial apoptosis by increasing BCL2 phosphorylation in response to low dose paclitaxel (10 nM). Two variants of CAV1 exist; the full-length form CAV1α (wild-type CAV1 or wtCAV1) and a truncated form CAV1β. The precise cellular functions of CAV1 variants are unknown. Only wtCAV1 has the Y14 region at the N-terminus and we now show that CAV1 variants play distinct roles in paclitaxel-mediated cell death/survival. CAV1β is increased in paclitaxel resistant cells compared to sensitive cells. Expression of wtCAV1, but not CAV1β, in sensitive cells significantly increased their responsiveness to paclitaxel. These activities reflect the essential role for Y14 phosphorylation since wtCAV1 expression, but not a phosphorylation-deficient mutant (Y14F), inactivates BCL2 and BCLxL through activation of c-jun N-terminal kinase (JNK). MCF-7 cells that express Y14F are resistant to paclitaxel and are re-sensitized by co-treatment with ABT-737, a BH3-mimetic small molecule inhibitor. Thus, we highlight novel roles for CAV1 variants in cell death: wtCAV1 promotes cell death whereas CAV1β promotes cell survival by preventing inactivation of BCL2/BCLxL via JNK in paclitaxel-mediated apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5671. doi:1538-7445.AM2012-5671
Abstract 992: Credentialing UHRF1 as a target for prostate cancer therapy
Authors: Walker David , Haffner Michael , Deshpande Neha , Wyhs Nicolas , Marzo Angelo De , Yegnasubramanian Srinivasan , Nelson William 
Published: August 2012

Abstract
Alterations in DNA methylation are a hallmark of prostate carcinogenesis. UHRF1 is an essential component in the machinery required for the maintenance of DNA methylation in actively dividing cells. In S-phase, UHRF1 binds nascent hemimethylated DNA and recruits DNA methyltransferases to copy the methylation pattern to the daughter DNA strand in a manner analogous to semi-conservative replication. Additionally, it has been shown that UHRF1 interacts with methylated histones and histone methyltransferases, making it an important epigenetic regulator in proliferating cells. Because of its ties to epigenetic gene silencing and cell proliferation, we hypothesized that UHRF1 could serve as a target for prostate cancer treatment. In this study, we have taken steps to credential UHRF1 as a therapeutic target in prostate cancer and have developed a high-throughput UHRF1-DNA binding assay to screen for UHRF1 inhibitors. We show that UHRF1 is overexpressed in a panel of prostate cancer cell lines and it appears to track with proliferation in prostate cancer tissue. Through loss-of-function studies in prostate cancer cell lines PC3 and DU145, we show that long-term UHRF1 depletion leads to a decrease in clonogenic survival and an overall reduction in global levels of DNA methylation. Further, we find that UHRF1 is required to maintain DNA methylation and epigenetic silencing of hypermethylated genes in prostate cancer cells. Additionally, ChIP experiments revealed that UHRF1 can be bound at the promoter CpG islands of epigenetically silenced genes in prostate cancer cells. With the goal of ultimately developing UHRF1 inhibitors, we have developed a time-resolved fluorescence resonance energy transfer (TR-FRET)-based assay, compatible with high-throughput screening, that can detect the binding of the SRA domain of UHRF1 to hemimethylated DNA. In summary, we have shown that UHRF1 plays a critical role in maintaining the DNA methylation of epigenetically silenced genes in prostate cancer and have developed an assay for high-throughput screening of UHRF1 inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 992. doi:1538-7445.AM2012-992
Abstract 995: Transient low doses of DNA demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells
Authors: Tsai Hsing-Chen , Li Huili , Neste Leander Van , Cai Yi , Robert Carine , Rassool Feyruz V. , Shin James J. , Harbom Kirsten M. , Beaty Robert , Pappou Emmanouil , Harris James , Yen Ray-Whay Chiu , Ahuja Nita , Brock Malcolm V. , Stearns Vered , Feller-Kopman David , Lin Yi-Chun , Welm Alana L. , Issa Jean-Pierre , Minn Il , Matsui William , Jang Yoon-Young , Sharkis Saul J. , Baylin Stephen B. , Zahnow Cynthia A. 
Published: August 2012

Abstract
Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitors, decitabine (5-aza-2′-deoxycytidine) and azacitidine (5-azacytidine) are proving efficacious clinically for hematological neoplasms, especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response often seen in patients. We now show that transient exposure of cultured and primary leukemic and epithelial tumor cells to decitabine or azacitidine at clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produces a “memory” for anti-tumor responses, including potent inhibition of subpopulations of cancer, stem-like cells which often resist other therapies. These inhibitory effects are accompanied by sustained decreases in genome-wide promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, such as cell cycle events mediated through FOXM1, cell invasion and motility, and granulocyte and breast cancer cell maturation. Notably, most of the key pathways altered by decitabine or azacitidine involve high priority targets for pharmacologic anti-cancer strategies, which provides molecular basis for possible combination therapies. Thus, low dose decitabine and azacitidine regimens may potentially have broad applicability for cancer management.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 995. doi:1538-7445.AM2012-995
Abstract 996: MBD-capture coupled with next generation sequencing elucidates genome-wide crosstalk between epigenetic marks and its role in cancer
Authors: Putiri Emily L. , Robertson Keith D. 
Published: August 2012

Abstract
Aberrations in DNA methylation are a hallmark of cancer, and these epigenetic changes lead to tumor suppressor gene silencing by hypermethylation, global genomic hypomethylation, and genomic instabilities. Post-translational histone modifications are important epigenetic marks that have been implicated in regulating DNA methylation patterning. Several known histone marks, including methylation of histone H3 at lysines 4 and 27 and monoubiquitylation of histone H2A (H3K4me, H3K27me, and H2Aub, respectively), are believed to differentially regulate DNA methyltransferase activity on DNA. The histone mark H3K4me is associated with gene activation, and H3K27me and H2Aub are associated with loci of transcriptional repression and DNA methylation, especially at hypermethylated genes in cancer. Recent studies have examined the genome-wide distribution of these histone modifications or have studied how their distribution relates to DNA methylation within specific loci, but these studies have not ascribed specific roles to these histone modifications in DNA methylation patterning, nor do we understand why only subsets of genes throughout the genome become hypermethylated in cancer. This poster demonstrates how the histone marks H3K4me, H3K27me, and H2Aub affect genome-wide DNA methylation patterning and transcriptional regulation, and we highlight several epigenetic targets of H3K27me and H2Aub epigenetic repression that participate in the pathogenesis of cancer. We have used siRNA transfection in NCCIT human embryonic carcinoma cells to target critical subunits of the complexes that establish each of these histone modifications. Through these siRNA treatments, we assessed the roles of each mark in establishing DNA methylation patterns throughout the genome and how these patterns relate to genome-wide gene expression. The effects of histone mark deficiency were analyzed by an assay that isolates methylated-CpG-containing DNA (MBD-capture) coupled to massively parallel DNA sequencing to identify sequences with altered methylation patterns. These sequencing results were correlated with patterns of gene expression determined by expression microarray analysis to identify gene targets whose epigenetic misregulation results in alterations in gene expression. In total, this poster demonstrates how histone modifications contribute to the control of the human DNA methylome and postulates how these marks exert downstream effects toward the pathogenesis of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 996. doi:1538-7445.AM2012-996
Abstract LB-116: Immunodeficient pigs as a large animal model for human tumors
Authors: Balivada Sivasai , Basel Matthew T. , Pyle Marla , Beck Amanda P. , Cino-Ozuna Ada G. , Kerrigan Maureen A. , Hill Jennifer L. , Wyatt Carol R. , Rowland Robert R. R. , Troyer Deryl L. 
Published: August 2012

Abstract
Currently, SCID mice are the major biomedical model for the study of human cancer and other diseases; however, they can be a poor model because there is a large discrepancy in body size and physiology between rodents and humans. Since most new anticancer drugs are first evaluated in rodents, most fail in phase I and phase II clinical trials. Thus, there is a tremendous demand for more sophisticated animal models, which may improve the translation efficiency from preclinical to clinical studies. We recently identified pigs that are severely immunocompromised. Here we tested these pigs as a model for human tumors. Three immunodeficient (ID) pigs and three normal (WT) pigs, six weeks of age, were tested for their ability to allow xenotransplanted human tumors to grow. Each pig was transplanted with 4 million A375 human malignant melanoma cells subcutaneously into the left ear and 4 million PANC-1 human pancreatic carcinoma cells subcutaneously into the right ear on day 0. The ID pigs were euthanized 6, 14, or 23 days after cell transplantation, based on their health condition. Palpable melanoma tumors were identified on day 13 after cell transplantation in the two remaining ID pigs. After euthanasia, full necropsy was performed on all pigs; tissues were collected from ears and other organs for histopathological analysis. Melanoma and pancreatic tumor xenotransplants were identified histologically in all three ID pigs. The presence of human cancer cells in these pigs was further verified with anti-human mitochondrial immunohistochemistry. No transplanted tumors were found, grossly, histologically, or immunohistochemically, in the WT pigs. We propose that this genetic line of ID pigs may prove to be a useful large animal model for human tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-116. doi:1538-7445.AM2012-LB-116
Abstract LB-122: A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors
Authors: Wolf Jurgen , LoRusso Patricia M. , Camidge Ross D. , Perez Jose Manuel , Tabernero Josep , Hidalgo Manuel , Schuler Martin , Tian Gary G. , Soria Jean Charles , Delord Jean Pierre , Campone Mario , Bachelot Thomas , van der Noll Ruud , Ringeisen Francois P. , Nogova Lucia , Sequist Lecia V. , Schellens Jan HM 
Published: August 2012

Abstract
The family of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) plays a critical role in cell proliferation and survival. A variety of genetic alterations (e.g. amplifications, mutations, and translocations) of these receptors and ligands have been found in diverse types of tumors. NVP-BGJ398 is a potent, selective, and orally bioavailable inhibitor of the FGFR tyrosine kinases. It inhibits the proliferation of various FGFR-dependent cell lines at nano-molar concentrations including breast and lung cancers harboring FGFR1 amplification, FGFR2-amplified gastric cancer cell lines and FGFR3-mutated bladder cancers. Objectives of the study: The purpose of this phase I-First In Human dose-escalation study is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD) of NVP-BGJ398 when administered orally to adult patients with advanced solid tumors. Secondary objectives include safety, tolerability, pharmacokinetics and preliminary anti-tumor activity in FGFR-dependent cancer. Methods: Patients received BGJ398 daily in a 28-day cycle in escalating dose cohorts starting from 5mg once daily. After cohort 3, patients had to have FGFR1 or FGFR2 amplification or FGFR3 mutation. Dose limiting toxicities (DLTs) were pre-defined and included both severe events and those resulting in significant dosing delays. Preliminary data: 26 patients have been treated, including 10 patients with FGFR1-amplified breast and 3 patients with FGFR1-amplified squamous cell lung cancer. The dose was escalated from 5 mg to 150 mg over 7 dose cohorts. One DLT of delayed dose occurred following a grade 3 AST/ALT event at 100 mg. Adverse events (AE) were generally grade 1-2. The most frequently observed AEs were diarrhea (37%) fatigue (37%) and nausea (32%) Hyperphosphatemia was observed, with increasing frequency at higher doses of NVP-BGJ398, and could be managed with phosphate binders and diuretics. One lung cancer patient with an FGFR1/CEP8 ratio of 2.6 by FISH analysis responded to 100 mg of NVP-BGJ398 with a 33% reduction in target lesions by CT scan at 8 weeks, confirmed at 12 weeks, and a substantial SUV decrease on PET. These observations provide early evidence that inhibition of the FGFR pathway is effective in patients with FGFR dependent cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-122. doi:1538-7445.AM2012-LB-122
Abstract LB-139: In situ Treg immunomodulation at a single tumor site with CpG and immune checkpoint antibodies cures metastatic disease
Authors: marabelle aurelien , Kohrt Holbrook , Brody Joshua , Torchia James , rajapaksa ranjani , Luong Richard , Zhou Gang , Levitsky Hyam , Tse Victor , Levy Ronald 
Published: August 2012

Abstract
Background: CD4+CD25+FOXP3+ regulatory T-cells (Tregs) infiltrate all tumor sites and play a central role in maintaining immune tolerance to cancers. Scientific question: Is the local immunomodulation of Tregs from a single tumor site sufficient to trigger a systemic anti-tumor immune response able to eradicate distant tumor sites ≤ Results: We found that tumor infiltrating Tregs preferentially express CTLA4 (CD152) and OX40 (CD134) compared to their counterparts in the blood and other lymphoid organs, both in mice and in human lymphomas. We show in a murine lymphoma model that OX40 and CTLA4 upregulation occurs specifically on Tregs directed against tumor antigens. Injections of low doses of anti-CTLA4 and anti-OX40 together with CpG, a TLR-9 agonist, directly into a single tumor site depletes the Tregs from the injected tumor but not from distant ones. This immunomodulation subsequently triggers an anti-tumor immune response able to cure mice with established disseminated disease. This triple combination is uniquely required as neither CpG alone nor mAbs without CpG are effective. Significance: immunomodulatory antibodies are currently under clinical development for cancer therapy. Their major toxicity is the triggering of auto-immune diseases. We show here that after injections of very little doses of these antibodies with CpG at one tumor site, their serum levels become undetectable. However, these doses are sufficient to trigger a systemic anti-tumor response able to eradicate distant sites. Impact: we recently have published positive results of intra-tumoral CpG in patients with follicular Lymphoma (Brody, Levy, et al. JCO, 2010). Anti-CTLA4 has just been approved by the FDA/EMEA in patients with metastatic melanoma. Anti-Ox40 antibodies are currently being tested in phase I/II clinical trials. Therefore, the combination described here can be tested in patients with injectable sites of lymphoma. Together, these results are in favor of a paradigm shift in cancer therapy where the immune system is targeted rather than the tumor itself.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-139. doi:1538-7445.AM2012-LB-139