bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 644: Anti-tumor activities of antibodies targeting the RON receptor and a biomarker of response
Authors: Whalen Kerry , Gifford James , Boudrow Andrea , Meetze Kristan , Winston William , Liu Qing , Lerner Lorena , Feng Bin , Jiang Jinwei , Cook Lynette , DiPrima Michael , Chen Ting , Weiler Solly , Gyuris Jeno , Han May 
Published: June 2012

Abstract
RON is a receptor tyrosine kinase of the MET family. Stimulation by its ligand, Macrophage Stimulating Protein (MSP), activates a signaling cascade leading to cell growth, migration, invasion and resistance to apoptosis. In animal models, RON overexpression in breast and lung results in tumor growth and metastasis. RON receptor activation in animal models also play a role in tumor-host interactions such as osteolytic bone destruction and tumor associated macrophage infiltration. RON overexpression has been demonstrated in several solid tumors including pancreatic, breast, ovarian and colon. RON overexpression is correlated with disease progression and shorter survival in ovarian and colon cancer. Several isoforms of RON have been reported, including a potentially oncogenic form, RON Δ160 in CRC. Given the strong evidence for the involvement of RON in numerous aspects of tumor biology, investigating an anti-RON antibody as cancer therapy is warranted. We have identified and characterized a panel of antagonistic murine anti-human RON antibodies. Humanization of two antibodies resulted in Superhumanized™ anti-RON antibodies that are capable of inhibiting MSP dependent RON downstream signaling, cell migration and invasion in vitro. The anti-RON antibodies have subnanomolar binding affinity to wildtype RON and RON Δ160 receptors. The lead antibody is capable of internalizing and degrading the receptor in vitro and in vivo. The antibodies are capable of inhibiting growth of engineered murine models that are driven by wildtype or RON Δ160 receptor, as well as traditional human cancer xenografts.
Given the complex role of RON in tumor biology, identification of response biomarkers is crucial for identifying the patient populations most likely to benefit from treatment. A multi-gene biomarker potentially predictive of tumor response to RON antibody, the RON pathway index, was tested and validated using a panel of human cancer cell line xenografts. Current results demonstrate a statistically significant correlation between the degree of tumor growth inhibition by anti-RON antibody treatment and RON pathway index value. Thus, we have identified a biomarker of tumor response to anti-RON antibody that can potentially help us identify tumor types or tumor subtypes of interest in the clinic.
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 644. doi:10.1158/1538-7445.AM2011-644
Abstract 66: Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5-deficient tumors
Authors: McKenna Elizabeth S. , Tamayo Pablo , Cho Yoon-Jae , Mora-Blanco E. Lorena , Sansam Courtney G. , Tillman Erik J. , Koellhoffer Edward C. , Pomeroy Scott L. , Roberts Charles W. M. 
Published: June 2012

Abstract
SNF5 (SMARCB1/INI1/BAF47), a core subunit of SWI/SNF chromatin remodeling complexes, is a potent tumor suppressor that is specifically inactivated in a variety of aggressive pediatric cancers. We have recently demonstrated that SNF5 acts as a tumor suppressor not genetically via maintenance of genome integrity, but epigenetically via transcriptional regulation. However, few of the target genes essential for oncogenesis following SNF5 loss have been identified. Here, we demonstrate that aberrant epigenetic silencing of the tumor suppressor gene BIN1 is a conserved event in SNF5-deficient cancers and contributes to tumorigenesis. Comparative genomewide expression analysis reveals that BIN1 expression is strongly downregulated in SNF5-deficient malignant rhabdoid tumors (MRT) relative to other human tumors, and we also observe decreased Bin1 expression in murine Snf5-deficient lymphomas. The underlying mechanism is epigenetic silencing as reintroduction of SNF5 into deficient tumor cell lines results in increased SWI/SNF recruitment to the BIN1 promoter and increased BIN1 expression. Furthermore, expression of BIN1 specifically compromises the proliferation of SNF5-deficient MRT cell lines. BIN1 encodes a family of alternatively spliced adaptor proteins that have been implicated in cellular differentiation, tumor suppression, and immune escape of transformed cells, but its regulation has not been well characterized. Identification of BIN1 as a key SNF5 target reveals a novel mechanism by which epigenetically based changes can drive cancer formation.
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 66. doi:10.1158/1538-7445.AM2011-66
Abstract 664: Polymerization of human βIII-tubulin is distinct from βI-tubulin in a cell-free system
Authors: Yang Chia-Ping H. , Horwitz Susan B. 
Published: June 2012

Abstract
Tubulins are a family of proteins consisting of 7 α- and 6 β-tubulin isotypes. Many studies have demonstrated that tumors overexpressing βIII-tubulin have a poor response to chemotherapy. Suppression of βIII-tubulin sensitizes non-small cell lung cancer (NSCLC) cells to microtubule-interacting agents, such as Taxol. βIII-tubulin has also been shown to mediate the incidence and progression of lung cancer. Tubulin isotype content of βI-, βIII-, βIV- and βV-tubulin in the human lung carcinoma cell line A549 is 50%, 8%, 36.5%, and 5.5%, respectively. In our study, the ability of six microtubule stabilizing agents, Taxol, epothilone B (EpoB), discodermolide (Disco), Ixabepilone, laulimalide and peloruside A, to polymerize tubulin in a 100,000 × g supernatant prepared from A549 cells was examined. The level of different tubulin isotypes in the drug-polymerized tubulin was determined by Western blot analysis with tubulin isotype specific antibodies. In the absence of drug, the level of polymerized βI-, βIII-, βIV- and βV-tubulin was 55%, 9%, 25%, and 48%, respectively. Ten µM Taxol caused a smalll increase (&lt;15%) in βI- and βV- tubulin polymerization, but it induced a 367% and 228% increase in βIII- and βIV-tubulin polymerization. Among the six drugs tested, Disco and EpoB exhibited the greatest ability to polymerize all isotypes. The differential βI- and βIII-tubulin polymerization effects also were observed when intact A549 cells were lysed in the presence of drugs, followed by centrifugation. In the absence of drug, the level of polymerized βI- and βIII-tubulin was 9% and 0.2%, respectively. In the presence of 10 µM Taxol, the level of polymerized βI- and βIII-tubulin was increased to 28% and 7% which corresponded to a 3- and 35-fold increase in βI- and βIII-tubulin polymerization, respectively. However, when purified bovine brain tubulin in the absence of all endogenous proteins was used, there was no differential effect of drugs on the polymerization of βI+II- and βIII-tubulin. The βI-, βII-, βIII-, and βIV-tubulin content in bovine brain is 3%, 58%, 25% and 14%, respectively. Disco and EpoB also have the strongest effects on the polymerization of all bovine brain tubulin isotypes. Our results indicate that polymerization of βIII-tubulin is distinct from that of βI-tubulin in a cell-free system and that endogenous cellular components may influence the polymerization of tubulin isotypes.
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 664. doi:10.1158/1538-7445.AM2011-664
Abstract 666: Synthesis and structure-activity relationships of compounds that induce methuosis, a novel type of non-apoptotic cell death
Authors: Robinson Michael W. , Young Ashley M. , Overmeyer Jean H. , Erhardt Paul W. , Maltese William A. 
Published: June 2012

Abstract
Methuosis is a caspase-independent form of necrotic cell death in which massive accumulation of vacuoles derived from macropinosomes ultimately causes cells to detach from the substratum and rupture. This form of death was initially described in glioblastoma cells overexpressing activated GTPases, such as Ras or Rac1, but methuosis-like forms of death have since been reported in other types of cells exposed to different stimuli. We have been interested in developing small molecules that can induce methuosis because of the possibility that stimulating this alternative death pathway may represent a useful therapeutic strategy for cancers that are refractory to apoptosis. We now describe the synthesis and biological testing of a class of small molecules that can effectively induce methuosis in glioblastoma cells at low micromolar concentrations. Details of the design and synthesis of a directed library of these novel compounds will be presented, including complete chemical structures and definition of structure-activity relationships. Each compound was evaluated for its ability to induce cytoplasmic vacuolization and reduce cell viability in U251 glioblastoma cells, using phase contrast microscopy, MTT and colony-forming assays as readouts. The results highlight a lead compound with an EC50 of approximately 1-3 micromolar, based on results from both MTT and colony-forming assays. Although the specific molecular target of these compounds is currently unknown, preliminary evidence indicates that they work at the level of endosome trafficking steps mediated by the Rab5 and Rab7 GTPases. The status of work toward target identification will be discussed. The potential significance of these studies is underscored by our recent observation that this class of compounds can induce methuosis in glioblastoma cells resistant to the front-line chemotherapeutic drug, temozolomide. This raises the possibility that the current lead compound may serve as a prototype for development of agents that could be used to trigger death by methuosis in drug-resistant cancers.
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 666. doi:10.1158/1538-7445.AM2011-666
Abstract 674: Novel combinatorial quinacrine cancer therapies for advanced colon cancer
Authors: Gallant Jean-Nicolas , Wang Wenge , Dolloff Nathan G. , Allen Joshua E. , El-Deiry Wafik S. 
Published: June 2012

Abstract
BACKGROUND: Although treatments have improved patient prognosis in early stages of colorectal cancer, new effective drugs with improved safety profiles are needed for improving the treatment of patients with advanced colon cancer. Quinacrine, a small molecule anti-malarial agent that has activity in giardiasis, lupus, prion disease, and used as a means of non-surgical sterilization, has shown cytotoxic activity across a broad range of cancers. The well characterized safety profile of quinacrine and its anticancer activity hold promise in novel combinatorial cancer therapies.
OBJECTIVES: To evaluate the potential of adding quinacrine to anticancer chemotherapeutics and targeted agents as a potential novel combinatorial therapy for advanced colon cancer and to detail the mechanism of action of quinacrine when combined with cancer chemotherapy and targeted agents.
METHODS: In vitro dose-response curves and isobolograms were constructed for single agent and dual agent therapies using quinacrine, 5-fluorouracil, gemcitabine, and sorafenib using the following colon cancer cell lines: HT-29, HT-29-luc, HCT-15, HCT-116, HCT-116 p53−/−, HCT-116 bax−/−, RKO, DLD-1, SW-480, and SW-620. Western blot analysis and flow cytometry were used to investigate potential mechanisms of action and to examine cell death. In vivo experiments were carried out to investigate toxicity and efficacy of combinatorial quinacrine chemotherapy in an athymic nu/nu mouse tumor xenograft model with human HT-29-luc cells.
RESULTS: Single-agent quinacrine demonstrates potent anticancer activity with an average IC50 of 5.79 ± 0.83 μM across all ten colon cancer cell lines screened. In combination, quinacrine enhanced the anticancer activity of 5-fluorouracil and gemcitabine while significantly synergizing with sorafenib. Western blot analysis revealed that quinacrine's anticancer activity partially arises from its ability to stabilize p53, elevate death receptor levels, and lower anti-apoptotic protein levels. Quinacrine, when combined with sorafenib, dramatically lowers levels of the anti-apoptotic protein MCL-1. In vivo studies have shown that quinacrine monotherapy at a daily dose of 150 mg/kg significantly lowers the tumor load of nu/nu mice.
CONCLUSIONS: Quinacrine is cytotoxic to a broad range of colon cancer cells lines and enhances the anticancer activity of chemotherapies such as 5-fluorouracil, gemcitabine, and sorafenib. The administration of quinacrine in combination with chemotherapy agents and targeted agents in patients with advanced colon cancer should be further explored in the clinic.
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 674. doi:10.1158/1538-7445.AM2011-674
Abstract 68: Increased H3K27 trimethylation is associated with decreased expression of miRNAs and bivalently modified genes in rhabdoid tumors
Authors: Gadd Samantha L. , Perlman Elizabeth J. 
Published: June 2012

Abstract
Background: Rhabdoid tumors (RT) are aggressive tumors of infancy for which no effective treatment is currently available. These tumors are characterized by genetic loss of the SMARCB1 (SNF5, INI-1) component of the SWI/SNF chromatin remodeling complex. We previously reported an overall pattern of repression of genes associated with bivalent histone modification in embryonic stem cells within RT. We hypothesize that loss of SMARCB1 in RT results in an overall failure to release the repressive (H3K27) histone methylation in genes responsible for early differentiation. To test this hypothesis, we performed chromatin immunoprecipitation (ChIP) using antibodies specific for permissive (H3K4) and H3K27 trimethylation, comparing an RT cell line (G-410) with a human embryonic kidney cell line (HEK293). In addition, we report the global miRNA analysis of RT using the Illumina 96-sample Universal Matrix Array.
Results: Those genes previously shown by others to be direct targets of SMARCB1 (PTN, CDK2NA, ATP1B1, HESR1, and FZD7) and genes previously shown to be down-regulated in RT (CDH2, SPON1, LEF1, SOX11, CDKN1B, SERPINE2, SPOCK1, DOCK4) all showed a significantly higher ratio of H3K27 methylation to H3K4 methylation (1.5-fold to 130-fold) in G410 cells compared with HEK293. In contrast, genes shown to have increased expression in RT (TFRC and DDX21) showed increased H3K4 methylation. Global miRNA analysis demonstrated striking downregulation of 156/158 (p&lt;0.05) miRNAs compared with other pediatric renal tumors. ChIP analysis for H3K4 and H3K27 associated with miRNAs mir127, mir134, mir519e, mir99b, and mir152 likewise showed increased association with H3K27.
Summary: Gene and miRNA expression strongly correlate with histone methylation patterns in the RT cell line. This suggests that loss of SMARCB1 in RTs results in striking repression of gene and miRNA expression which may be due to aberrant repressive (H3K27) histone methylation. The use of histone methylation inhibitors may therefore merit investigation for this pediatric tumor for which there is no effective 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 68. doi:10.1158/1538-7445.AM2011-68
Abstract 682: Design and discovery of novel small molecule modulators of reactive oxygen species-mediated cell signaling
Authors: Pathania Divya , Sechi Mario , Palomba Michele , Cosseddu Alessia , Sanna Vanna , Berrettini Francesco , Sias Angela , Taheri Laleh , Neamati Nouri 
Published: June 2012

Abstract
Oxidative stress is an important hallmark of cancer. Elevated levels of intrinsic reactive oxygen species (ROS) make tumor cells more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm the adaptive antioxidant capacity of cancer cells and trigger ROS-mediated cell death. Increasing ROS production or decreasing ROS scavengers shows potential for selectively targeting tumor cells that are under persistent oxidative stress. Recently, we have discovered novel class of quinazolinediones that exert their anticancer effects by modulating ROS-mediated cell signaling.The sub-micromolar anti-proliferative properties of these compounds were demonstrated by MTT and colony formation assays in a panel of cancer cell lines of different origins. Treatment with these agents induced cell cycle arrest, and increased superoxide production in cancer cells. Furthermore, proteomics analysis of 600 target antibody array revealed that these molecules significantly affected several cell signaling pathways implicated in carcinogenesis, cancer progression, redox signaling, and cell death.In conclusion, quinazolinediones are promising lead compounds that selectively enhance ROS production and induce ROS-mediated cell death in cancer cells, and warrant further preclinical studies.
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 682. doi:10.1158/1538-7445.AM2011-682
Abstract 685: PTX-008 antiproliferative effects in cancer cells are mediated though galectin-1 inhibition and MAPK-dependent G2/M cell cycle arrest
Authors: Astorgues-Xerri Lucile , Bonezzi Katiuscia , Serova Maria , Bieche Ivan , Riveiro Maria E. , Cvitkovic Esteban , Noel Kay , Giavazzi Raffaella , Taraboletti Giulia , Raymond Eric , Faivre Sandrine 
Published: June 2012

Abstract
Background. Galectin-1 is a multifunctional protein involved in various aspects of tumorigenesis and has been described as a promising cancer target. PTX-008, a small molecule interacting with galectin-1, is currently investigated as an anticancer agent in various preclinical models. The aim of the present study was to study molecular mechanism associated with the cellular effects of PTX-008 in cancer cells.
Materials and Methods. Antiproliferative effects were evaluated in a panel of 20 human cancer cell lines by MTT assay. Effects of PTX-008 on cell cycle and protein expression were assessed by flow cytometry and western blot analysis, respectively. mRNA expression was evaluated with qRT-PCR.
Results. PTX-008 induces potent antiproliferative effects in our panel of cell lines at concentrations ranging 1-27µM. Interestingly, exposure to PTX-008 for &gt;48 hours inhibits galectin-1 protein level. Furthermore, we have found a clear correlation between low expression of mRNA and proteins levels of galectin-1 and PTX-008 sensitivity in a panel of 20 cancer cell lines (R2=0.59, p&lt;0.05). However, inhibition of galectin-1 by shRNA in SQ20B cells led to no significantly changed PTX-008 antiproliferative activity suggesting that PTX-008 may not exclusively act thought galectin-1 protein down expression. Previous studies showed that galectin-1 might interact with H-RAS and K-RAS, regulating the magnitude of MAPK signal output. In RAS/RAF wild-type SQ20B cells, exposure to 3µM PTX-008 for &gt;5 hours inhibits pERK1/2, pAKT, and pS6, suggesting the important role of MAPK and AKT/mTOR in downstream signalling of galectin-1 in our model. Cell cycle analysis of SQ20B treated with PTX-008 showed a dose-dependent accumulation in G2/M phase without apoptosis induction. Consistent with the inhibition in G2 to mitosis transition, PTX008-induced cell cycle changes were associated with a decrease of Wee1 and an increase of Cdc2 phosphorylation but no inactivation of cdc25C. Inhibition of MAPK with UO126 abolished PTX-008 inhibition of cdc2 reinforcing the important role of MAPK-inhibition in cellular effects of PTX-008.
Conclusion. Our findings show that PTX-008 inhibits cancer cells proliferation by interacting with galectin-1, blocking G2/M transition, and inhibiting MAPK signalling 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 685. doi:10.1158/1538-7445.AM2011-685
Abstract 694: Cyclosporin-modulated intensified dosage chemotherapy well-tolerated for saving eyes with intraocular retinoblastoma
Authors: Chan Helen S.L , Héon Elise , Dimaras Helen , Gallie Brenda L. 
Published: June 2012

Abstract
PURPOSE: Cyclosporin inhibits the multidrug resistance P-glycoprotein. Since 2000, we tested increased carboplatin and increased etoposide dosages in a cyclosporin-modulated carboplatin-etoposide-vincristine protocol, followed by focal laser/cryotherapy consolidation, to avoid elective radiation of newly diagnosed retinoblastoma (RB) patients, since radiation increases the secondary cancer risk in patients with heritable RB. We report the results for International Classification Groups A, B, C and D eyes.
METHOD: Since Neupogen support became available, we increased the mainly myelotoxic carboplatin to 28 mg/kg (from 18.7 mg/kg in a previous trial) and etoposide to 12 mg/kg (from 7.7 mg/kg in a previous trial), but kept the mainly neurotoxic vincristine unchanged at 0.05 mg/kg, modulated by the same cyclosporin schedule (33 mg/kg over 3 hours on each of the 2 days per cycle). We treated 35 eyes in 23 patients: 2 A eyes, 8 B eyes, 8 C eyes and 17 D eyes. Radiation or enucleation for recurrence was considered failure.
RESULTS: We report the long-term results at median followup of 8.1 years (range 1.7-10.5 years). Eye event-free rates were 100% for both Groups A and B eyes, and 50% for Group C (4/8) and 47% for Group D (8/17) eyes. Four C eyes failed and all had enucleation only. Nine D eyes failed and 6 were enucleated and 3 radiated. No child lost both eyes. Toxicity rates were acceptable with 15.7% fever-and-neutropenia, 0.7% bacterial sepsis, 9.7% blood transfusion and 27.6% platelet transfusion, and no long-term renotoxicity or ototoxicity.
CONCLUSION: This protocol was well well-tolerated, with no child losing both eyes, and most avoiding radiation. The same protocol is being tested in a multicenter trial.
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 694. doi:10.1158/1538-7445.AM2011-694