bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 588: Silencing of MnSOD attenuates ATRA-induced neurofilament expression in neuroblastoma cells
Authors: Silvis Anne M. , Kiningham Kelley 
Published: June 2012

Abstract
Differentiation therapy with retinoids is a means to treat high-risk neuroblastoma patients when the tumor has recurred after initial attempts of removal by surgery, radiation, and/ or chemotherapy. A metabolite of Vitamin A, all-trans retinoic acid (ATRA) is the main signaling retinoid in vivo and one of the most potent differentiation inducers for human neuroblastoma in vitro. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that converts the superoxide anion to hydrogen peroxide. Previously we have reported that ATRA increased MnSOD expression and activity in SK-N-SH neuroblastoma cells. However, our current study suggests that this upregulation may limit the ability of ATRA to induce differentiation. Treatment with ATRA upregulated the expression of neurofilament (an early marker of neuronal differentiation) as early as 48 hrs. Although MnSOD activity was not significantly increased by ATRA until 72 hrs, silencing of the MnSOD gene with siRNA enhanced neurofilament expression over that of cells infected with a control siRNA construct at 48 hrs. This suggests that even basal levels of MnSOD activity can attenuate an early marker of differentiation. We also demonstrated that ATRA decreased catalase expression and increased dichlorofluoroscein fluorescence, suggesting an increase in hydrogen peroxide. Therefore, these data suggest that rather than being scavenged by catalase, hydrogen peroxide may remain present in the cell after ATRA treatment to also limit the differentiation potential of the cells. Taken together, it is apparent that the alteration of redox status by retinoids may contribute to the modulation of genes which are involved in differentiation. (Funding: Centers for Biomedical Research Excellence 1P20RR020180 (KKK) and 5P20RR016477; WV-INBRE 5P20RR016477; WV-NASA 91-175B).
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 588. doi:10.1158/1538-7445.AM2011-588
Abstract 591: Expanding the therapeutic window through pharmacological activation of the RB pathway in breast cancer treatment
Authors: McClendon Kathleen , Dean Jeffry L. , Rivadeneira Dayana , Reed Christopher A. , Witkiewicz Agnieszka , Gao Erhe , Koch Walter J. , Force Thomas , Knudsen Erik S. 
Published: June 2012

Abstract
Triple negative breast cancer (TNBC) is a highly aggressive disease that is most often treated with cytotoxic chemotherapies, such as anthracyclines and platinum compounds. While effective for certain tumors, these therapies are known to cause severe toxicities in numerous tissues. Thus, targeting pathways to both exploit therapy-sensitive tumors and ameliorate tissue toxicity is of utmost significance. Loss of the retinoblastoma tumor suppressor (RB) protein is a frequent event in TNBC, and is expected to alter therapeutic sensitivity by perturbing cell cycle checkpoints and yielding a predilection towards cell death. Conversely, it is possible that the same principles that drive sensitivity to cytotoxic agents in an RB-deficient setting could be used to prevent toxicities in an RB-proficient setting (i.e. normal tissues). Thus, modulation of the RB pathway could be critical for expanding the therapeutic window in the treatment of breast cancer. To address this hypothesis, combination studies of pharmacological activation of the RB pathway and cytotoxic chemotherapies commonly used to treat TNBC were performed in vitro and in vivo. Results indicate that activation of the RB pathway can modulate the efficacy of cytotoxic compounds in the treatment of TNBC. The mechanisms behind these observations were attributed directly to RB-mediated regulation of DNA damage and repair signaling pathways, as well as apoptosis. RB-deficiency resulted in bypass of these mechanisms and thus enhanced sensitivity to cytotoxic therapies. These results were supported by in silico data demonstrating that RB-deficient TNBC is associated with better clinical outcome in response to chemotherapy. Importantly, functional studies indicated that RB pathway activation can provide protection against the toxicity of frequently used chemotherapeutic compounds in normal tissue. Combined, these studies suggest that RB pathway status could be utilized in the clinic to direct combination treatments that would exploit the sensitivity of RB-deficient tumors to cytotoxic chemotherapies while simultaneously providing protection for normal tissues.
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 591. doi:10.1158/1538-7445.AM2011-591
Abstract 598: Characterization of biological activity in colorectal cancer cells to anticancer regimens
Authors: Roh Seon Ae , Choi Eun Young , Lee Kang Hong , Kim Jin Cheon 
Published: June 2012

Abstract
There have been significant advances in the use of chemotherapy in the treatment of colorectal cancer (CRC) patients over the last 20 years. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available chemotherapy according the biological activity. In metastatic CRC, novel molecular targeted agents are being developed as the pathways that characterize cell growth, the cell cycle, apoptosis, angiogenensis and invasion provide novel targets for cancer therapy. The purpose of this study was to evaluate the efficacy of monotherapy and combination chemotherapy with targeted drugs in the CRC cell death pathway. The chemosensitivities of 12 CRC cell lines to established regimens [FX (5-FU + leucovorin + oxaliplatin) and FR (5-FU + leucovorin + irinotecan)], two biologically targeted drugs (bevacizumab + cetuximab) were comparatively evaluated through various cell death pathways; apoptosis, angiogenesis, invasion and autophagy. In this study, the cell deaths by apoptosis and invasion were associated with the respective chemotherapeutic regimens. Monotherapy using bevacizumab and cetuximab did not induce significant tumor inhibition, but treatment with combination of FX and FR led to significantly higher response rates than those to FX and FR alone. SW480 cell was expressed significantly higher apoptotic cell death and activasion of caspase-3 to the all drugs. Additionally, the MMP-9 activity remarkably reduced in the drug-treated SW480 cell compared with other cells. The SW480 cell shows the microsatellite-stable, functionally p53-deficient, hMLH1-proficient and kras mutation. These molecular and genentic profiling were associated with the chemosensitivity of SW480 cell to respective regimens. In future studies, it will important to combine these genetic profiling with the various CRC cancer cell death pathways to identify the tumor response to chemotherapy and finally realize an individualized treatment regimen to each patient.
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 598. doi:10.1158/1538-7445.AM2011-598
Abstract 617: Small molecule that simultaneously inhibits Myc oncoprotein and activates HIF1A
Authors: Xue Chengyuan , Cheung Leanna , Norris Murray D. , Haber Michelle , Burkhart Catherine , Fedtsova Natalia , Gudkov Andrei , Makarov Sergei S. 
Published: June 2012

Abstract
Aberrant expression of Myc oncoproteins is a major causal factor in a large proportion of human cancer. In particular, MYCN oncogene amplification is one of the most powerful prognostic markers identified in the childhood cancer neuroblastoma and, as such, represents a valuable therapeutic target for the development of novel treatment approaches. A diverse chemical library of small molecules was screened using a cell-based assay to identify inhibitors of MYCN. Among a number of molecules identified as potential Myc inhibitors, M606 was found to reduce protein expression of MYCN and its downstream target genes in the MYCN-amplified neuroblastoma cell line BE(2)-C. A similar effect was also observed in a number of c-Myc over-expressing tumor cell lines. Analysis of signalling pathways affected by M606 using FACTORIAL™ technology (Attagene Inc.) indicated that this small molecule inhibited Myc mediated transcription in a dose-dependent manner. Interestingly, hypoxia inducible factor 1 alpha (HIF1A) was induced ∼100 fold. Consistently, we observed HIF1A protein accumulation and nuclear translocation post-M606 treatment under normoxic conditions accompanied by activation of transcription of the HIF1A target, VEGF. siRNA-mediated knockdown of c-Myc or HIF1A in HepG2 cells followed by M606 treatment demonstrated that downregulation of c-Myc and upregulation of HIF1A by M606 are two independent events. Furthermore, inhibition of HIF1A prolyl hydroxylases by dimethyloxalylglycine (DMOG) resulted in downregulation of c-Myc protein independent of any HIFA upregulation. These results suggest that the same molecular mechanism, targeted by M606 and presumably involving inhibition of prolyl hydroxylases, can affect both HIF1A and Myc but in opposite ways. Further development of this compound may be useful in the treatment of cancers in which Myc oncoproteins are overexpressed as well as in the treatment or prevention of ischemic injury since recent studies suggest HIF1A activation may protect against ischemia-reperfusion injury.
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 617. doi:10.1158/1538-7445.AM2011-617
Abstract 631: Monovalency unleashes the full therapeutic potential of the DN-30 anti-Met antibody
Authors: Pacchiana Giovanni , Chiriaco Cristina , Stella Maria C. , Petronzelli Fiorella , De Santis Rita , Galluzzo Maria , Carminati Paolo , Comoglio Paolo M. , Michieli Paolo , Vigna Elisa 
Published: June 2012

Abstract
Met, the high affinity receptor for Hepatocyte Growth Factor (HGF), is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (DN-30) that induces Met proteolytic cleavage (receptor ‘shedding’) followed by proteasome-mediated receptor degradation, leading to inhibition of HGF/Met-mediated biological activities. However, DN-30 binding to Met also results in partial activation of the Met kinase due to antibody-mediated receptor dimerization. To safely harness the therapeutic potential of DN-30, its shedding activity must be disassociated from its agonistic activity. We have generated a DN-30 Fab fragment that maintains high affinity Met binding, elicits efficient receptor shedding and down-regulation, and does not promote kinase activation. In Met-addicted tumor cell lines, DN-30 Fab displays potent cytostatic and cytotoxic activity in a dose-dependent fashion. DN-30 Fab also inhibits anchorage-independent growth of several tumor cell lines. In mouse tumorigenesis assays using Met-addicted carcinoma cells, intra-tumor administration of DN-30 Fab or systemic delivery of a chemically stabilized form of the same molecule results in reduction of Met phosphorylation and inhibition of tumor growth. These data provide proof-of-concept that monovalency unleashes the full therapeutic potential of the DN-30 antibody and point at DN-30 Fab as a promising tool for Met-targeted 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 631. doi:10.1158/1538-7445.AM2011-631
Abstract 632: The efficacy of IGF-I receptor monoclonal antibody for human gastrointestinal carcinomas is independent for mutation status of k-ras
Authors: Adachi Yasushi , Yamamoto Hiroyuki , Ii Masanori , Li Hua , Ohashhi Hirokazu , Arimura Yoshiaki , Endo Takao , Imai Kohzoh , Carbone David P. , Shinomura Yasushisa 
Published: June 2012

Abstract
Background & Aims: Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of many tumors, including gastrointestinal cancers. We have previously shown successful therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in the patients with gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation. Methods: We assessed the effect of figitumumab on signal transduction, proliferation, and survival in 6 gastrointestinal cancer cell lines with or without k-ras mutation, colon and pancreatic adenocarcinoma, esophageal squamous cancer; and hepatoceller carcinoma. Combination effects of figitumumab and chemotherapy were studied. Then figitumumab was evaluated in the treatment for human gastrointestinal. cancer xenografts in nude mice. Results: Figitumumab blocked autophosphorylation of IGF-IR and the downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. The drug inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis in all cell lines. Moreover, the combination of the monoclonal antibody and chemotherapy was effective against tumors on mice. The effect of figitumumab is not influenced by the mutation stasis of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in tumors on mice. The drug did not affect on neither murine body weight nor blood concentrations of glucose, insulin, IGFBP-3, and growth hormone. Conclusions: IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic utility in human gastrointestinal carcinomas even if k-ras mutated types.
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 632. doi:10.1158/1538-7445.AM2011-632
Abstract 639: Inhibition of HER2 signaling using targeted therapeutics in breast cancer cell lines
Authors: Korkola James , Bayani Nora , Cooper Brian , Heiser Laura M. , Spellman Paul T. , Feiler Heidi S. , Wooster Richard , Gray Joe W. 
Published: June 2012

Abstract
ERBB2/HER2 amplification occurs in 20-30% of all breast cancers and is associated with an aggressive clinical behavior. Therapeutics that target HER2 offer a modest survival benefit when given as monotherapy. Recent studies indicate that in the case of the HER2/EGFR inhibitor lapatinib, there is an initial down-regulation of the PI3K-AKT signaling pathway followed by reactivation of the pathway through p-HER3. Inhibition with much higher doses of lapatinib in vitro prevents the reactivation of the pathway, implying that more effective inhibition of HER2 could lead to more durable responses. To explore this phenomenon more fully, we examined response to lapatinib in a panel of 22 HER2 amplified breast cancer cell lines. Of the 22, there were 5 that were resistant to lapatinib, failing to reach 50% growth inhibition (GI50) even at doses as high as 5 uM. These lines have also been reported to be resistant to trastuzumab. However, all the cell lines in the panel were sensitive to BIBW-2992, which is an irreversible EGFR/ERBB2 inhibitor, with GI50 values in the nanomolar range. Initial western blot analysis indicated that in response to BIBW-2992, there was down-regulation of p-AKT and p-HER3, but that there was recovery of both over time to levels that were comparable to untreated cells. Finally, we observed strong synergistic interactions between BIBW-2992 in combination with a PI3K inhibitor in almost every HER2+cell line tested. These results suggest that even in the setting of resistance to lapatinib and trastuzumab, all HER2 amplified cell lines in our panel are still addicted to HER2 signaling, and that more efficient inhibition of HER2 can result in significant inhibition of growth and loss of viability in HER2 positive breast cancer cell lines. BIBW-2992 was effective against HER2 amplified cells even though inhibition of p-AKT and p-HER3 was not complete. However, addition of PI3K pathway inhibitors resulted in strong synergism in combination with BIBW-2992. These studies set the stage for clinical investigations into the efficacy of such irreversible HER2 inhibitors in patients with HER2 positive breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 639. doi:10.1158/1538-7445.AM2011-639
Abstract 643: Targeting cancer with a selective ATP-mimetic inhibitor of polo like kinase-2
Authors: Jatiani Shashidhar S. , Cosenza Stephen C. , Billa Vinay K. , Reddy M.V. Ramana , Reddy E Premkumar 
Published: June 2012

Abstract
The Polo like kinases play key roles in mitosis. While the upregulation of PLK1 in cancer is well documented and PLK3 has been demonstrated to be a tumor suppressor, little is known about the oncogenic significance of PLK2. PLK2 kinase activity is essential for centriolar duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. Protein tyrosine hyper-phosphorylation and the upregulation of serine/threonine kinases associated with cell cycle progression have been linked to the etiology of cancer. In our attempt to develop ATP-mimetic compounds that are cytotoxic against a panel of cancer cell lines, we identified several sulfonyl pyridopyrimidines that possess nanomolar activity. The most potent of these compounds, ON1231320, was found to be a specific PLK2 inhibitor when profiled against a panel of 288 wild-type, 55 mutant and 12 special kinases. Further in vitro testing revealed that ON1231320 is a selective inhibitor of PLK2 with no inhibitory activity against PLK1, PLK3 and PLK4. Confirmation of this interaction and its selectivity was obtained from pull down studies using lysates of tumor cells and a biotinylated analog of ON1231320. The cytotoxic effect of the drug is mediated by apoptosis as evidenced by the induction of Caspase 3/7 activity and by the cleavage of PARP in a dose dependent manner. ON1231320 affects cell cycle progression by blocking tumor cells in the G2/M phase however it does not affect normal human fibroblasts. ON123120 exhibits an excellent safety profile with no overt signs of toxicity, no loss of body weight and 100% survival in mice given a single peritoneal dose of 200 mg/kg. Our ongoing efforts include efficacy studies in nude mouse models, identification of the structural determinants of the interaction between ON1231320 and PLK2 by computational and crystallographic methods and the identification of novel PLK2 substrates to elucidate its role in cancer biology.
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 643. doi:10.1158/1538-7445.AM2011-643
Abstract 649: Mirk/dyrk1B kinase inactivation increases gemcitabine efficacy towards quiescent pancreatic cancer cells
Authors: Ewton Daina Z. , Vilenchik Maria , Polonskaia Ann , Hoffman Ann , Zipf Karen , Boylan John F. , Heimbrook Dave , Hu Jing , Friedman Eileen A. 
Published: June 2012

Abstract
A major problem in the treatment of cancer is the presence of residual quiescent cancer cells that are relatively insensitive to most chemotherapeutic drugs and radiation. Such cancer cells are believed to cause tumor recurrence when they re-enter the cell cycle under favorable conditions of the microenvironment. Gemcitabine is the drug most often used for treatment of pancreatic cancer, but the response rate is less than 20%. Since stratagems to increase delivery of gemcitabine by inhibiting stromal hedgehog signaling have shown some success, identifying methods to increase gemcitabine efficacy is timely. The serine/threonine kinase Mirk/dyrk1B is expressed at very low levels in most normal tissues, but is overexpressed or amplified in most pancreatic cancers. Mirk maintains pancreatic cancer cells in a viable quiescent state through its transcriptional co-activator functions for a set of antioxidant proteins that decrease intracellular levels of reactive oxygen species (Cancer Res 2009;69:3317-24). We now show that Panc1 and SU86.86 pancreatic cancer cells undergo a reversible quiescent arrest in G0 through activation of Chk2 and autophagy to reduce ribosomal RNA levels, with little apoptosis or senescence. Depletion of Mirk/dyrk1B by either induced shRNA or transfected RNAi duplexes or inhibition of Mirk's kinase activity by a small molecule inhibitor increased DNA damage in quiescent pancreatic cancer cells, either grown attached to petri dishes or in small clumps in suspension as a model for ascites. DNA damage was detected by increased phosphorylation of the histone protein H2AX and by an increase in S phase checkpoints after the quiescent cells re-entered cycle in response to serum mitogens. Pharmacological inhibition of Mirk kinase induced a dose-dependent cleavage of the apoptotic marker proteins PARP and caspase 3, reduced Akt activation, and led to cleavage of the autophagic marker protein LC3. Pretreatment with the Mirk kinase inhibitor increased tumor cell kill 5-fold by short exposures to marginally toxic gemcitabine concentrations. In prior studies Mirk depletion had no detectable effect on the viability of normal diploid fibroblasts (Cancer Res 2007;67:7247-55), while other investigators have shown that embryonic knockout was not lethal (Leder et al, Biochem J 2003;372:881-8). Thus the small molecule Mirk/dyrk1B kinase inhibitor sensitized pancreatic cancer cells to low gemcitabine concentrations, while knockout or depletion of Mirk/dyrk1B had no detectable effect on normal tissue.
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 649. doi:10.1158/1538-7445.AM2011-649