bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B7: Activation of PPARα suppresses HIF-1α signaling in human cancer cells.
Authors: Zhou Jundong , Zhang Shuyu , Avery Jori E. , Wu Jinchang , Ding Wei-Qun 
Published: June 2012

Abstract
Background: Hypoxia inducible factor-1α (HIF-1α) is a therapeutic target in solid tumors because it activates transcription of the genes associated with tumor growth, angiogenesis and chemo/radio-resistance. Activation of PPARα has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain obscure. The present study examined the effects of PPARα activation on HIF-1α mediated signaling in human cancer cells.
Methods: The human cancer lines MCF-7 (breast) and A2780 (ovarian), and human endothelial line, EA.hy926 were used as model systems for this study. Hypoxia was achieved via a hypoxia chamber. The HRE-luciferase reporter gene and Western blot were applied to analyze HIF-1α expression and activity. RT-PCR and co-immunoprecipitation were performed to understand the molecular mechanisms of PPARα-mediated suppression of HIF-1α signaling. The level of vascular endothelial growth factor (VEGF) in cultured medium was determined using an ELISA, and in vitro angiogenesis was evaluated using the tube formation assay.
Results: Incubation of cancer cells with 1 % oxygen for 16 hours significantly induced HIF-1α expression and activity. Treatment of the cells with PPARα agonists, but not a PPARγ agonist, prior to hypoxia diminished hypoxia-induced HIF-1α expression and activity. Consistently, a PPARα antagonist attenuated PPARα agonist-induced suppression of HIF-1α signaling. Over-expression of an HA-tagged HIF-1α and HIF-1α-P402/P564A mutant protein demonstrated that activation of PPARα promotes HIF-1 α degradation in our model system. This was further confirmed by the use of MG-132, a proteasome inhibitor, which reversed PPARα-mediated suppression of the HIF-1α signaling, and by RT-PCR analysis of HIF-1α mRNA, which was unchanged by PPARα activation. Using the co-immunoprecipitation technique, we found that activation of PPARα enhances the binding of hydroxylated HIF-1α to the Von Hippel-Lindau tumor suppressor, a protein known to mediate HIF-1α degradation through the ubiquitin-proteasome pathway. Consequential to the PPARα-mediated suppression of HIF-1α signaling, vascular endothelial growth factor secretion from cancer cells was found to be significantly reduced, and the tube formation by EA.hy926 cells was dramatically impaired.
Summary: Activation of PPARα suppresses HIF-1α expression and activity by promoting HIF-1α degradation in cancer cells. PPARα agonists are potential anticancer agents that inhibit tumor angiogenesis via the suppression of HIF-1α signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B7.
Abstract B70: Participation of fibroblast growth factor receptors (FGFRs) in acquired resistance to EGFR-specific TKIs in NSCLC.
Authors: Ware Katie E. , Heasley Lynn E. 
Published: June 2012

Abstract
Despite initial and often dramatic responses of specific NSCLC tumors to EGFR TKIs such as gefitinib and erlotinib, nearly all develop resistance and eventually relapse. We have investigated both rapid and chronic mechanisms of resistance to EGFR-specific TKIs in lung cancer cell lines. Following 3 to 4 day treatments with gefitinib, FGFR2 and FGFR3 mRNA and protein are selectively and rapidly (24 to 48 hrs) increased in NSCLC cell lines in which EGFR is the dominant oncogenic driver via mutation or amplification. This induction is mediated, in part, by transcriptional mechanisms and indicates that EGFR signaling functions to repress expression of FGFR2 and FGFR3. Moreover, EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF-stimulated ERK activation and transformed growth in the continued presence of EGFR TKIs. These studies highlight FGFR2 and FGFR3 induction as a rapid molecular response that may modulate initial sensitivity of EGFR-driven lung tumors to EGFR-specific TKIs. We have also employed NSCLC cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs, gefitinib (reversible) and BIBW2992 (irreversible), through chronic (2–3 months) adaptation in tissue culture. To date, three (HCC4006, H1650, HCC2279) of the eight chronically-adapted NSCLC cell lines exhibit a marked induction of FGF2 and FGFR1 upon acquisition of gefitinib resistance (Table 1). Additionally, two of eight undergo marked loss of epithelial differentiation as measured by decreased E-cadherin. The induction of FGFR1 was not mediated by gene amplification as assessed by FISH analysis. Importantly, these chronically-adapted cell lines were highly sensitive to both FGFR-specific TKIs and an FGF ligand trap, FP-1039, as measured by ERK signaling and growth assays. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs may provide a novel autocrine receptor tyrosine kinase-driven growth pathway in a subset of lung tumors that were initially sensitive to EGFR-specific TKIs. We are presently exploring the in vivo relevance of this mechanism using primary tumor specimens obtained pretreatment and following tumor progression on EGFR-specific TKIs. Combined, these studies indicate that FGFR-specific TKIs may be valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to reduce acquired resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B70.
Abstract B73: Molecular mechanisms of glioma resistance to EGFR tyrosine kinase inhibitors.
Authors: Wykosky Jill E. , Cavenee Webster , Furnari Frank 
Published: June 2012

Abstract
EGFR-targeted therapies such as the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have had limited success clinically in glioblastoma (GBM). However, some of the most common mechanisms of resistance to these agents in other solid tumors are rarely present in GBM. In an effort to identify molecular mechanisms of acquired resistance to EGFR TKIs in GBM, we utilized ink4a/arf −/− astrocytes over-expressing EGFR and having wild-type or deleted PTEN. To model TKI-resistance in vitro, cells were seeded in soft agar with 1 μM gefitinib or erlotinib for 2 weeks; during this time the growth of colonies was inhibited. The dose was escalated to 2 μM and after 3 weeks, TKI-resistant colonies began to form and were isolated to generate clonal cell lines. In three PTEN wild-type TKI-resistant lines, EGFR expression was not altered and gefitinib inhibited receptor phosphorylation in a manner identical to that observed in parental cells, thereby ruling out the possibility that the cells are resistant because the drug cannot reach its site of action and inhibit its target. Interestingly, two of these three cell lines demonstrated decreased PTEN expression and increased AKT phosphorylation. The remaining cell line had no change in total PTEN levels, and appeared identical to parental cells with regard to AKT phosphorylation. Removal of resistant cells from the maintenance dose of TKI resulted in restoration of EGFR and ERK phosphorylation to a level several-fold greater than that in parental cells. Notably, the TKI-resistant phenotype was reversible, and these cells became significantly more sensitive to gefitinib and erlotinib than parental cells. Overall, we have generated and characterized a model system for the identification of mechanisms of resistance to EGFR TKIs in GBM. We have identified at least two different resistance scenarios in cells with wild-type PTEN: decrease in PTEN expression, and another as-of-yet unknown mechanism that does not appear to involve changes in the PI3K pathway. The reversibility of resistance and subsequent increased sensitivity to TKIs have potential clinical implications. This work forms the basis for our effort to uncover novel targets or approaches to therapy that may increase the utility of these drugs for treatment of GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B73.
Abstract B8: Selective inhibition of Stat3 Tyr705 phosphorylation inhibits angiogenesis in breast cancer xenografts.
Authors: McMurray John S. , Klostergaard Jim , Robertson Fredika M. , Mandal Pijus K. , Auzenne Edmond J. , Liao Warren S. 
Published: June 2012

Abstract
Signal transducer and activator of transcription 3 (Stat3) is recruited, via its SH2 domain, to phosphotyrosine residues on growth factor and IL-6 family receptors at which time it is phosphorylated on Tyr705 by Janus kinases, Src, or the kinase activity of the receptor. Phosphorylation of Tyr705 (pStat3) leads to dimerization, translocation to the nucleus, and transcription of downstream genes. Stat3 is activated in several human cancers and is considered a drug target. Starting with pTyr-Leu-Pro-Gln, we have been developing phosphopeptide mimics to target the SH2 domain with the goal of blocking recruitment to receptors to uncouple Stat3 from its signaling role. We have developed cell-permeable, phosphatase-stable prodrugs that inhibit constitutive and IL-6-stimulated Tyr705 phosphorylation at concentrations of 0.5 − 1 μM in a variety of human cancer cell lines. They are selective for Stat3 over Stat1, Stat5, Src, and PI3K. At 5 μM they are not cytotoxic to a panel of human cancer cell lines. Higher concentrations lead to off-target effects and cytotoxicity. Recent reports indicate that Ser727 phosphorylated Stat3 participates in electron transfer in the mitochodria and unphosphorylated Stat3 participates with NF-κB-mediated transcription. As opposed to Stat3 knockdown techniques which cannot discriminate the multiple roles of Stat3, our prodrugs are potential tools to selectively probe Stat3 phosphorylation. Both intra-tumoral and intra-peritoneal administration of our lead prodrug, PM-73G, resulted in reduction of orthotopic breast tumor xenografts in mice. There was no evidence of apoptosis, reduction of cyclin D1 or survivin. Treated tumors exhibited significant reduction in microvessel density. Thus, selectively inhibiting Tyr705 phosphorylation is a potential antiangiogenic treatment modality.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B8.
Abstract B9: Evidence that the small molecule antiangiogenic agent PTX008 targets galectin-1.
Authors: Dings Ruud P.M. , Miller Michelle M. , Mayo Kevin H. 
Published: June 2012

Abstract
Inhibition of angiogenesis is a promising avenue for the treatment of cancer in the clinic. Although many or most angiostatic compounds being developed are inhibitors related to various components of growth factor pathways, these have had limited success in the clinic, and new angiostatic compounds that target different systems are sorely needed. Currently, there is growing evidence indicating the importance of galectin-1 in tumor angiogenesis. Galectins are proteins that generally bind β-galactoside-containing glycoconjugates and are involved in various pathological disorders like tumor endothelial cell adhesion, proliferation and migration. Recently, we designed a non-peptidic, calixarene-based galectin-1 antagonist, PTX008, as a relatively small, protein surface topomimetic of the antiangiogenic peptide anginex.
Although we had demonstrated that PTX008 inhibits tumor angiogenesis and tumor growth in vivo, we have yet to confirm that it indeed targets galectin-1. Here, we do just that. By using NMR spectroscopy and flow cytometry, we demonstrate that PTX008 interacts with galectin-1 at a site near to its carbohydrate binding domain and by doing so can compete off galectin-1 from binding to β-galactoside-containing glycans on the surface of cells in vitro. Overall, this research contributes to our ability to design pharmaceutical agents that target galectin-1 and thereby inhibit tumor growth in animals and potentially in the clinic.
This work was supported by a research grant from the NIH National Cancer Institute (CA-096090) to KHM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B9.
Abstract B91: Assosiation of tumor supressor gene p53 with lung cancer in Pakistani population.
Authors: Munawar Saba 
Published: June 2012

Abstract
Lung cancer is the most common cause of cancer related death in men and second most common in women, after breast cancer. It is known to be responsible for 1.3 million deaths worldwide annually. The p53 gene, is a tumor suppressor gene, i.e. its activity stops the formation of tumors. The gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. In present study we check Association of P53 polymorphism with lung cancer in Pakistani population. Polymorphisms in human P53 gene (16bp duplication in intron 3) were studied in patients with lung cancer and controls. Three types of genotypes were seen, homozygous insertion (1\1), homozygous deletion (2\2) and heterozygous insertion/deletion (1/2). Frequency of 1/2 allele was 0.2 in controls and 0.32 in lung cancer patients. This difference is statistically significant (P = 0.053, 95 CI). Our study further showed that smoking increases the risk of lung cancer. Study of polymorphism in p53 gene will help in understanding the patho-physiology of the lung cancer and will open new fronts in future therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B91.
Abstract C102: Mitigating the path to destruction: Continuous flow focused resonance nano-permeabilization (CO-FORN) to improve targeted cancer drug delivery.
Authors: Kumar Rajah Vijay , Augustus Meena , Ebner Reinhard , Kumar Ranjit 
Published: June 2012

Abstract
Rotational Field Quantum Magnetic Resonance (RFQMR) is a device-mediated novel therapeutic modality for cancer, currently in the clinical stage of development. It can also be used to deliver an electromagnetic force with strong, embedded, variable radio signals to induce Continuous Flow Focused Resonance Nano-permeabilization or CO-FORN concomitantly with drugs of choice for cancer treatment. Transient permeabilization of cells by Focused Resonance pulses induces a significant increase of anti-tumor drug concentration within the tumor and enables a practical solution to deliver valuable systemic chemotherapy and mitigate associated adverse effects. CO-FORN was administered to a refractory medullobalstoma patient who had previously received metronomic chemotherapy with Cyclophosphamide and VP16, significantly helping to reduce the associated cytotoxicity and myelosuppression commonly accompanying such treatment.
The protocol allows for extremely accurate RFQMR dosing for therapeutic purposes. RFQMR can be applied as an extraneous source to permeate intractable tumors by creating molecular dimension-specific pore sizes. Targeted drug delivery is enabled thereby minimizing associated systemic drug toxicities. It has been shown that electroporation of cultured cells potentiates cytotoxicity of various chemotherapy agents and other targeted molecules by several hundred fold. This potentiation can be highly controlled using RFQMR by adjusting delivery parameters like molecular mass of the drug, peak plasma concentration, total tissue volume, cell membrane characteristics etc. Specific tumors can be resonated with high instantaneous magnetic fields and radio frequency (RF), followed by nano second signals which penetrate only resonating cells.
The CO-FORN technique can potentiate antitumor effectiveness of drugs from 10 to 70 times and can be highly localized and used without implanting any electrodes, probes or particles into the body. Exposure to non-ionizing, non-thermal RFQMR does not cause uncontrollable destruction and entropy within the cell but more likely re-organizes related bio-structures. In principle, depending on the specific variations within the configured RFQMR, a predictable cell response can be expected. The technology allows for extremely accurate RFQMR dosing for therapeutic purposes. Of the several disease indications and applications that the device has been evaluated in extensive R&D efforts at the Center for Advanced Research & Development (CARD) in Bangalore India, the use of RFQMR to permeabilize tumors in conjunction with systemic chemotherapy, is an innovative application.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C102.
Abstract C11: Relationship between GLIPR-1 and c-Myc expression in progression of gastric cancer.
Authors: Kim Jeong Min , Wang Brandon J. , Zhang Xiaglan , Lee Joon Gyo , Kim Tae Soo , Jung Minkyu , Jeung Hei-Cheul , Chung Hyun Cheol , Thompson Timothy C. , Rha Sun Young 
Published: June 2012

Abstract
Glioma Pathogenesis Related-Protein (GLIPR)-1 is up-regulated by p53 and has proapoptotic, antiangiogenic, immunostimulatory and metastasis-suppressing activity in prostate cancer. How ever its expression and biological role is not well known in gastric cancer. Meanwhile, c-Myc overexpression has shown to be related to on the cell growth, proliferation, invasion and cell cycle regulation in gastric cancer. Here, we investigated the expression pattern of GLIPR-1 and its relation with c-Myc expression in gastric cancer.
The protein expressions of GLIPR-1 and c-Myc were evaluated by western blot with whole lysate of 39 gastric cancer cell lines. Band intensities were measured by Image J program. By Immunohistochemisty, we checked the expression of GLIPR-1 in formalin-fixed paraffin-embedded gastric cancer tissues of stage Ito IVwith 20 samples for each stage.
GLIPR-1 was overexpressed in 20 of 39 (51.3%) and c-Myc was overexpressed in 23 of 39 (60%) gastric cancer cell lines. 16 of 39 cell lines (41.1%) had co-expression. Level of GLIPR-1 expression was higher in cell lines established from primary site of gastric cancer (n=13) than the cell lines from metastasis site (n=26) (p &lt; 0.01). On the other hand, c-Myc was overexpressed in the cell lines of metastasis site than primary sites (p&lt;0.01). GLIPR-1 expression of two group cell lines was negatively correlated with c-Myc expression (R = −0.48). In IHC, GLIPR-1 was expressed in nucleus and cytosol of gastric cancer cells, and GLIPR-1 expression was stage-specifically reduced.
This study showed that GLIPR-1 is downregulated while c-Myc is overexpressed in advanced gastric cancer, ssuggestig their associative role in gastric cancer. In addition, as GLIPR-1 is decreased throughout the disease progression. GLIPR-1 might be the specific therapeutic target for advanced gastric cancer. Also, there is the potential to develop GLIPR-1 and c-Myc expression as prognostic biomarker for gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C11.
Abstract C118: Optimization of MM-111 and lapatinib dosing regimens using mathematical modeling and quantitative biology.
Authors: Kirouac Daniel C. , Lahdenranta Johanna , Overland Ryan , Oyama Shinji , Yarar Defne , Onsum Matt , McDonagh Charlotte , Nielson Ulrik 
Published: June 2012

Abstract
Designing therapeutically optimal dosing regimens for targeted biologic therapies is an open problem in translational oncology. There are at least two underlying reasons for this problem: First, biologics are generally well tolerated so it is not guaranteed that the maximum tolerated dose (MTD) will be observed in a Phase 1 dose escalation; and second, since targeted therapies work in only a subset of patients, there will be limited efficacy data available to determine a Phase 2 dose. This problem is further compounded by the use of combination drug treatments. MM-111 is a novel bispecific antibody against ErbB3 (HER3), using an ErbB2 (HER2) targeting arm to enhance avidity and inhibitor potency. Pre-clinical data shows that combining MM-111 with the ErbB2 inhibitor lapatinib (Tykerb®) results in synergistic tumor growth inhibition. We desired to leverage our pre-clinical modeling, signaling, pharmacokinetic (PK), pharmacodynamic (PD), and efficacy data to optimize dosing regimens of the combination therapy. While this study design is focused on MM-111 combined with lapatinib, this strategy is generally applicable to molecular targeted therapeutics given alone or in combination.
Our approach was to integrate a mathematical model of the MM-111 and lapatinib's mechanism of action, incorporating ErbB-family signal transduction, transcriptional regulation, and resulting tumor proliferation, with pre-clinical PK models of the two drugs. This integrated model was trained using in vitro dose response data from BT-474-M3 cells treated with the ErbB3 ligand heregulin plus combinations of the two drugs. Levels of phospho- and total ErbB3, ERbB2, AKT, ERK, and p27 were quantified using ELISA, and cell growth effects quantified using the Cell Titer Glow assay. This was then integrated with a 2-compartment PK-model, to predict PD profiles and tumor growth effects in murine xenografts treated with the drug combinations. After validation of our model with these initial in vivo studies, we designed therapeutically optimal dosing schedules in silico. The novel dosing strategies are now being validated in xenografts, and will help inform future clinical studies. By integrating PK/PD with known molecular mechanisms of action, we are able to rationally design combination treatment strategies to maximize therapeutic synergy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C118.