bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 650: Ex vivo analysis of the mTOR/PI3K & MEK/ERK inhibitors, BEZ235 & AZD6244, alone and in combination in human tumor primary culture micro-spheroids: Exploration of horizontal pathway targeting
Authors: Nagourney Robert Alan , Bernard Paula J. , Francisco Federico R. , Wexler Ryan , Evans Steven S. 
Published: June 2012

Abstract
Therapeutic targeting of signal transduction pathways offers fertile ground for the discovery of small molecule kinase inhibitors and novel combinations. The success of Imatinib in CML, the first clinically approved oral TKI, reflects in part, the linear association between the malignant phenotype and c-Abl activation. However, most solid tumors reveal complex interactions between signal pathways that cross talk at points of commonality, the subject of prior report (Nagourney, RA Proc. AACR, 2010). To examine the clinical potential of BEZ235 and AZD6244, inhibitors of the PI3K & MEK/ERK pathways, we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD™) (Nagourney RA, Curr. Treat Options in Oncology, 2006) to tumor micro-spheroids isolated from 24 patients. Drugs were tested alone and in combination. Five point dose response curves were interpolated to provide LC50 values. Synergy was assessed by median effect. Activity comparisons were conducted by modified Z-Score. LC50 values by Z-score for AZD revealed Melanoma &gt; Breast &gt; NSCLC &gt; Myeloma &gt;Ovarian &gt; Uterine &gt;Sarcoma &gt; Renal, while BEZ revealed Breast &gt; Renal &gt; NSCLC &gt; Ovarian &gt; Myeloma &gt; Sarcoma &gt; Uterine. By combining BEZ with AZD, we then explored the simultaneous inhibition of the MEK/ERK and PI3K/mTOR pathways. Results in 5 of the first 6 analyses revealed activity & synergy for the dual pathway inhibitor combination. These results support the clinical relevance of targeting the MEK/ERK and PI3K/mTOR pathways and more importantly suggest dual pathway inhibition (horizontal) to be a productive strategy for further clinical developmental. Disease specific profiles and sequence dependence are being explored and will be reported. Supported in part by the Vanguard Cancer Foundation and The Nagourney Institute.
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 650. doi:10.1158/1538-7445.AM2011-650
Abstract 672: PBI-1402, a first-in-class erythropoiesis regulating agent, inhibits tumor growth and metastasis of murine mastocytoma and does not overshoot hemoglobin: Comparison with erythropoietin
Authors: Gagnon Lyne , Sarra-Bournet François , Geerts Lilianne , Hince Kathy , Lagraoui Mouna , Laurin Pierre , Penney Christopher , Grouix Brigitte 
Published: June 2012

Abstract
BACKGROUND: PBI-1402 reduces the need for transfusion and increases hemoglobin (Hb) level and red blood cell count (RBC) in chemotherapy-induced anemia (CIA) by a mechanism of action distinct from erythropoietin (EPO).
AIM: The objective was to compare the effect of PBI-1402 and EPO on modulation of tumor growth.
METHODS: The effect of PBI-1402 (200 mg/kg, oral, once a day) or EPO (200 or 2000 U/kg, s.c. injection, twice a week) was studied in a subcutaneous P815 mastocytoma model. P815 cells express both PBI-1402 and EPO receptors. Tumor growth, metastasis, serum nitric oxide (NO) and hematocrit (Ht) were assessed.
RESULTS: P815 tumor growth is rapid and metastasizes to the liver. Inflammation is also associated with P815 tumor growth. PBI-1402 significantly reduced tumor growth (T/C=37%) and invasion as demonstrated by a 33% reduction of mice with liver metastasis. In comparison, EPO had no effect (200 U/kg, equivalent dose used in CKD treatment). However, high dose EPO (2000 U/kg, equivalent dose used in human cancer treatment) exacerbated tumor growth (T/C: 135%). Both doses of EPO induced a significant increase in the percentage of mice with liver metastasis (2X, 200 U/kg, and 3X, 2000 U/kg) compared to control. PBI-1402 treatment had no effect on NO and did not overshoot normal hematocrit. However, treatment with high dose EPO significantly increased NO and Ht levels (Table 1).
CONCLUSION: These results suggest that oral treatment with PBI-1402 may inhibit growth and metastasis of cancer cells. As an important safety feature, PBI-1402 does not induce overshoot of hemoglobin. In contrast to EPO, PBI-1402 may offer the advantage of reducing tumor growth and metastasis while preventing anemia induced by chemotherapy. In conclusion, PBI-1402 has the potential to be a safe erythropoiesis-regulating agent useful in treating anemia in cancer patients.

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 672. doi:10.1158/1538-7445.AM2011-672
Abstract 680: Antitumor activity of CDDP and nuclear receptor PXR
Authors: Kishimoto Shuichi , Fukushima Shoji 
Published: June 2012

Abstract
The goal of this study was to evaluate the effect of the possibility of compound that regulate the function of nuclear receptor as agent enhancing the activity of CDDP. Cell lines used in this study were HepG2 and some CDDP-resistant HepG2 cells that were established in our laboratory. These CDDP-resistant HepG2 cells show IC50 values several times higher than that of HegG2 cells. Changes in gene expression were assessed in RT-PCR assays, and the ability of apoptosis induction was assessed as caspase-3 activity. Gene expressions of nuclear receptors in HepG2 cells after exposure to CDDP were examined over time. Interestingly, IC90 dose of CDDP induced significant reduction in PXR mRNA expression with remarkable apoptosis, but IC50 dose of CDDP did no apoptosis and no significant change in PXR mRNA expression. Also, six established CDDP-resistant HepG2 cells show increased PXR mRNA expression relative to parent HepG2 cells. Therfore, PXR agonist and antagonist were used to elucidate if PXR could modulate the sensitivity of cells to CDDP. HepG2 cells exposured to PXR agonist rifampicin for 24 hr showed increased PXR mRNA expression. In HepG2 cells, pre-exposure to rifampicin followed by exposure to CDDP and coexposure to rifampicin and CDDP reduced induction of apoptosis compared to exposure to CDDP alone. Moreover, almost total suppression of apoptosis induced by CDDP was achieved by pre-exposure for 48 hr followed by coexposure to rifampicin for 24 hr. PXR antagonist leflunomide caused a slight enhancement in apoptosis induced by CDDP in HepG2 cells and a significant enhancement in apoptosis induced by CDDP in CDDP-resistant HepG2 cells. We concluded that nuclear receptor PXR is an important factor which regulates the expression of genes that affect on the antitumor activity of CDDP and that PXR antagonist can be a candidate as an agent augmenting the antitumor activity of CDDP.
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 680. doi:10.1158/1538-7445.AM2011-680
Abstract 683: Biological significance of conjugated linoleic acid in ovarian carcinoma
Authors: Shahzad Mian M. , Al-Niaimi Ahmed , Felder Mildred A. , Kapur Arvinder , Claussen Nick , Jallow Fatou , Van Galder Hannah R. , Connor Joseph P. , Patankar Manish S. 
Published: June 2012

Abstract
Background: Conjugated linoleic acid (CLA) has long been recognized to exert protective effects on carcinogenesis in breast, prostate and colon malignancies. Recent data suggests that CLA plays a key role in inhibiting several important survival pathways in breast cancer cell. However, data on effects of CLA in epithelial ovarian carcinoma are lacking and was the focus of this study.
Methods: A2780 and SKOV3 ovarian cancer cell were treated with increasing concentrations of two different isomers of CLA (9:11, 10:12) and effect of CLA on cell viability was determined using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay at different time points with and without oxaliplatin. Additionally, effect of CLA isomer 10:12 were evaluated on A2780 ovarian cancer cell apoptosis by flow (Annexin V/PE).
Results: CLA isomer-10:12 significantly affected the ovarian cancer cell viability in a time and dose dependent fashion. Seventy-two to 96h of CLA treatment (isomer 10:12, 7µμ) resulted in ∼50% reduction in cell viability compared to control (p&lt;0.01). A 20 µM dose of the CLA isomer 10:12 resulted in &gt;80% reduction in live cell compared to controls. However, CLA isomer 9:11 had no effect in all doses and time points tested (0.001 µM- 50mM). Additionally, at IC50 dose of oxaliplatin treatment, the addition of CLA, resulted in a substantial reduction (by ∼50%, p&lt;0.05) in percent live cell compared to oxaliplatin monotherapy.
Conclusion: Our data indicate that CLA can significantly hamper the survival of ovarian cancer cell. These findings may have therapeutic implications for ovarian cancer management and needs further exploration.
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 683. doi:10.1158/1538-7445.AM2011-683
Abstract 692: Drug treatment causes evolution
Authors: Flach Edward , Fedorenko Inna , Paraiso Kim , Smalley Keiran SM , Anderson Alexander RA 
Published: June 2012

Abstract
A targeted drug treatment, PLX40720, eliminates the bulk of melanoma tumours, but there is always regression. We assert that the tumour population is heterogenous. Then the drug treatment is a selection process, targeting specific subpopulations. When the treatment ends, phenotypic drift causes reversion towards the original wild-type population.
Our model is a discrete population of cells. The cells each have a distinct phenotype. This phenotype determines their fitness. The fitness changes under drug conditions: we define a fitness landscape for both drug and drug-free conditions. We validate the model using population experiments on four melanoma cell lines (1205Lu, WM164, WM793, WM983A). We find initial growth curves, death rates and regrowth curves under drug treatment.
Matching the clinical approach, we treat the cell lines chronically with drug for six months. We then stop treatment and examine the reversion of the resistant cell lines to wild-type over a period of several weeks. There is only partial reversion to wild-type. We return to the model to incorporate this experimental data. We extend the complexity of the fitness landscape to multiple fitness “wells". Reversion after drug treatment only populates one of these wells. This more complex landscape reproduces the experimental observations.
The model concept extends naturally to considering combination therapies. We also discuss the effect of modifying the local environment of the tumour: the drug treatment may become more effective. This approach gives a quantitative assessment of treatment strategies.
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 692. doi:10.1158/1538-7445.AM2011-692
Abstract 7: PKC-ι promotes glioblastoma cell survival by phosphorylating and inhibiting BAD through a phosphotidylinositol 3-kinase pathway
Authors: Desai Shraddha , Acevedo-Duncan Mildred 
Published: June 2012

Abstract
Robust expression of atypical protein kinase C-iota (PKC-ι) is a hallmark of human glioma, benign and malignant meningiomas [R. Patel, et. al. (2008) Cell Prolif. 41, 122-135]. The phosphoinositide (PI) 3-kinase pathway is frequently found to be over stimulated due to activating mutations in growth factor receptors or loss of function of the tumor suppressor PTEN. Protein kinase C-ι is often activated by the PI 3-kinase pathway and is an essential downstream targeted mediator. We investigated the role of PKC-ι in two human glial tumor derived cell lines T98G and U87MG. PKC-ι directly phosphorylated and inactivated Bad, a pro-apoptotic BH3-only molecule of the Bcl-2 family at three phospho specific residues, Ser-112, Ser-136 and Ser-155. PKC-ι was also observed to co-localize and directly associate with Bad in the cytoplasm of the cells (as shown by Immunofluorescence, Immunoprecipitation, and Western blotting). Furthermore, purified, active PKC-ι induced direct phosphorylation of Bad at all three serine residues subsequently disrupting Bad/Bcl-XL dimerization. Reduction of PKC-ι upon RNA interference exhibited a corresponding reduction in Bad phosphorylation as did Wortmannin and LY294002, known PI3-Kinase inhibitors. Depletion of PKC-ι by siRNA treatment also induced apoptosis with release of cytochrome C, caspase 3 activation and PARP cleavage. These data provide evidence for novel PI3-kinase/PKC-ι/BAD cell survival pathway.
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 7. doi:10.1158/1538-7445.AM2011-7
Abstract 723: Acquired resistance to PLX4720 involves both ERK re-activation and suppression of BH3-only proteins in human melanoma cells
Authors: Shao Yongping , Aplin Andrew E. 
Published: June 2012

Abstract
B-RAF is mutated to a constitutively active form in 8% of human cancers. Tumors harboring mutant B-RAF are often dependent on B-RAF-MEK-ERK1/2 signaling for the maintenance of malignant properties. Evidence for oncogene addiction has been underscored in early phase clinical trials in which the RAF inhibitor, PLX4032/RG7204, caused partial or complete responses in 81% of mutant B-RAF harboring melanoma patients. However, the average duration of response was 7-8 months with the majority of patients relapsing, indicating the acquisition of resistance to PLX4032. Since understanding the mechanisms of resistance will drive the design of future combinatorial trials, we undertook an in vitro analysis of melanoma cell acquired resistance to PLX4720, the tool compound for PLX4032. Through continuous culture in the presence of PLX4720, we developed mutant B-RAF melanoma cell populations that display resistance to B-RAF inhibitors. Resistance was associated with a partial re-activation of ERK1/2 signaling, recovery of G1/S cell cycle events, and suppression of BH3-only proteins, Bim-EL and Bmf, in the presence of PLX4720. Preventing the ERK1/2 re-activation with MEK inhibitors blocked G1-S cell cycle events but failed to induce apoptosis or up-regulate Bim-EL and Bmf levels. These data indicate that acquired resistance to PLX4032/4720 likely involves ERK1/2 pathway re-activation and ERK1/2-independent silencing of BH3-only protein up-regulation.
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 723. doi:10.1158/1538-7445.AM2011-723
Abstract 76: Epigenetic silencing of argininosuccinate synthetase renders human bladder cancer cells sensitive to pegylated arginine deiminase
Authors: Allen Michael , Syed Nelofer , Luong Fiona , Howarth Kimberley , Gorman Patricia , Tomlinson Ian , Roylance Rebecca , Lu Yong-Jie , Nicholas Lemoine , Dan Berney , Crook Tim , Szlosarek Peter W. 
Published: June 2012

Abstract
Tumors deficient in argininosuccinate synthetase (ASS1), a key enzyme involved in arginine synthesis, are auxtrophic for arginine and sensitive to amino acid deprivation. Based on reports of instability at 9q34 in bladder cancer, the locus of ASS1, we investigated ASS1 status using a variety of molecular and genetic techniques and assessed the impact of arginine deprivation on the viability of bladder cancer cell lines in vitro and in vivo. Initially, we revealed very low mRNA levels and no ASS1 protein in 3 of 7 bladder cancer cell lines (253J, EJ28 and UMUC-3). The ASS1-negative cell lines were all hypermethylated at the ASS1 promoter, compared with the ASS1-positive cell lines, which were hypomethylated. There was no evidence for ASS1 mutations by gene sequencing or loss of heterozygosity by fluorescence in situ hybridization and single nucleotide polymorphism arrays. An analysis of 48 patients with bladder cancer revealed 65% were ASS1-negative by immunohistochemistry, with evidence for ASS1 methylation as the mechanism for ASS1 inactivation. The arginine depleting agent, pegylated arginine deiminase (ADI-PEG20), triggered caspase-dependent and independent apoptosis of 253J and EJ28 cell lines, respectively, whereas ASS1-positive control bladder cell lines were resistant to ADI-PEG20. We have identified downregulation of ribonucleotide reductase M2 (RRM2) as a biomarker of ADI-PEG20 activity and ongoing work is focused on combining ADI-PEG20 with cisplatin-doublet chemotherapy in vivo. In summary, we propose that epigenetic silencing of ASS1 renders bladder cancer sensitive to ADI-PEG20, providing a novel approach for the treatment of a common and therapeutically challenging 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 76. doi:10.1158/1538-7445.AM2011-76
Abstract 762: ONT-10, a liposomal vaccine targeting hypoglycosylated MUC1, induces a potent cellular and humoral response and suppresses the growth of MUC1 expressing tumors
Authors: Pestano Linda A. , Christian Brenda , Koppenol Sandy , Millard Jeff , Christianson Gary , Klucher Kevin , Rosler Rob , Peterson Scott R. 
Published: June 2012

Abstract
MUC1 is highly expressed in multiple tumor histologies and is hypoglycosylated relative to normal tissue, with prematurely terminated carbohydrate modifications including αN-acetylgalactosamine (Tn). The aberrant glycosylation state of MUC1 makes this antigen immunologically distinct in tumor relative to normal tissues and an attractive vaccine target.
ONT-10 is a liposomal formulated vaccine that incorporates a synthetic glycopeptide antigen that includes two complete 20 amino acid tandem repeats from human MUC1, including six glycosylated sites modified by Ser- or Thr-O- Tn, and is incorporated into the liposomal drug product via two C-terminal lipid serines. The ONT-10 drug product is formulated with the novel, fully synthetic lipid A adjuvant, penta erythritol lipid A (PET Lipid A). PET Lipid A displays a similar spatial distribution of lipid chains as natural Lipid A, but is composed of pure 6-acyl moieties, resulting in enhanced potency as an activator of Toll-like Receptor 2 and 4 (TLR2, TLR4).
In preclinical studies, immunization of mice with ONT-10 induces a prominent T cell and antibody response to MUC1 and results in a substantial growth inhibition of MUC1 expressing tumors. T cell recall assays show a Th1 cytokine pattern with strong IFNγ production in spleen derived CD4 and CD8 cells in response to Tn-MUC1. At doses as low as 5μg/mouse ONT-10 results in a high titer anti-MUC1 antibody response composed principally of IgG2b and IgG3 that show preferential binding to Tn-MUC1 and selectively target tumor cells that express human MUC1. In a preventative B16-MUC1 tumor model, vaccination with 5μg ONT-10 potently suppresses tumor growth, resulting in 99% mean tumor growth inhibition relative to controls with 9/12 animals tumor free four weeks after tumor cell implantation. Similarly, in a MC38-MUC1 tumor model 5μg ONT-10 results in an 90% reduction in tumor growth relative to controls. Based on these preclinical data, we propose that the combination of the glycopeptide antigen structure and improved Lipid A adjuvant in ONT-10 offer advantages relative to previous MUC1 targeted vaccines by potently activating both humoral and cellular immunity against hypoglycosylated MUC1 and that these features may provide additional therapeutic benefit to patients with MUC1 expressing 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 762. doi:10.1158/1538-7445.AM2011-762
Abstract 779: Role of CD44 in LAK cell-mediated killing of melanoma
Authors: Mckallip Robert J. , Law Gabriela , Sun Jingping 
Published: June 2012

Abstract
Lymphokine-activated killer cells play an important role in various immunologically-based treatments of cancer, including in the use of IL-2 therapy for the treatment of malignant melanoma. In previous studies, we demonstrated that the expression of CD44 on splenocytes is significantly elevated following exposure to IL-2. Therefore, in the current study we examined the potential significance of CD44 expression on lymphokine activated killer (LAK) cells in their interaction and killing of melanoma cells. Stimulation of splenocytes with IL-2 led to a significant increase in the expression of CD44 on T cells, NK cells and NKT cells. Treatment of melanoma bearing CD44WT mice with IL-2 led to a significant reduction in the local tumor growth while treatment of melanoma bearing CD44KO mice with IL-2 was ineffective at controlling tumor growth. Furthermore, the ability of splenocytes from IL-2 treated CD44KO mice to kill melanoma tumor targets was significantly reduced when compared to the anti-tumor activity of splenocytes from IL-2 treated CD44WT mice. The importance of CD44 expression on the LAK cells was further confirmed by the observation that adoptively transferred IL-2-activated splenocytes from CD44KO mice were significantly less effective at controlling tumor growth in vivo. Next the significance of the increased expression of CD44 in tumor killing was examined and showed that following stimulation with IL-2, distinct populations of cells with low (CD44lo) or elevated (CD44hi) expression of CD44 are generated and that the CD44hi cells are responsible for killing of the melanoma cells. The reduced killing activity of the CD44KO LAK cells did not result from reduced activation or expression of effector molecules but was due, at least in part, to a reduced ability to adhere to B16F10 tumor cells.
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 779. doi:10.1158/1538-7445.AM2011-779