bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4476: The effect of electrochemotherapy on metastatic potential of human melanoma cells SK-Mel28
Authors: Cemazar Maja , Todorovic Vesna , Mlakar Vid , Glavac Damjan , Sersa Gregor 
Published: June 2012

Abstract
Electrochemotherapy is a local treatment, combining chemotherapy and application of electric pulses to the tumour. Electrochemotherapy with bleomycin or cisplatin has demonstrated its effectiveness in controlling local tumour growth in the treatment of malignant melanoma and is proposed as one of the treatment options for in-transit melanoma metastases in Europe. An important aspect of successful treatment is prevention of metastasis, however, it is known that metastasis can be induced by different treatment modalities. Alterations in tumour microenvironment caused by surgery or radiation therapy, can lead to increased formation of metastasis. Furthermore, formation of metastases can be directly linked to migratory potential of the cells. Although electrochemotherapy is now routinely used for treatment of various cancers in many cancer centres, the effect of electrochemotherapy on the metastatic potential of tumour cells is not known. Therefore, the aim of this study was to evaluate the effect of electrochemotherapy with bleomycin and cisplatin on the metastatic potential of human malignant melanoma cells.
Human malignant melanoma cells SK-MEL 28 were treated by electrochemotherapy with a range of bleomycin concentrations from 0.01 nM to 1μM and cisplatin concentrations from 2 to 80 μg/mL. SK-MEL 28 cells that were viable 48 h after electrochemotherapy were tested for their metastatic potential by ability to migrate and invade through Matrigel coated porous membrane. In addition, cell adhesion and proliferation using MTS assay were also tested. Furthemore, RNA was isolated from the cells 16 h after each treatment and differentially expressed genes were investigated by microarray analysis to evaluate the effect of electrochemotherapy with bleomycin or cisplatin on expression of genes involved in the development of cancer. The Gene Ontology Tree Machine program was used for gene enrichment analysis.
Migration and invasion of melanoma cells that survived 48h after electrochemotherapy with bleomycin or cisplatin were not changed compared to control untreated cells. Also, there were no changes observed in cell adhesion on Matrigel. Gene expression analysis demonstrated that a very low number of genes were differentially expressed after electrochemotherapy with either bleomycin or cisplatin. Specifically, the expression of metastasis promoting genes was not increased after electrochemotherapy.
Our data suggest that electrochemotherapy with bleomycin or cisplatin does not increase metastatic behaviour of human melanoma cells, having important clinical implication for safe use in treatment of melanoma metastases.
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 4476. doi:10.1158/1538-7445.AM2011-4476
Abstract 4477: Characterization of AZD5363, an orally bioavailable, potent ATP-competitive inhibitor of AKT kinases with pharmacodynamic and antitumor activity in preclinical models
Authors: Davies Barry R. , Luke Richard , Dudley Phillippa , Greenwood Hannah , Crafter Claire , Cosulich Sabina , Page Ken , Yates James , Lane Clare , Yu Derek , Zhang Jingchuan , Pass Martin 
Published: June 2012

Abstract
AKT is a key node in the most frequently de-regulated signaling pathway in human cancer, and has been shown to mediate resistance to a range of cytotoxic, anti-hormonal and targeted therapies. AZD5363 inhibits all AKT isoforms with a potency of &lt;10 nM, and inhibits phosphorylation of the AKT substrate PRAS40 in BT474c cells with a potency of 0.31 μM. AZD5363 monotherapy inhibits the proliferation of 22/150 solid and hematological tumour cell lines with a potency of &lt; 1μM. Cell lines derived from breast cancers show the highest frequency of response. Pharmacodynamics have been studied in BT474c xenografts growing in nude mice following oral dosing. A dose of 300 mg/kg AZD5363 significantly inhibits pPRAS40, pGSK3β and pS6 for at least 24 h; pPRAS40 was inhibited by 70-90% for 24 h following a 300 mg/kg dose. These biomarkers were also significantly inhibited for at least 8 h following a 100 mg/kg dose. A good correlation was observed between plasma exposure of AZD5363 and inhibition of PRAS40 phosphorylation (EC50 ∼ 0.1 μM). Chronic dosing of AZD5363 causes dose-dependent inhibition of BT474c xenografts; schedules of 300 mg/kg qd and 150 mg/kg bd resulted in &gt;90% inhibition of BT474c xenograft growth. Chronic monotherapy dosing resulted in profound growth inhibition or regression of multiple other xenografts derived from a range of solid tumour types. AZD5363 also greatly enhanced the anti-tumor activity of cytotoxic and novel targeted therapies in xenograft models. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic and anti-tumor activity in vivo, and has potential to treat a range of solid and hematological malignancies. AZD5363 is currently in phase 1 clinical trials.
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 4477. doi:10.1158/1538-7445.AM2011-4477
Abstract 448: Mechanism of action differences of transmembrane versus secretory tumor necrosis factor-α on tumor growth; role of tumor-associated myeloid cells
Authors: Ardestani Shidrokh , Li Bin , Deskins Desirae , Young Pampee 
Published: June 2012

Abstract
Tumor Necrosis Factor alpha (TNF-α) is a major inflammatory cytokine, produced by a wide variety of cell types including macrophages, T lymphocytes endothelial cells and tumor cells. TNF-α is expressed as a membrane-tethered protein (tmTNF-α), cleaved by tumor necrosis factor-α-converting enzyme (TACE) and subsequently released into extracellular space as a soluble TNF-α (sTNF-α). Recent studies from our laboratory and others have shown that low level expression of TNF-α by tumor cells substantially increases tumor growth, vascularity and decreases tumor necrosis, in part by increasing tumor content of a proangiogenic myeloid subtype (Li et al., Cancer Res. 2009, 1;69(1):338-48). To better understand the mechanism by which TNF-α modulates the myeloid phenotype, we generated murine Lewis lung carcinoma (LLC) and B16F10 melanoma tumor cells transduced with retrovirus expression vectors directing modest overexpression of a membrane tethered moiety, tmTNF-α. Heterotopic implantation of tmTNF-α expressing lines resulted in significantly decreased growth than control tumors in both tumor models. Our studies showed that this was not due to effects on the tumor cells themselves but likely due to effects on tumor stroma as the effect of tmTNF-α was lost in TNF-α receptor deficient mice. Further evaluation showed an absence of tumor associated myeloid cells within the tumor, which suggested apoptosis of migrated myeloid cells or inhibition of myeloid recruitment into the tumor environment. There is a significant gap in our knowledge on the mechanism of transmembrane isoform of TNF-α and its potential anti-tumorogenic role. In this study our goal is to identify the mechanism in which tmTNF-α promotes tumor regression and to understand how it modulates host bone marrow derived myeloid 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 448. doi:10.1158/1538-7445.AM2011-448
Abstract 4480: Combination of a PI3K/mTOR inhibitor and a MEK inhibitor at suboptimal dose significantly inhibits growth of lung adenocarcinoma tumors in KrasG12D-LSL mice
Authors: Shojaei Farbod , Simmons Brett H. , Lee Joseph H. , Wong Anthony , Los Gerrit , Kan Julie , Christensen James G. 
Published: June 2012

Abstract
The KrasG12D-LSL conditional GEMMs (genetically engineered mouse models) are a valuable tool in translational research to study tumor progression and to investigate efficacy of anti-tumor compounds in a variety of cancer types. Here, intranasal delivery of adeno-Cre resulted in the expression of mutant Kras leading to development of tumor lesions in the lungs including adenomatous hyperplasia, large adenoma and adenocarcinoma. Treatment of tumor bearing mice at adenocarcinoma stage (at 14 weeks post adeno-cre inhalation) with suboptimal dose of PF-04691502 (PI3Ka/mTOR inhibitor; 7.5 mg/kg; SID) and PD-0325901 (MEK inhibitor, 1.5 mg/kg; SID) reduced tumor lesions in mice treated with single agents and significantly inhibited tumor growth in mice treated with combination of both compounds. In addition, immunohistochemistry showed inhibition of pS6 in the treated animals particularly in the combination group providing a proof of mechanism for the tumor growth inhibition. Similar response was observed when mice bearing H460 (carry Kras and PIK3CA mutations) orthotopic lung tumors were treated with the combination regimen. These observations provide some clue to further pursue efficacy of PF-04691502 plus PD-0325901 in the clinical settings and also in more invasive models such as KrasG12D-LSLp53flox/flox mice.
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 4480. doi:10.1158/1538-7445.AM2011-4480
Abstract 4483: SR13668, a selective 12-lipoxygenase inhibitor, suppresses tumor growth by modulating the Akt signaling pathway
Authors: Jong Ling , Chao Wan-Ru , Green Carol , Kapetanovic Izet , Sambucetti Lidia , Collins Nathan 
Published: June 2012

Abstract
SR13668, an orally active cancer therapeutic agent, exhibits potent antitumor activity against various human cancer xenografts (e.g., breast, prostate, lung and ovarian cancer) without significant toxicity. An exploratory IND study of SR13668 has been completed with a two-stage design to compare the bioavailability of five SR13668 formulations, and the preferred formulation will be subjected to investigation in subsequent phase I testing.
SR13668 inhibits growth factor-stimulated phosphorylation of Akt and its downstream target GSK3β in PC-3 prostate and high pAkt expressing MDA-MB-468 breast cancer cells in a dose-dependent manner. SR13668 was also shown to block FGF- and IGF-stimulated Akt activation. Screening a broad selection of kinase targets, including Akt(1,2,3), PI3K, and PDK1, indicated that SR13668 is not a kinase inhibitor. Preliminary mechanistic studies showed that SR13668 selectively inhibits 12-lipoxygenase (12-LOX), but does not affect other lipoxygenases (5-LOX and 15-LOX), or cyclooxygenases (COX-1 and COX-2).
12-LOX plays a major role in promoting cancer progression, invasion and metastasis as well as tumor angiogenesis. 12-LOX has been regarded as a novel target for cancer therapy, since it is generally absent in normal epithelia and is often constitutively expressed in various epithelial cancers. Unlike direct inhibitors of PI3K or Akt, SR13668 has no adverse effects on fasting glucose levels or body weights after 14 days of oral treatment with SR13668 at 500 mg/kg/day, a dose more than 10 times higher than that needed for antitumor activity.
Pharmacologic intervention studies with lipoxygenase inhibitors for the prevention or inhibition of cancers have been difficult to interpret, as there are very few isoform-selective LOX inhibitors available. SR13668 is a highly specific 12-LOX inhibitor. No off-target activities were observed, when screened against a broad collection of 40 diverse enzymes and 80 transmembrane and soluble receptors, ion channels and monoamine transporters. The Phase 0 clinical study showed that SR13668 has long half-life (11.2 ± 3.1 hours), and patients did not experience significant adverse events related to SR13668 treatment; thus SR13668 is a promising candidate for further clinical investigation.
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 4483. doi:10.1158/1538-7445.AM2011-4483
Abstract 4490: Tocotrienols inhibit PI3/Akt and ERK pathways to induce growth arrest in pancreatic cancer cell lines by downregulation of Her-2/ErbB2 receptors
Authors: Chakraborty Kanishka , Ramsauer Victoria , Kang S Shin , Lightner Janet , Campbell S , Stone WL , Krishnan Koyamangalath 
Published: June 2012

Abstract
Abstract: Pancreatic cancer is the fifth leading cause of cancer death in the United States. Alternate strategies to treat and prevent this cancer are urgently required. In this regard, novel therapeutic agents that can inhibit signaling pathways implicated in the proliferation and survival of pancreatic cancer cells are of immense interest. Tocotrienols are members of the Vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side-chain that confers superior anti-cancer properties. The ability of tocotrienols to selectively inhibit the HMG CoA reductase pathway through post-translational degradation of HMG CoA reductase and to suppress the activity of transcription factor NFκβ could be the basis for some of these properties. Data: Our studies indicate that γ- and Δ-tocotrienol have potent anti-proliferative activity in pancreatic cancer cells (Panc-28, MIA-PACA-2 and BXPC-3). Indeed both tocotrienols induced cell death (&gt; 50%) by the MTT cell viability assay in all three pancreatic cancer cell lines. We also examined the effects of the tocotrienols on the Akt and the Ras/Raf/MEK/ERK signaling pathways by Western blotting analysis. γ- and Δ-Tocotrienol treatment of cells reduced the activation of ERK MAP kinase and that of its downstream mediator RSK (ribosomal protein S6k) in addition to suppressing the activation of protein kinase, Akt. Suppression of activation of Akt by gamma-tocotrienol led to downstream upregulation of Fox-03 and GSK-3b. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level. Tocotrienols but not tocopherols were able to induce the observed effects. Conclusion: Our results suggest that the tocotrienol isoforms of vitamin E can induce apoptosis in pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the PI3/Akt and ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and needs further investigation.
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 4490. doi:10.1158/1538-7445.AM2011-4490
Abstract 4496: Preclinical efficacy of the novel dual PI3K/mTOR inhibitor, BEZ235 compared with RAD001 in HER2+ breast tumors
Authors: De Pradip K.R , Sun Yuliang , Dey Nandini , Leyland-Jones Brian 
Published: June 2012

Abstract
Background: HER2 overexpression occurs in 20-25% of patients with breast cancer and is associated with aggressive disease and decreased survival. HER2 activates multiple cellular signaling pathways including the PI3K-AKT-mTOR pathway. The sustained activation of the PI3K-AKT-mTOR pathway or the activating mutation of PIK3CA (p110α) is one of the major causes of drug resistance including trastuzumab.
Purpose: Inhibitors of mTOR1 have been shown to be active in patients with solid tumors. As the phosphatidylinositol 3-Kianse (PI3K) pathway activates numerous other kinases, transcription factors, and proteins associated with cell growth/survival and apoptosis besides mammalian target of rapamycin (mTOR), suppression of this pathway upstream of mTOR may be more effective than inhibition of mTOR1 in HER2+ breast cancer models.
Experimental Design: To examine this possibility, the dual pan-PI3K/mTOR inhibitor, BEZ235 was compared with mTOR1 inhibitor, RAD001 in trastuzumab-sensitive HER2+ (BT474 and SKBR3), trastuzumab-resistant (BT474HR), and PIK3CA mutated/HER2+ breast cancer cells (HCC1954 and U893)
Results: Treatment of HER2+ breast cancer cell lines with BEZ235 or RAD001 in vitro showed 1) RAD001 mediated AKT activation was blocked when cells were treated with BEZ235, 2) BEZ235 dose- and time-dependently blocked AKT phosphorylation (both at Ser473 and Thr308), 3) both drugs completely blocked the activation P70S6K, but BEZ235 more efficiently blocked 4EBP1 phosphorylation than RAD001, 4) ERK activation was significantly attenuated by BEZ235, while inhibition of mTOR1 by RAD001 lead to activated ERK, 5) BEZ235 was significantly more effective than RAD001 in reducing HIF1α expression following heregulin stimulation, 6) activation of caspase3 (from the expression level of cleaved caspase3) was also greater following treatment with BEZ235 than RAD001, and 7) integrin-dependent breast tumor cell migration was significantly abrogated with BEZ235 in association with inhibition of RAC1-GTP, but this was not seenwith RAD001.
Conclusion: Our preclinical in vitro data demonstrate that concurrent inhibition of PI3K and mTOR is likely to be a more effective strategy in the treatment of both sensitive and resistant HER2+ breast cancers than the inhibition of mTOR1 alone.
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 4496. doi:10.1158/1538-7445.AM2011-4496
Abstract 4499: HM5016699, a novel and selective PI3K/mTOR dual inhibitor
Authors: Ren Yongxin , Zhang Weihan , Cui Yumin , Guo Mingchuan , Long Jingwen , Sai Yang , Wang Jian , Yan James , Li Jia , Qing Weiguo , Su Weiguo 
Published: June 2012

Abstract
PI3KCA gene amplification and mutations have been identified in many types of tumors, suggesting the dysregulation of PI3K/AKT/mTOR axis plays pivotal roles in tumorigenesis and development. Reported here is the discovery of HM5016699 as a potent, reversible ATP-competitive PI3K/mTOR dual inhibitor for treatment of cancer. HM5016699 showed potent kinase inhibition with IC50 of 0.01, 0.206, 0.052, 0.051 and 0.059 µM on PI3Kα, β, γ, Δ and mTOR, respectively. It demonstrated high selectivity on PI3K family and mTOR over a panel of 274 kinases. Of the 67 tumor cell lines screened from lung, colon, breast, ovarian, and other tumor types, we found that the tumor cells with HER2 gene amplification or PTEN loss tended to be sensitive to HM5016699, while the tumor cells harboring PI3KCA mutations and wild type Ras/Raf were mostly sensitive to the compound. HM5016699 could also show p-Erk inhibition and apoptotic induction at higher concentrations in the tumor cells harboring Ras/Raf mutations, suggesting it might bring benefits to patients carrying Ras/Raf mutations in the clinic. Consistent with in vitro studies, HM5016699 exhibited dose dependent tumor growth inhibition on multiple human xenografts models. It was found that the tumors with PIK3CA mutation or PTEN deletion were highly sensitive to HM5016699 with ED50s ranging from 0.6 to 1.8 mg/kg in U87MG (pTEN null), SKOV3 (H1047) and H1975 (G118D), whereas in tumors with Ras/Raf mutations, such as DLD-1(G13D), A549 (G12S) and HT-29(V600E), its ED50s were from 3.0 to 15.0 mg/kg. The decreased phosphorylation of AKT and S6 was observed in the tumor xenograft tissues treated with HM5016699, which was well-correlated with compound exposure. Therefore, we concluded that HM5016699 demonstrated both in vitro and in vivo activity through acting on PI3K/mTOR pathway. HM5016699 exhibited a favorable pharmacokinetic profile and acceptable safety window in rats. The pre-clinical study results suggest that HM5016699 could be a promising anti-cancer agent.
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 4499. doi:10.1158/1538-7445.AM2011-4499
Abstract 45: Accurate total and allele-specific copy number measurements in mosaic tumors
Authors: Curry Bo , Sampas Nick , Anderson Paige , Peter Brian 
Published: June 2012

Abstract
For the characterization of genomic copy number changes that occur in the development and progression of cancer, oligonucleotide array comparative genomic hybridization (aCGH) offers high-resolution and precise determination of chromosomal copy number and genome-wide aberrations. We recently reported a new method for making simultaneous measurements of single nucleotide polymorphisms (SNPs) and copy number alterations in the same microarray assay. The combined assay can detect copy-number neutral events, such as acquired loss of heterozygosity (LOH), as well as allelic imbalance in and around amplified regions.
Previously reported algorithms for analyzing Agilent CGH+SNP data were able to genotype primarily diploid samples and to detect regions of constitutional LOH. However, tumor heterogeneity, aneuploidy and variable sample quality create significant challenges for both solid and liquid tumors. Our earlier methods were often unable to cope with the high levels of aneuploidy sometimes found in solid tumors, or with admixtures of normal cells and aberrant cells. We now describe new computational methods which can determine total copy number, aneuploid fraction, and allele-specific copy number in many aneuploid tumor samples, even when mixed with up to 80% normal tissue.
We report results from genomic DNA isolated from a cancer cell line, a blood sample, and a solid tumor. Each of these sample types presents novel challenges. The cell line we studied, though largely monoclonal, is highly aneuploid. The blood DNA is of high quality, but the fraction of tumor cells in the sample is low. The solid tumor DNA is of relatively low quality, and composed of multiple aberrant clones. We were able to determine the aneuploid fraction of the tumors, and to measure copy number variation in samples with as little as 20% tumor cell content. In addition to detecting copy-neutral LOH regions, we also measured allele-specific copy number, both of the aberrant clone and of admixed normal cells.
The new analysis methods allow the extension of the extra allelic information available from the CGH+SNP assay to cancer samples.
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 45. doi:10.1158/1538-7445.AM2011-45