bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3548: Selective targeting of pancreatic tumors lacking methylthioadenosine phosphorylase (MTAP)
Authors: Bertino Joseph R. , Lee Kuo-Chi , Johnson-Farley Nadine , Lubin Martin 
Published: June 2012

Abstract
The pancreatic cancer cell line, Mia PACA, lacks MTAP, and as a result is unable to salvage adenine and methionine, products of methylthioadenosine (MTA) metabolism by MTAP, and is more sensitive to de novo purine synthesis inhibitors (thiopurines, methotrexate, azaserine and L-alanosine). In addition, MTAP deficiency creates a condition where normal, but not tumor tissues, can be protected from 5-fluorouracil (5-FU) toxicity by MTA. In normal tissue, MTA is converted to adenine, consuming 5-phosphoribose-1-pyrophosphate (PRPP) and competitively inhibiting phosphoribosylation of 5-FU (and subsequent cellular retention and inhibition of thymidylate synthase and incorporation into RNA). In MTAP deficient tumors, MTA can not generate adenine; the relative lack of adenine, and abundance of PRPP favors phosphoribosylation of 5-FU to nucleotides. The MTAP gene is linked to the tumor suppressor p16INK4 locus on chromosome 9p21. This locus is frequently deleted in human cancer. As a result, relative or complete MTAP deficiency is common in several human cancers, including pancreatic cancer (33%). We have transfected the Mia PACA cell line with MTAP cDNA and generated three sublines that express MTAP. The parenteral cell line lacking MTAP expression is more sensitive to 5-FU (4 h treatment), and toxicity is not ameliorated by pretreatment with MTA. In contrast, the three sublines expressing MTAP are a log less sensitive to 5FU, when pretreated with MTA.
As pancreatic cancer is known to be somewhat responsive to treatment with 5-FU, but doses are limited by toxicity, the protection of the host from toxicity by MTA pretreatment may allow higher doses of 5-FU to be safely given and allow gemcitabine, another antimetabolite used to treat patients with pancreatic cancer, to be added in full doses.
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 3548. doi:10.1158/1538-7445.AM2011-3548
Abstract 3553: Scutellaria barbata inhibits angiogenesis through downregulation of HIF-1 α expression in lung tumor
Authors: Lee Che-Hsin , Shen Yu-Ting , Wu Chao-Liang , Chow N-H , Shiau Ai-Li 
Published: June 2012

Abstract
Hypoxia, a hallmark of many solid tumors, is associated with angiogenesis and tumor progression. Hypoxia-inducible factor-1 (HIF-1) plays a significant role in tumor angiogenesis. In this study, we constructed a selective platform to screen the traditional Chinese medicine as anti-angiogenic agent. We examined the molecular mechanism by which Scutellaria barbata (S. barbata) regulates HIF-1-dependent expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. Hypoxia stimulated with the HIF-1 expression promotes angiogenesis by increasing VEGF expression and secretion. Herein, the expression of VEGF was decreased by treatment with S. barbata in tumor cells. Meanwhile, S. barbata reduced the migration and proliferation of endothelial cells under hypoxic condition. S. barbata inhibited the expression of HIF-1α, as well as phosphorylated their upstream signal mediators AKT. S. barbata significant retarded the tumor growth by 56% in vivo and immunohistochemical studies in the tumors revealed decreased intratumoral microvessel density. These results suggest that the traditional Chinese medicine therapy using S. barbata, which exerts anti-angiogenic activities, represents a promising strategy for the treatment of tumors.
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 3553. doi:10.1158/1538-7445.AM2011-3553
Abstract 3559: A new selective ALK inhibitor CH5424802 shows potent efficacy against ALK-positive cancers including the gatekeeper mutant-driven tumors
Authors: Sakamoto Hiroshi , Tsukaguchi Toshiyuki , Hiroshima Sayuri , Kodama Tatsushi , Kobayashi Takamitsu , Fukami Takaaki A. , Oikawa Nobuhiro , Tsukuda Takuo , Ishii Nobuya , Aoki Yuko 
Published: June 2012

Abstract
The recent development of targeted protein kinase inhibitors has provided new opportunity in cancer treatment. However, certain factors limit the efficacy of cancer therapies, such as a narrow therapeutic index caused by inhibition of multiple kinases, and the emergence of resistant mutants. Thus, kinase inhibitors with more potent and selective properties and effectiveness against resistant mutants need to be developed. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a new chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as non-small cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven tumors. Our results support the potential for the clinical evaluation of CH54242802 for long-term treatment of patients with ALK-driven tumors. CH5424802 is currently being investigated in Phase I/II clinical trials for patients with ALK-positive NSCLC.
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 3559. doi:10.1158/1538-7445.AM2011-3559
Abstract 3561: Pazopanib inhibits a subpopulation of PDGFR+ astrocytes in the neuro-inflammatory microenvironment of breast cancer brain metastases
Authors: Gril Brunilde , Vidal-Vanaclocha Fernando , Qian Yong , Liewehr David J. , Steinberg Seth M. , Palmieri Diane , Steeg Patricia S. 
Published: June 2012

Abstract
Brain metastases occur in approximately 35% of metastatic breast cancer patients whose tumors overexpress HER2. Using a quantitative model system to study breast cancer brain metastasis, HER2 overexpression increased the brain colonization of a brain seeking subline of MDA-MB-231 cells (231-BR-HER2). Since HER2 has been shown to induce overexpression of VEGF, we hypothesized that the anti-angiogenic drug pazopanib would reduce the metastatic outgrowth of breast cancer cells in the brain. Pazopanib is a multispecific tyrosine kinase inhibitor targeting VEGFR-1, -2, and -3, PDGFR alpha and beta, and c-kit. We previously showed that pazopanib directly targets the tumor cell through the disruption of B-Raf pathway. Pazopanib prevented the outgrowth of 231-BR-HER2 large brain metastasis by 73% (p&lt;0.0001). Metastasis has been described as an interaction of tumor cells and their environment. Here we evaluated the effect of pazopanib on the brain neuro-inflammatory microenvironment.
Previously, activated microglia and activated GFAP-expression astrocytes were observed around and within experimental brain metastases as well as from resected human brain metastases of breast cancer. In our experiments, the 231-BR-HER2 cell line was injected into the left cardiac ventricle of immunocompromised mice; mice were treated with vehicle, 30mg/kg or 100mg/kg pazopanib twice a day beginning on day 3 post-injection. Brain metastases were counted using H&E staining and brain slides were immunostained with markers for brain micro-environment components.
In the brain metastases, using an antibody to the phosphorylation site tyrosine 751 of PDGFR beta, a subpopulation of GFAP+ astrocytes was observed, previously undescribed. P-PDGFR beta + astrocytes were only detected around the brain metastases, suggesting a specific activation of astrocytes by tumor cells. Pazopanib treatment resulted in a trend, 76% (p=0.13) and 80% (p=0.070) decrease of the pY751 PDGFR beta + astrocyte population, at 30 and 100mg/kg respectively. In contrast, Pazopanib did not have any effect on NG2+pericyte, collagen IV or microglia expression. The data suggest a specific effect of pazopanib on the brain microenvironment. Collectively, the data identify an effect of pazopanib on the brain microenvironment, as well as tumor cells, which makes this drug an interesting candidate for brain metastasis prevention.
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 3561. doi:10.1158/1538-7445.AM2011-3561
Abstract 3563: A highly selective Erk1/2 Inhibitor with in-vivo anti tumor potency
Authors: Seipelt Irene , Guenther Eckhard , Blumenstein Lars , Mueller Gilbert , Schmidt Peter , Aicher Babette , Teifel Michael , Gerlach Matthias 
Published: June 2012

Abstract
Mutations in receptor tyrosine kinases, Ras or B-Raf frequently manifest constitutive activation of the Ras/Raf/Mek/Erk pathway in a variety of human cancers. The mitogen activated protein kinase Erk1/2 is an important regulator of cell proliferation and was shown to be over-activated by these dysregulated or mutated upstream signals.
AEZS-131 selectively inhibits Erk1/2 with an IC50 of 4 nM, blocks cellular Rsk-1 phosphorylation, modulates downstream cellular substrate activation, arrests tumor cells in G1 and inhibits the growth of multiple human tumor cell lines in the nanomolar range. We have studied the response of human cancer cells (Hct116) in in-vivo mouse xenograft experiments. AEZS-131 significantly inhibited tumor growth at daily doses of 30mg/kg. Currently, AEZS-131 is undergoing in-vivo combination experiments with PI3K inhibitors.
Since pharmacological inhibition of Erk1/2 reverses Ras and Raf activation also in cells demonstrating resistancy to common Raf inhibitors like GDC-0879 and PLX4720, it appears likely to put more attention on the downstream kinase Erk1/2 as therapeutic target. Furthermore, in instances of coincident activation of the Raf and PI3K pathways, combinations of AEZS-131 and PI3K inhibitors may prove efficacious.
Here we present the in-vitro and in-vivo characterisation of the first in-class Erk1/2 inhibitor showing in-vivo efficacy as single therapy agent.
Early development of the Erk1/2 inhibitor AEZS-131 by Æterna Zentaris is integral part of our in-house kinase research program comprising the investigation of different compounds for single Erk1/2 inhibition, single PI3K inhibition and dual kinase inhibitions. All compounds are exclusively synthesized by our Drug Discovery Department.
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 3563. doi:10.1158/1538-7445.AM2011-3563
Abstract 3569: Changes in signaling pathways induced by vandetanib in a human medullary thyroid carcinoma model as detected by reverse phase protein arrays
Authors: Broutin Sophie , Commo Frédéric , De Koning Leane , Hego Caroline , Marty Bérengère , Talbot Monique , Caillou Bernard , Dupuy Corinne , Ryan Anderson Joseph , Schlumberger Martin , Bidart Jean-Michel 
Published: June 2012

Abstract
Introduction: Medullary thyroid carcinomas (MTC) frequently involve activating mutations in the proto-oncogene tyrosine-kinase receptor RET. Vandetanib (ZD6474, ZACTIMATM) is a potent inhibitor of RET and VEGFR-2 tyrosine-kinase activities which is currently in phase III clinical trial in MTC. The aim of this study was to investigate in vitro and in vivo molecular effects of vandetanib on MTC signaling pathways using a proteomic approach based on reverse-phase protein arrays (RPPA).
Methods: The human MTC TT cell line, bearing a RETC634W activating mutation, was cultured in the absence or the presence of vandetanib (100, 500, 1000 nM) during 4, 24 and 72 hours. MTC TT xenografted athymic nu/nu mice received vandetanib (50 mg/kg/day p.o.) or placebo and xenografts were removed after 1 and 4 days of treatment. Twenty-eight protein extracts from in vitro (n=24) and in vivo (n=4) experiments were profiled by RPPA analysis. Equal amounts of lysates were printed in serial dilutions onto nitrocellulose-coated glass slides. Each slide was then probed with each of a 20-antibodies set, specific for oncogenic pathways (PI3K/AKT/mTOR, MEK/p44-42, STAT3, NFκB) and cell cycle/apoptotic proteins (CDK1, PARP, cleaved-PARP).
Results: In in vitro experiments, vandetanib treatment induced an increase of cleaved-PARP (p&lt;10-5) with a 3-fold rise after 72 hours at 100 nM. Phosphorylation of NFKB was not significantly modified when compared to actin. In contrast, phosphorylation of STAT3 significantly decreased after 72 hours of vandetanib treatment. Overall, the MAPK signaling pathway was dramatically inhibited by vandetanib, as substantiated by the decrease of MEK and p44-42 phosphorylation when compared to their total protein forms (p&lt;10-3). Inhibition of p44/42 and STAT3 phosphorylation were also observed in MTC TT xenografted mice treated by vandetanib. Several proteins were re-analyzed by western-blot and/or immunohistochemistry analyses and the results were in agreement with those observed in RPPA.
Conclusions: Together these observations demonstrated that, at the protein level, vandetanib induces apoptosis and mainly inhibits MAPK and AKT pathways in MTC. Furthermore, our experimental approach confirmed the interest of this method of protein arrays for analyzing changes in signaling pathways induced by tyrosine-kinase inhibitors.
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 3569. doi:10.1158/1538-7445.AM2011-3569
Abstract 3581: Characterization of human breast cancer cells with acquired resistance to the EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib
Authors: De Luca Antonella , Faraso Stefania , D'Alessio Amelia , Gallo Marianna , Lamura Luana , Maiello Monica R. , Normanno Nicola 
Published: June 2012

Abstract
The epidermal growth factor receptor (EGFR) and the ErbB-2 receptor are co-expressed in a subset of breast carcinomas that show a more aggressive phenotype. The dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib has been recently approved for the treatment of metastatic breast cancer patients whose tumors overexpress ErbB-2. We investigated the mechanisms of acquired resistance to lapatinib in breast cancer cells. For this purpose, we used as model the SK-Br-3 human breast carcinoma cell line that express high levels of ErbB-2, and moderate levels of EGFR and ErbB-3. We selected lapatinib-resistant SK-Br-3 cells by stepwise dose escalation of lapatinib. After six months of selection, we isolated SK-Br-3 cells that were able to grow in 1 μM lapatinib. The IC50 of lapatinib for parental SK-Br-3 cells was 140 nM, whereas the IC50 for the lapatinib-resistant SK-Br-3 derived cell line (Lap-R) was &gt; 4 μM. Treatment with lapatinib significantly inhibited the activation of EGFR, ErbB-2 and ErbB-3 in both parental and Lap-R SK-Br-3 cells. However, following treatment with lapatinib, Lap-R cells showed a persistent activation of AKT and MAPK, which in contrast were completely inhibited in parental SK-Br-3 cells, as measured by both western blotting and a Luminex-based phosphoprotein array. In addition, treatment with lapatinib produced a slight activation of c-Src in parental cells, whereas significant levels of c-Src activation were detected in Lap-R cells cultured in presence of lapatinib. Lap-R cells also showed higher levels of expression of the chemokine receptor CXCR-4 than parental cells. In agreement with these findings, Lap-R cells showed a significantly higher ability to invade a matrigel-coated membrane as compared with parental SK-Br-3 cells, as measured with a Boyden-chamber based colorimetric invasion assay. Preliminary findings demonstrate that inhibition of c-Src with the selective src kinase inhibitor saracatinib produces a more significant inhibition of Lap-R cell invasion as compared with parental SK-Br-3 cells. Taken together, these findings suggest that activation of c-Src signalling might play a role in acquired resistance to lapatinib in breast cancer 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 3581. doi:10.1158/1538-7445.AM2011-3581
Abstract 3585: Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo
Authors: Yamaguchi Takayuki , Kakefuda Reina , Tajima Nobuyuki , Sowa Yoshihiro , Sakai Toshiyuki 
Published: June 2012

Abstract
Purpose: MAPK-pathway is one of the most important pathways for a new anticancer drug development. We performed a high-throughput screening for compounds that induce expressions of p15INK4b, and finally identified a novel MEK1/2 inhibitor JTP-74057 (GSK1120212) being evaluated in clinical trials. We characterized its antitumor activities in vitro and in vivo.
Experimental design: The MEK inhibitory activity was evaluated using recombinant proteins, and its specificity was confirmed against multiple kinases. Several colorectal cancer cell lines were used for proliferation assay, apoptosis assay, and xenograft model.
Results: JTP-74057 strongly inhibited MEK1/2 kinase activities, but did not inhibit other 98 kinase activities. Treatment with JTP-74057 resulted in growth inhibition accompanied with upregulation of p15INK4b and/or p27KIP1 in most colorectal cancer cell lines, which we tested. Daily oral administration of JTP-74057 for 14 days suppressed tumor growth both of HT-29 and COLO205 xenografts in nude mice. Interestingly, the tumor regression was observed only in COLO205 xenografts, and COLO205 was also much more sensitive to JTP-74057 for inducing apoptosis than HT-29 in vitro. Treatment with an Akt inhibitor enhanced the JTP-74057-induced apoptosis in HT-29 cells. Finally, JTP-74057 exhibited an additive or a synergistic effect in combination with the standard-of-care agents, 5-fluorouracil, oxaliplatin or SN-38.
Conclusions: JTP-74057, a highly specific and potent MEK1/2 inhibitor, exerts favorable antitumor activities in vitro and in vivo. Sensitivity to JTP-74057-induced apoptosis might be an important factor for the estimation of in vivo efficacy, and the treatment with an Akt inhibitor enhanced the induction of apoptosis. These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal 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 3585. doi:10.1158/1538-7445.AM2011-3585
Abstract 3587: XL184: c-Met inhibition is effective in a mouse xenograft model of metastatic uveal melanoma
Authors: Yeh Iwei , Griewank Klaus , Ding Vivianne W. , Bastian Boris C. 
Published: June 2012

Abstract
Oncogenic mutation of GNAQ is an early event in uveal melanoma development. Identification of critical downstream effectors of GNAQ could allow for targeted therapy of this deadly form of melanoma. We identified c-Met upregulation as a downstream effect of GNAQ Q209L mutation by analyzing expression changes in immortalized mouse melanocytes transduced with GNAQ Q209L. By Western blot, we established that c-Met protein expression is increased in human uveal melanoma cell lines that harbor a GNAQ activating mutation compared to lines with wild-type GNAQ.
XL184 is a small-molecule tyrosine kinase inhibitor that has activity against c-Met. In vitro assays of XL184 demonstrated preferential activity against human uveal melanoma cell lines (OMM1.3 and Mel202) with GNAQ activating mutations. Intravenous injection of 1×106 OMM1.3 cells into immunocompromised NSG mice results in the development of multiple liver tumor nodules after 6-8 weeks, recapitulating liver tropism (over 80% of patients with metastatic uveal melanoma have liver metastases). We treated mice starting four weeks after OMM1.3 intravenous injection with XL184. After four weeks of treatment, the treated mice demonstrated decreased liver tumor size with central tumor necrosis on histologic examination. The activity of XL184 is likely through its inhibition of c-Met signaling as we found little expression of the other targets of XL184 in OMM1.3. In conclusion, XL184 demonstrates activity in a mouse xenograft model of metastatic uveal melanoma, and has potential to be active against hepatic metastases of uveal melanoma, the major cause of mortality in this rare 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 3587. doi:10.1158/1538-7445.AM2011-3587