bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3603: Endoxifen pharmacokinetics and bioavailability in female mice
Authors: Ames Matthew M. , Reid Joel M. , Buhrow Sarah A. , Walden Chad A. , Safgren Stephanie L. , Goetz Matthew P. 
Published: February 2011

Abstract
In collaboration with NCI, we are developing endoxifen (END), the active metabolite of tamoxifen (TAM), as a drug for the treatment of estrogen receptor positive breast cancer. Tamoxifen treated women with reduced or absent CYP2D6 enzyme activity have significantly lower END plasma concentrations. In a retrospective analysis of two different prospective tamoxifen trials (NCCTG and ABCSG), we have demonstrated that genetic or drug-induced reductions in CYP2D6 metabolism are associated with a higher risk of breast cancer recurrence in Tam treated ER positive breast cancer. To test the hypothesis that clinically relevant concentrations and exposures of END are achieved following oral administration of END, we characterized the pharmacokinetics of i.v. and oral END and oral TAM in female mice. Endoxifen was synthesized and provided by NCI/DTP. Plasma samples were analyzed using a validated reverse-phase HPLC method with fluorescence detection. Following i.v. administration of a 1 mg/kg dose, peak plasma concentration, terminal elimination half-life and plasma clearance values were 0.26 µM, 6.5 h and 11.8 L/h/kg, respectively. Oral pharmacokinetics and bioavailability were determined following doses of 50 and 200 mg/kg. Peak plasma concentrations of 0.76 µM were achieved with a 50 mg/kg dose and plasma concentrations above 0.1 µM were maintained for longer than 8 h. Peak plasma concentrations of 8 µM were achieved with a 200 mg/kg dose and plasma concentrations above 2 µM were maintained for 24 h. Bioavailability was 50% and greater than 100% following the 50 mg/kg and 200 mg/kg doses, respectively. Based on pharmacokinetic data for oral END and TAM normalized to a 50 mg/kg oral dose, END plasma concentrations and total exposure were 20-fold greater following oral END as compared to oral TAM. In conclusion, END has high oral bioavailability in mice and substantial plasma concentrations are achieved and maintained after a single oral END dose. Compared to an equivalent oral dose of Tam, substantially higher END concentrations are achieved following oral END. These data suggest that the primary administration of End may overcome the limitations related to human CYP2D6 metabolism, and support the ongoing development of endoxifen as a primary therapy for ER breast cancer. Supported by the Mayo Comprehensive Cancer Center Grant (CA15083) and the Mayo Clinic Breast Cancer SPORE (CA 116201; MMA, JMR, MPG).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3603.
Abstract 3606: Gene and miRNA expression profiles in lung cancer cells cooperated with drug sensitivity to PKC inhibitor enzastaurin
Authors: Masahiro Seike , Okano Tetsuya , Shimokawa Tsuneo , Gemma Akihiko 
Published: February 2011

Abstract
PKC-beta inhibitor, Enzastaurin, is being evaluated in a Phase III trial as a maintenance therapy for the treatment of diffuse large B-cell lymphoma (DLBCL), as well as being evaluated in several Phase II studies across a variety of more common tumor types including: breast, colon, lung, ovarian and prostate cancers. Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin in non small cell lung cancer cells (NSCLC). To ascertain the potential for PKC-beta inhibitor-based treatment in NSCLC, we analyzed the antitumor effects of enzastaurin in 22 NSCLC cell lines via MTT assay. To identify a molecular model of sensitivity to PKC-beta inhibitor treatment in NSCLC, we conducted a gene and miRNA expression profiling study using cDNA arrays and Taqman MicroRNA Arrays on the same set of cell lines and related the cytotoxic activity of enzastaurin to corresponding gene and miRNA expression pattern. In addition, pathway analysis was done with Pathway Architect software. We used eight genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. We also identified unique miRNA expression patterns correlated with enzastaurin sensitivity. Our results suggested that PKCβ inhibitor may be promising anticancer drugs to NSCLC and the eight-gene classifier is useful in predicting drug sensitivity to PKC-beta inhibitors and may contribute to achieving individualized therapy for NSCLC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3606.
Abstract 3608: PTEN mutation associated with EGFR TKI de novo resistance
Authors: Kim Youngwook , Ko Jeonghun , Cui Zheng Yun , Ahn Myung Ju , Park Keunchil 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR) is overexpressed in 60-80% of non-small cell lung cancer patients. Recent identification that EGFR-tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib, has marked therapeutic effect in a subset of lung cancer patients has prompted extensive clinical trials, which revealed strong association between EGFR-TKI responder groups and the presence of activating mutations in the tyrosine kinase domain of EGFR. Molecular biomarkers used in predicting EGFR TKI responsiveness, however, can vary depending on individual circumstances. Albeit small number of patients, a subset of lung cancer patients does not respond to gefitinib or erlotinb de novo, despite the presence of EGFR activating mutations. The molecular basis of the de novo resistance to EGFR-TKI in EGFR mutant remains largely unidentified.
Here we report that EGFR mutated H1650 cells harbor PTEN deletion mutation, which confers EGFR mutant lung cancer cells with EGFR-TKI resistance. We show that erlotinib in combination with dual PI3K/mTOR inhibitor BEZ235 inhibits the cell viability of H1650 cells in vitro, consistent with a recent report by Sos et al. that showed PTEN etiology in EGFR-TKI de novo resistance in H1650 cells. Combination of erlotinib and PI3K/mTOR inhibitors in xenograft animal model studies. Unexpectedly, we also show that tumor growth of H1650 cells can be proprely controlled in xenograft in vivo animal model with erlotinib alone, raising the possibility that patients with PTEN deletion in the context of EGFR dependent lung cancer can still benefit from EGFR-TKI therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3608.
Abstract 3612: Potent preclinical anti-tumor activity of MGCD265, an orally active Met/VEGFR multitargeted kinase inhibitor in Phase II clinical development, in combination with an EGFR inhibitor
Authors: Fournel Marielle , Dupont Isabelle , Bonfils Claire , Dubay Marja , Ste-Croix Hélène , Beaulieu Carole , Beaulieu Normand , Lemoyne Christian , Wang James , Isakovic Lubo , Claridge Stephen , Saavedra Oscar , Raeppel Franck , Raeppel Stephane , Mannion Michael , Vaisburg Arkadii , Martell Robert E. , Besterman Jeffrey M. , Maroun Christiane R. 
Published: February 2011

Abstract
MGCD265 is an oral multitargeted receptor tyrosine kinase inhibitor in Phase II clinical development. MGCD265 targets the Met receptor tyrosine kinase and blocks Met activities which contribute to cancer development and progression such as cell proliferation, motility/invasion, angiogenesis and tumor cell survival. Although there is a large body of literature supporting Met activities as key to epithelial-mesenchymal transition and tumorigenesis, it is now accepted that the coordination of Met signaling with other regulators is central to oncogenesis. Met engages in cross-talks with several membrane proteins including the EGFR. Met and EGFR are coexpressed on tumor cells and functionally cooperate to amplify activating signals. Moreover, in NSCLC, Met gene amplification or overexpression of HGF, has been identified as a major molecular mechanism through which tumors evade EGFR inhibition by specific inhibitors such as gefitinib and erlotinib. Taken together, these studies provide a compelling rationale for concomitantly inhibiting Met and EGFR. In the present study, we have analyzed the in vivo anti-tumor activity of MGCD265 in combination with an EGFR-specific inhibitor, erlotinib. We demonstrate that this combination achieves greater antitumor responses than treatment with either agent alone, in multiple xenografts including NSCLC models. This is observed in the absence of overt toxicity. Furthermore, the PK of MGCD265 and erlotinib was analyzed when the two agents were co-administered, and indicated that there are no drug-drug interactions. In addition, in a NSCLC xenograft model that expresses an EGFR mutant resistant to erlotinib (T790M), MGCD265 significantly improved the anti-tumor activity when combined with erlotinib. The mechanisms underlying efficient tumor growth inhibition by this combination are presently under investigation. Preliminary results suggest that in addition to downregulating Met activation, MGCD265 may modulate EGFR activation by inhibiting the expression of the EGFR ligands TGFα and EREG. These preclinical studies provide support for the clinical development of MGCD265 in combination with erlotinib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3612.
Abstract 3615: Erlotinib in combination with different chemotherapeutics is active in a SCID mouse/ human melanoma model
Authors: Schicher Nikolaus , Pehamberger Hubert , Hoeller Christoph 
Published: February 2011

Abstract
Erlotinib is a novel EGF-receptor targeting drug which has been tested in various cancers for its activity, has shown impressive results in non small cell lung cancer, but has so far failed as a single agent in other cancer types. We and others have recently shown that the combination of erlotinib with e.g. the monoclonal VEGF antibody bevacizumab or chemotherapy is more powerful in inducing apoptosis and reducing proliferation or angiogenesis. Due to the fact that erlotinib induces accumulation of tumor cells in the G1-phase of the cell cycle this leads to the assumption that erlotinib prior to or concomitant with chemotherapy might negatively interact with it. The aim of our study was to test different dosing schedules of erlotinib in combination with dacarbazine, paclitaxel or cisplatin in a SCID mouse/ human melanoma xenotransplantation model with 518 A2 and M24 met cell lines. We hypothesize that pausing erlotinib before chemotherapy leads to greater apoptosis.
Six to eight week old female SCID mice were injected with 518 A2 or M24 met melanoma cells and treated either with erlotinib, dacarbazine, paclitaxel or cisplatin as single agents or a combination of erlotinib with either chemotherapy. Groups were divided in control, erlotinib, chemotherapy, erlotinib concurrently with chemotherapy or with a break of 5 days prior to chemotherapy.
While the cytotoxic drugs did show single agent activity in the model system used, the combination with erlotinib exhibited a higher reduction in tumor volume. These effects were substantiated by immunohistochemical analysis where we observed a reduction of angiogenesis and proliferation as well as an increase in apoptosis in the combined treatment arms as assessed with ki-67, CD31 and cleaeved caspase 3 staining, respectively. Interestingly, withholding erlotinib before treatment did not alter the activity of dacarbazine, thereby excluding an inhibitory effect of EGF-receptor inhibition under these conditions.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3615.
Abstract 3616: 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 Frederic , Hego Caroline , Marty Bérengère , Dupuy Corinne , Ryan Anderson Joseph , Schlumberger Martin , Bidart Jean-Michel 
Published: February 2011

Abstract
Introduction: Medullary thyroid carcinomas (MTC) frequently involve activating mutations in the proto-oncogene tyrosine-kinase receptor RET. Vandetanib (ZD6474, ZACTIMA) is a potent inhibitor of VEGFR-2, EGFR and RET 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) for 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, NFKB) 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 analysis 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 inhibits MAPK and STAT3 pathways in MTC. Furthermore, our experimental approach confirmed the utility of protein arrays for analyzing changes in signaling pathways induced by tyrosine-kinase inhibitors.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3616.
Abstract 3620: Efficacy of Vandetanib on EGFR mutant lung cancer cells with PTEN loss
Authors: Takeda Hiromasa , Ohashi Kadoaki , Kataoka Itaru , Ichihara Eiki , Takigawa Nagio , Tanimoto Mitsune , Kiura Katsuyuki 
Published: February 2011

Abstract
Introduction
EGFR gene is frequently mutated in non-small cell lung cancer (NSCLC) of never smokers, especially in Asian ethnicity. The mutations often predict dramatic response to EGFR-tyrosine kinase inhibitors (TKIs) like gefitinib. PTEN is a tumor-suppressor gene deactivating PI3K in downstream of EGFR signaling. Approximately 2% to 9% in NSCLC tumors were considered to be PTEN loss. PTEN loss and EGFR mutation co-occurred in 1 out of 24 EGFR mutant patients with lung adenocarcinoma (Sos, et al. Cancer Res 69, 2009). PTEN loss was considered to represent primary or acquired resistance to EGFR-TKIs. Therefore, a new strategy is needed to break through for the resistance due to PTEN loss.
Objective
We clarify the effectiveness of vandetanib, EGFR and vascular endothelial growth factor receptor (VEGFR) inhibitor, against lung cancer cell lines harboring EGFR mutations with PTEN loss.
Materials and methods:
Two EGFR mutant (deletion in exon19) NSCLC cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN loss) were used. Other two cell lines with PTEN loss, prostate cancer cell line (PC-3) and glioblastoma cell line (U-87MG) were also examined. We transfected intact PTEN gene into H1650 cells and knocked down PTEN expression in the PC-9 cells using shRNA. Antiproliferative activity was determined by MTT assay in terms of 50% inhibitory concentration (IC50) values. We also examined the effectiveness of the drugs (15 mg/kg/day) in xenograft model. Protein expression profile was examined by Western blotting. Expression of VEGFR mRNA levels was also assessed by RT-PCR.
Results
PC-9 cells were more resistant to vandetanib (IC50: 0.08 μM) than to gefitinib (IC50: 0.01 μM). However, mean IC50 values of vandetenib were significantly lower than those of gefitinib against H1650 cells (2 μM vs 25 μM), PC-3 cells (8 μM vs 25 μM), and U87MG cells (6 μM vs 28 μM) with PTEN loss. EGFR downstream signals including pAKT, pMAPK, and pSTAT3, and VEGFR were not different in the H1650 cells treated with vandetanib or gefitinib. In the xenograft model using H1650 cells, vandetanib was also more effective than gefitinib. Although PTEN transfected H1650 cells did not restore sensitiveness to gefitinib in vitro, the xenograft tumors responded to gefitinib as well as vandetanib. Knockdown of PTEN lead six times more resistance to gefitinib in PC-9 cells.
Conclusion
PTEN loss may play a role to determine the sensitivity to gefitinib in NSCLC with EGFR mutations. Vandetanib is more effective in NSCLC with EGFR mutation and PTEN loss.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3620.
Abstract 3621: The multi-tyrosine kinase inhibitor Sunitinib reduces prostate cancer growth through autocrine and paracrine mechanisms
Authors: NGUEWA PAUL A. , Díaz Roque Díaz , Redrado Miriam , Collantes María , Peñuelas Ivan , Saenz Irene Manrique , Serrano Diego , Agliano Alice , Calvo Alfonso 
Published: February 2011

Abstract
Prostate cancer (PrCa) is the most common malignancy and the second leading cause of cancer death in men. Although localized PrCa can be successfully cured, advanced hormone refractory tumors are resistant to current therapeutic regimes. Therefore, novel approaches for effective malignancy control are still required. Molecular targeted therapies have emerged as promising alternatives to classical chemo/radiotherapy. The clinical benefit of the multi-tyrosine kinase inhibitor Sunitinib, which blocks the activity of receptors such as PDGFR, VEGFR1/2, FLT3, and c-KIT has been proven in renal carcinoma, GIST, and neuroblastoma. In this work, we have tested the therapeutical efficacy of sunitinib against PrCa both in vitro and in vivo, using the androgen-independent cell line PC-3. These cells express target receptors PDGFRa/b, and VEGFR1/2. Sunitinib dramatically reduced cell proliferation in vitro (P&lt;0.0001) in a dose-dependent manner (with an IC50 of 1-2 micro-M) and colony formation (P&lt;0.0001), through an autocrine mechanism. Moreover, when combined with doses of 2 and 4 Gy ionizing radiation, sunitinib enhanced the inhibitory activity of radiotherapy in colony formation assays. In vivo experiments revealed that PC3 tumor-bearing mice treated with 80 mg/Kg/day sunitinib had significantly smaller tumors (63% reduction) than controls. A single dose of 6 Gy caused tumor shrinkage by 80%, whereas the combination of both therapies resulted in more than 90% tumor reduction, suggesting that sunitinib could be used as a radiosensitizer. Positron emission tomography (PET) analyses with 18-FDG, FMISO, and FLT tracers showed a decrease in glucose uptake, hypoxia, and cell proliferation, respectively, in sunitinib-treated mice, as compared to controls. Immunohistochemical analysis for CD-31 revealed an expected reduction in tumor angiogenesis in sunitinib-treated tumors in comparison with untreated tumors. Overall, these data support the use of sunitinib as a clinically relevant drug for the treatment of PrCa.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3621.
Abstract 3622: Preclinical characterization of EMD1214063, a potent and highly selective inhibitor of the c-Met kinase in Phase I clinical trials
Authors: Bladt Friedhelm , Blaukat Andree , Dorsch Dieter , Fittschen Claus , Friese-Hamim Manja , Graedler Ulrich , Meyring Michael , Rautenberg Wilfried , Schadt Oliver , Stieber Frank 
Published: February 2011

Abstract
c-Met, the receptor for hepatocyte growth factor (HGF), is a well characterized receptor tyrosine kinase, which is crucial for cell functions, such as survival, proliferation, motility and migration. Activating point mutations of c-Met have been identified in human malignancies, including renal carcinoma and lung cancer and constitutive activation of the HGF/c-Met pathway leads to tumor development and progression in cancer animal models. In the light of these findings, c-Met has become a key target for oncology therapeutics.
In order to develop c-Met specific inhibitors, we have conducted a biochemical HTS run with the recombinant kinase domain of c-Met. This approach has enabled us to identify a new class of c-Met inhibitors. Our report will focus on pharmacological and pre-clinical data, characterising EMD1214063, a promising therapeutic candidate currently under clinical testing.
Inhibition of the c-Met kinase by EMD1214063 was potent and highly selective. In in vitro kinase reactions and binding assays, EMD1214063 at a dose of 1μM, inhibited only 5 additional kinases in a panel of more than 250 different potential off-targets more than 50%. In vitro, EMD1214063 interfered with survival, anchorage-independent growth and HGF-induced migration of tumor cells, by blocking HGF-dependent as well as constitutive phosphorylation of c-Met.
In vivo, oral administration of EMD1214063 resulted in a strong inhibition - ranging from delayed growth to complete regression - of HGF-dependent and -independent c-Met driven tumor xenografts. Such anti-tumor activity was observed at a broad dose range, suggesting that EMD1214063 has a wide therapeutic index. The inhibitor was well tolerated, as indicated by the lack of significant weight loss in treated mice. The mechanism of action of EMD1214063 was investigated in vivo in a series of PK/PD studies. Administration of a single dose of EMD1214063 induced a complete and long-lasting inhibition of c-Met phosphorylation in the tumor xenografts. Furthermore, it strongly reduced the plasma levels of tumor-derived IL-8. c-Met phosphorylation and plasma IL-8 levels decreased as a function of the drug concentration in the tumor and plasma.
Taken together, the high c-Met selectivity, potency and in vivo efficacy of EMD1214063 render this compound a very promising candidate for the treatment of patients bearing c-Met-driven tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3622.