bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 590: Antiproliferative effects and signaling profiles of the novel HSP90 inhibitor NVP-AUY922 in non-small cell lung cancer
Authors: Ueno Tsuyoshi , Toyooka Shinichi , Tsukuda Kazunori , Munenori Takaoka , Soh Junichi , Maki Yuho , Muraoka Takayuki , Tanaka Norimitsu , Asano Hiroaki , Yamane Masaomi , Oto Takahiro , Kiura Katsuyuki , Naomoto Yoshio , Miyoshi Shinichiro 
Published: June 2012

Abstract
Background; Gefitinib and erlotinib, which have been designed to inhibit tyrosine kinase of epidermal growth factor receptor (EGFR), showed drastic anti-tumor effect on NSCLCs with common EGFR mutations, but acquired resistance is a major problem to failure this treatment. Heat shock protein (HSP) 90 inhibitors have been developed as promising anti-cancer agents, because HSP90, a molecular chaperone, plays a pivotal role in NSCLC survival as it stabilizes a large set of client proteins, many of which are important for tumor cell survival and proliferation. In this study, we examined “NVP-AUY922,” a new HSP90 inhibitor, and showed its effects against NSCLCs.
Methods: We used 24 NSCLC cell lines with specific genetic alterations, which are K-ras mutation, B-raf mutation and EGFR mutation. Cell proliferation was determined by modified MTS assay. The expressions of client proteins were assessed by Western Blotting.
Results: NVP-AUY922 exhibited strong antiproliferative effects to most NSCLC cell lines, except H1395 and Calu3. One of resistant cells is a B-raf mutator and another has no specific genetic alterations, but NSCLCs with EGFR mutations were sensitive. The average IC50 of NVP-AUY922 in sensitive cells was 18.7 + 8.32 nM. In most cell lines, higher depletion of both total and phosphorylated client proteins such as MET, HER2, EGFR and AKT, were shown by NVP-AUY922 treatment with higher concentration. But in Calu3, a resistant cell line, they did not decrease in lower concentration. MET, HER2 and EGFR were suppressed for whole duration tested, while the expression of AKT was depleted for 48 hours and then recovered at 72 hours after treatment. The client protein of H1395 decreased in lower concentration and the cause of resistance to NVP-AUY922 has been unknown so far.
Conclusions; NVP-AUY922 was effective to most NSCLC cell lines at low concentration and suggested to be a promising new drug of NSCLCs, even those resistant to EGFR-TKIs.
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 590. doi:10.1158/1538-7445.AM2011-590
Abstract 595: E-3810 antitumor activity in human xenografts expressing different levels of FGF receptor 1
Authors: Colella Gennaro , Damia Giovanna , D'Incalci Maurizio , Cereda Roberta , Peitz Ingmar , Kelter Gerhard , Cavalletti Ennio , Spinelli Silvano , Camboni Gabriella 
Published: June 2012

Abstract
E-3810 is a novel small molecule that selectively inhibits VEGF receptor-1, -2 and -3 and FGF receptor-1 (FGFR-1) tyrosine kinases currently undergoing a Phase 1 clinical trial in Europe. We have previously shown that the compound has strong anti-angiogenic effects in vivo and displays potent activity in all the human xenograft models in which it has been tested. We have also recently demonstrated that interference with FGF/FGFR pathway could result in a higher drug cytotoxic activity in those cell lines whose growth in vitro was dependent on the pathway. In order to corroborate these findings in an in vivo setting, a panel of human xenografts characterized by different expression of FGFR-1and FGF2 ligand is being screened for the response to E-3810 given at its optimal dose (20 mg/kg per os daily). Athymic female mice were transplanted s.c. with the different human xenografts and, when tumor masses reached the size of 80-120 mg, were randomized to receive vehicle or E-3810 for 14 days. Results are available for 7 models (see table reported below).

All the selected tumors displayed similar growth rates, except for RXF_486 that grew more slowly. Tumor growth resumed upon drug withdrawal, at a rate seemingly higher where FGFR-1 was highly expressed. These preliminary results confirm the strong activity of E-3810 in a large panel of tumours, with growth control and, sometimes, regressions. Studies are ongoing to enlarge the panel of models and to confirm the observed trend suggesting a somewhat higher sensitivity to E-3810 in tumors expressing higher FGFR-1 and\or FGF ligand.
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 595. doi:10.1158/1538-7445.AM2011-595
Abstract 596: ABCG2 is upregulated in SN-38 resistant colorectal cancer cells
Authors: Costich Tara L. , Sill Kevin , Rios-Doria Jonathan 
Published: June 2012

Abstract
Irinotecan, a member of the camptothecin chemotherapeutic drug family, is a first and second line therapy for patients with colorectal cancer. However, as with most chemotherapeutic therapies, patients’ tumors eventually develop drug resistance. Therefore, identifying mechanisms of chemotherapeutic resistance will allow for the development of additional molecular therapeutic targets. In this study SN-38, the highly insoluble active metabolite of irinotecan, was used to investigate corollary resistance to irinotecan. SN-38 resistant HT-29 cells were generated and compared to parental untreated HT-29 cells. Cells were characterized following treatment with either DMSO soulubilized SN-38 or IVECT encapsulated SN-38, a triblock copolymer micelle, in aqueous solution. The ATP-binding cassette transmembrane transporter protein, ABCG2, was found to have more than 40-fold expression in the SN-38 resistant HT-29 cells compared to the parental line. The increased expression of ABCG2 protein correlated with increased resistance to SN-38 in HT-29 cells and also with increased cell efflux. Cytotoxicity studies demonstrated that SN-38 resistant HT-29 cells were affected in a similar manner by IVECT polymer encapsulated SN-38 micelles and DMSO dissolved free SN-38. Cell cycle analysis showed that SN-38 resistant cells had an abrogated S phase arrest compared to parental cells. Cell treatment with free SN-38 was limited by its solubility in addition to DMSO toxicity. Further, IVECT polymer encapsulation improved SN-38 aqueous solubility allowing for increased concentration administration. Efflux proteins such as ABCG2 have been found to be upregulated in numerous types of cancers by several classes of chemotherapeutic drugs. Since transporter proteins have an important role in cell efflux, ABCG2 overexpression could serve as an additional target for pharmacological modulation. Finally, the increased solubility of SN-38 by IVECT polymer encapsulation allows for potential in vivo clinical applications of SN-38, a molecule that is 1000 times more active than its prodrug irinotecan.
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 596. doi:10.1158/1538-7445.AM2011-596
Abstract 603: Overexpression of G protein-coupled receptor kinase 2 in hepatocellular carcinoma cells suppresses proliferation by inducing G2/M phase arrest
Authors: Wei Zhengyu , Hurtt Reginald , Doria Cataldo 
Published: June 2012

Abstract
G protein-coupled receptor kinase 2 (GRK2) was originally identified as a key player in G protein-coupled receptors desensitization. A growing body of evidence has demonstrated that GRK2 may have broader ‘effector” functions by interacting with a variety of non-receptor signaling proteins and involves in the regulation of many cellular processes such as proliferation, cell cycle progression and migration. In this study, we investigated the role of GRK2 in human hepatocellular carcinoma (HCC) cells. We screened five HCC cell lines and found that Huh7 and Mahlavu had the highest and lowest of basal GRK2 expression levels respectively. We then overexpressed wild type (WT) GRK2 and its kinase-dead mutant (K220R) in these two HCC cells using recombinant adenoviruses. We found that only WT GRK2 overexpression but not the K220R mutant overexpression significantly reduced cell viability. We thus performed BrdU incorporation assay and found that only WT GRK2 overexpression reduced cell proliferation. We further examined this anti-proliferative function by propidium iodide staining to analyze cell cycle progression. Our data showed that enhanced WT GRK2 induced cell cycle arrest at G2/M phase, from 21.4% to 41.8% in Huh7 and 25.9% to 48.4% in Mahlavu, respectively. Furthermore, our western blotting results showed that overexpression of GRK2 induced the up-regulation of p53 (Ser15) phosphorylation and Cyclin B1 in a dose dependent manner. Our results indicated that overexpression of GRK2 had a profound suppressive effects on HCC cell growth and suggested that gene transfer of GRK2 may open a new therapeutic option for the treatment of human HCC.
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 603. doi:10.1158/1538-7445.AM2011-603
Abstract 608: Oncogenic role of cullin 4 E3 ubiquitin ligase (CRL4-CDT2) in epithelial ovarian cancer
Authors: Ring Kari E. , Abbas Tarek , Bryant Jennifer , Dutta Anindya , Jazaeri Amir A. 
Published: June 2012

Abstract
Objective: Ubiquitination is a key posttranslational modification involved in the tight regulation of biological processes including cell-cycle regulation and DNA replication and repair. Our objective was to investigate the expression and function of CDT2, a substrate recognition factor for the CUL4 E3 ubiquitin ligase family (CRL4-CDT2) in ovarian cancer.
Methods: CDT2 expression was evaluated using realtime RT-PCR in 26 serous ovarian cancers 11 normal ovaries, and 14 fallopian tube fimbria specimens and confirmed by Western blotting on a subset of the above. Immunohistochemistry was performed using tissue microarrays consisting of over 130 independent ovarian cancer samples of various histologies, as well as, normal fallopian tube samples using antibodies to CDT2 and p21. Each samples was represented at least in triplicate and scored semi-quantitatively. CDT2 knockdown was accomplished using siRNA and overexpression via retroviral transduction. Cell growth was evaluated using MTT assays. Statistical analysis were performed using either parametric (t test) as well as non-parametric (Mann-Whitney and Kruskal Wallis) methods as indicated. Comparison of p21 and CDT2 expression was performed using Spearman's correlation.
Results: CDT2 mRNA expression was approximately 9 fold higher in serous ovarian cancers compared to normal ovary and fallopian tube fimbria samples (P&lt;0.00001). Western blotting confirmed this differential expression at the protein level. Immunohistochemistry validated CDT2 overexpression in ovarian cancers and did not reveal any differences between serous and other histological subtypes. Immunohistochemical staining did not reveal any significant correlation between the expression of CDT2 and p21, a previously identified target of CRL4-CDT2. Knockdown of CDT2 expression resulted in 31% reduction in cell viability in high CDT2 expressing ES2 cells (P&lt;0.0001) but had minimal effect in low CDT2 expressing SKOV3 cells. However, overexpression of CDT2 in SKOV3 cells did not influence growth of these cells. Knockdown of other component of CRL4-CDT2 ubiquitin ligase (Cul4A and DDB1) also reduced growth of ES2 cells. Finally CDT2 protein levels significantly increased upon in vitro transformation of fallopian tube epithelial cells (described elsewhere) and in subsequent mouse xenografts established from these cells.
Conclusions: The results of this ongoing investigation are the first to suggest an oncogenic role for the CRL4-CDT2 ubiquitin ligase in ovarian cancer. The mechanism of action remains unknown but does not appear to involve p21 degradation.
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 608. doi:10.1158/1538-7445.AM2011-608
Abstract 619: O6-Benzylguanine inhibits tamoxifen-resistant breast cancer cell growth and resensitizes breast cancer cells to anti-estrogen therapy
Authors: Joshua Smith S. , Bobustuc George C. , Isley Beth , Limaye Arati , Ticku Jonathan , Madero-Visbal Rafael , Colon Jimmie , Baker Cheryl H. , Kalkunte Srivenugopal S. , Konduri Santhi D. 
Published: June 2012

Abstract
Endocrine therapies using anti-estrogens are less toxic and very effective for breast cancers however tumor resistance to tamoxifen remains a stumbling block for successful therapy. Based on our recent study on the involvement of the DNA repair protein MGMT in pancreatic cancer (Clin Cancer Res. 15, 6087, 2009), we investigated whether MGMT overexpression mediates tamoxifen resistance. Specifically, we determined whether administration of MGMT inhibitor [O6-benzylguanine (BG)] at a non-toxic dose alone or in combination with the anti-estrogens (tamoxifen/fulvestrant) curtails human tamoxifen resistant breast cancer cell growth. Furthermore, we also determined whether BG sensitizes breast cancer cells to tamoxifen using tamoxifen resistant cells.
MGMT expression was found to be increased in breast cancer cells relative to normal breast epithelial cells. Also, MGMT levels were significantly higher in tamoxifen resistant MCF-7 compared to the parent cells. Silencing of the ER-α expression using a specific siRNA resulted in augmentation of MGMT mRNA and protein levels by two fold. We also observed an inverse correlation between MGMT and p53 levels in breast cancer cell lines; moreover, p53 downregulation was accompanied by increased MGMT expression. Other experiments showed that BG alone or BG in combination with tamoxifen or fulvestrant decreased ER-α expression, whereas tamoxifen alone and fulvestrant alone increased and decreased the same respectively. All these treatments increased the p21cip1 mRNA and protein expression significantly. BG inhibited tamoxifen resistant breast cancer growth in a dose-dependent manner and it also resensitized resistant breast cancer cells to anti-estrogen therapy (TAM/ICI). These combinations also enhanced the cytochrome C release and PARP cleavage, indicative of apoptosis. In breast cancer xenografts, BG alone or a combination of BG with tamoxifen or fulvestrant caused a significant tumor growth delay and immunohistochemistry revealed that BG inhibited the expression of MGMT, ER- α, ki-67 and increased p21cip1 staining. These findings suggest that MGMT inhibition may provide a novel and effective approach for overcoming tamoxifen resistance (supported by a Florida Biomedical grant to SK).
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 619. doi:10.1158/1538-7445.AM2011-619
Abstract 62: Inhibition of Men1-deficient tumor growth by inactivation of the Rbp2 histone demethylase
Authors: Lin Wenchu , Francis Joshua , Watanabe Hideo , Yan Qin , Kaelin William G. , Meyerson Matthew 
Published: June 2012

Abstract
Abstract: Mutation of the tumor suppressor gene MEN1 causes both human inherited and somatic tumors in multiple endocrine tumors. Dissection of mechanism on MEN1 tumor model will shed light on tumor biology and the targeting therapies on neuroendocrine tumors lacking Men1. Loss of tumor suppressor menin may be tumorigenic because it leads to decreased histone H3 lysine 4 trimethylation and therefore decreased expression of specific genes such as CDKN1B. Reversing the tumorigenesis caused by menin deficiency might therefore be achieved by inhibition of histone H3 lysine 4 demethylation. Rbp2 (also known as KDM5A) is an excellent candidate for such a demethylase because loss of the Rbp2 gene leads to increased expression of CDKN1B. Using a tissue-specific knockout approach, I have disrupted Men1 alone or both Men1 and Rbp2 in mouse pancreatic islets through RIP-Cre transgene (RIP = “rat insulin promoter”) and have observed that loss of Rbp2 dramatically inhibits tumor growth in Men1-deficient islets. Histological assays have found that 100 percent of Men1f/f RIP-Cre mice (13 out of 13) at 10 months old or older harbor tumors of the pancreatic islets, whereas only 7 out of 21 Men1f/f; Rbp2f/f RIP-Cre mice contain tumors or large hyperplastic islets. Furthermore, Inactivation of Rbp2 extends the life span of Men1-deficient mice. The median survival age of Men1f/f RIP-Cre mice in this cohort is 313 days, the median survival age of Men1f/f; Rbp2f/f RIP-Cre (n=72) is 486 days (p&lt;0.0001). In addition, a number of targets shared by both Men1 and Rbp2 have been identified via expression profiling. Studies from this project may provide insight to the cause of endocrine tumors and may develop a molecular target for treatment of endocrine tumors and the MEN-1 syndrome through modulation of histone methylation.
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 62. doi:10.1158/1538-7445.AM2011-62
Abstract 627: Etp-47187 a novel potent and efficacious dual inhibitor of phosphoinositide-3-kinases and mTOR
Authors: Kurz Guido , Pizcueta Pilar , Rico Rosario , Cebrián David , Aguirre Enara , Soilan David , Ortega Miguel A. , Martinez Sonia , Rabal Obdulia , Saluste C Gustavo , Casas Estela , Villanueva Patricia , Garcia Ana B. , Albarran Maria I. , Alfonso Patricia , Gonzalez Ester , Lorenzo Milagros , Ramos Francisco , Palacios Irene , Cebria Antonio , Rodriguez Antonio , Noya Beatriz , Garcia Ana M. , Rodriguez Sonsoles , Martin José I. , Alvarez Rosa , Hernandez Ana I. , Salgado Antonio , Cerdon Elena , Fominaya Jesus , Granda Teresa G. , Lopez Ana Rodriguez , Pastor Joaquin , Bischoff James R. 
Published: June 2012

Abstract
The phosphoinositide-3-kinase (PI3K) signaling pathway is activated in a variety of solid and non-solid tumors. In many instances this is due to either activating mutations in the catalytic subunit of PI3Kα, p110α, or inactivating mutations or deletions of the tumor suppressor PTEN. In addition, the PI3K pathway is activated by mutations in certain receptor tyrosine kinases as well as by mutation of the oncogene KRAS. All of these lesions lead to enhanced activity of both PI3K and mTOR. Hence there is great interest to discover inhibitors of PI3K and mTOR for the treatment for cancer. Following a rational design strategy, we identified the fused thiadiazole derivative ETP-47187 as a potent dual inhibitor of PI3Kα and mTOR Kis = 0.18 nM and 1.2 nM, respectively. ETP-47187 also inhibits three oncogenc mutants of p110α: p110α E542K Ki = 0.38 nM, p110α E545K Ki = 0.2 nM and p110α H1047R Ki = 0.29 nM as well as PI3Kβ, PI3KΔ and PI3Kγ Kis 2.7, 0.26 and 1.5 nM, respectively. The compound inhibits PI3K signaling in treated tumor cell lines; the EC50 for inhibition of the phosphorylation of Akt was 5 nM. ETP-47187 has a pharmacokinetic profile suitable for oral dosing in mice (%F = 73%, Cl = 0.11 L/hr/kg; Vds = 0.38 L/h/kg). Treatment of tumor bearing mice with the compound causes a dose dependent reduction in P-Akt levels in the tumor. Once a day treatment of mice bearing human tumor xenografts with ETP-47187 results in significant tumor growth delay and is well tolerated. In a mouse model of lung cancer induced by expression of an oncogenic mutant KRAS, treatment with ETP-47187 blocked tumor growth and lead to a significant PET response. These and combination data will be discussed. We believe ETP-47187 and compounds like it are suitable to propose for clinical development in cancer patients with activated PI3K signaling.
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 627. doi:10.1158/1538-7445.AM2011-627
Abstract 636: C-Met antibodies with distinctive characteristics including induction of receptor degradation without activation and tumor specificity
Authors: Greenall Sameer , Gherardi Ermanno , Scott Andrew , Johns Terrance G. 
Published: June 2012

Abstract
The hepatocyte growth factor receptor (c-Met) is a cell surface, disulphide linked heterodimeric receptor tyrosine kinase consisting of an extracellular 50 kDa α-chain and an extracellular/intracellular 145 kDa β-chain containing the tyrosine kinase domain. The two chains of the mature c-Met arise from the proteolytic cleavage of a single-chain precursor. The α-chain and N-terminal part of the β-chain associate to form the SEMA domain which contains the binding site for hepatocyte growth factor (HGF). Aberrant signalling due to dysregulation of the c-Met receptor is often associated with more aggressive cancers in a range of tumor types, making it a target for cancer drug development. Mice were immunized with the SEMA domain of c-Met followed by cancer cells expressing c-Met in order to generate antibodies that target this receptor. We created 3 antibodies that exclusively bound the unprocessed form of c-Met. Fine epitope mapping using overlapping linear peptides showed all 3 antibodies had distinct binding sites; one each for the α- and β-chain and one with a conformational epitope. Since this unprocessed form of c-Met is only found on the surface of cancer cells, and not normal cells, these antibodies are tumor specific and may be extremely valuable as targeting agents. We also identified a series of antibodies that bind a defined peptide on the α-chain of c-Met and stimulate c-Met degradation without concurrent activation of the receptor; a problem with previous antibodies that enhance c-Met degradation. Through their ability to down-regulate c-Met, these antibodies inhibited HGF induced migration of SK-OV-3 ovarian cancer cells, inhibited ligand-independent proliferation of A549 lung cancer cells and had anti-tumor activity against U87MG glioma xenografts that possess a HGF/c-Met autocrine loop. The generation of cancer-specific c-Met antibodies and novel antagonist antibodies opens up new strategies for targeting this crucial receptor in range of cancer types.
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 636. doi:10.1158/1538-7445.AM2011-636