bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2832: Fibroblast growth factors in head and neck cancer: Genetic alterations and therapeutic targeting with ponatinib
Authors: Rieke Damian T. , Zuo Zhixiang , Endhardt Katharina , Keck Michaela , Khattri Arun , Mahmutoglu Derya , Leung Kelley , Dinali Mohamed El , Braegelmann Johannes , Seiwert Tanguy Y. 
Published: August 2012

Abstract
Background: FGF signaling plays an important role in cancer. Little is known about its involvement in head and neck squamous cell carcinoma (HNSCC). FGFR1 focal amplification and high expression (Freier, Schwaenen et al.), expression of FG-BP (Li et al.) and FGF2 autocrine signalling loops (Marshall et al.) have been described in connection with HNSSC. We therefore examined copy number alterations for several FGFR and FGF-related Genes in 159 patient tissues and cell lines as well as expression levels in 116 patient tissues and 40 cell lines. Based upon our findings we tried a combined FGFR-inhibiton with ponatinib in 5 head and neck cancer-cell lines alone and in combination with gefitinib. Methods: Copy Number Data analysis for 144 patient tissues and cell lines (Nanostring) as well as for 20 cell lines (aCGH) of which 5 were covered by both techniques and showed comparable results. Expression data analysis for 116 tissues and 40 cell lines (Agilent). Viability for 5 cell lines treated with gefitinib and ponatinib alone and in combination. Immunoblotting was performed to deterimed PI3K-AKT and MAPK signaling. Results: Frequent copy number increase could be detected for FGF19 in tissues and cell lines. FGFR1 copy number increase could be seen in only 1 tissue sample, but appeared to be deleted in several samples. High relative expression could be detected for FGFBP1 in tissues and cell lines. Viability testing showed high efficacy in 5/5 cell lines tested for ponatinib but was not solely mediated by AKT or MAPK signaling. Combined treatment with ponatinib and gefitinib was more effective than treatment with either agent alone and synergy was present. Conclusions: FGF signaling is important in Head and Neck Cancer. FGF19 amplification is frequent. We were unable to replicate FGFR1 amplification with only one tissue showing FGFR1 copy number increase. High expression levels could be shown for FGFBP1, providing an alternative hypothesis for explaining the efficacy of FGF2 inhibition as previously shown (Marshall et. al.). Ponatinib is effective as a single agent on HNSSC cell line models and shows synergistic effect in combination with gefitinib. It is promising to evaluate FGF pathway inhibition (e.g. with ponatinib) in its ability to overcome EGFR-inhibitor resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2832. doi:1538-7445.AM2012-2832
Abstract 2858: Mirk/dyrk1B kinase inhibition increases ROS and apoptosis in ovarian cancer cells, but has little effect on normal diploid cells
Authors: Hu Jing , Friedman Eileen A. 
Published: August 2012

Abstract
Quiescent cancer cells in vivo, including stem cell populations, are relatively insensitive to most chemotherapeutic drugs and radiation. Tumor cells in culture can be placed in G0 by serum or nutrient deprivation, and then can be targeted by a small molecule Mirk kinase inhibitor. Mirk/dyrk1B levels are elevated up to 10-fold in quiescent tumor cells where Mirk blocks cell cycling and increases viability by decreasing reactive oxygen species (ROS). In prior studies Mirk was detected in 75% of ovarian cancers, and was amplified in a subset. In contrast, Mirk expression was quite low in most normal cell types and Mirk knockout or depletion had no detectable effects on normal cells. Response to a Mirk kinase inhibitor was compared between two strains of normal diploid fibroblasts, early passage cultures of normal human ovarian epithelial cells, and a series of ovarian cancer cell lines where Mirk had been shown to be an active kinase. Serum-starved normal diploid cells entered a G0 quiescent state and had minimal response to the Mirk inhibitor, but serum-starved cancer cells were kept in cycle by the Mirk inhibitor, which reduced E2F4 sequestration by p130/Rb2 by 2-3fold. Mirk inhibitor treated cancer cultures had several-fold more sub-G0/G1 apoptotic cells and about 30-fold higher levels of the apoptotic proteins cleaved PARP and cleaved caspase 3 compared with normal diploid cells. The Mirk inhibitor increased total ROS levels and superoxide levels only in the cancer cells, in a rapid time-course of 2-3 days. Cancer cell loss after Mirk kinase inhibitor treatment was due at least in part to ROS, since the ROS scavenger N-acetyl cysteine reduced the amount of cleaved PARP and the extent of cancer cell loss. The Mirk inhibitor decreased the EC50 of cisplatin up to 9-fold in ovarian cancer cells. Thus ovarian cancer cells, which exhibit elevated Mirk expression/amplification and active Mirk kinase, were shown to be more susceptible to the Mirk kinase inhibitor than normal diploid cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2858. doi:1538-7445.AM2012-2858
Abstract 2861: Inhibition of mTOR and AKT as a potential strategy for the treatment of basal-like breast cancer
Authors: Ma Cynthia X. , Guo Zhanfang , Xu Siguang , Li Shunqiang , Ellis Matthew 
Published: August 2012

Abstract
Basal-like breast cancer is an aggressive disease, for which effective targeted therapies are lacking. The frequent loss of phosphatase and tensin homolog (PTEN) and aberrant activation of phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway in basal-like breast cancer make it an attractive therapeutic strategy to target AKT and mTOR. To evaluate the effect of PTEN loss on tumor cell sensitivity to mTOR inhibition, we performed PTEN knockdown experiment in vitro using a basal-like breast cancer cell line WU-BC3, which was derived from a patient with triple negative breast cancer. A more dramatic reduction in cell proliferation was observed in WU-BC3 siPTEN compared to that in WU-BC3 siControl following 7 days of treatment with the mTOR inhibitor MK-8669 (p&lt;0.001). We then tested MK-8669 and MK-2206 (an allosteric, selective pan-AKT inhibitor), either alone or in combination, in 2 Human Tumor in Mouse (HIM) models of basal-like breast cancer, WU-BC4 and WU-BC5, that are deficient in PTEN expression in vivo. In both models, MK-8669 alone significantly inhibited tumor growth (p&lt;0.001). However, the combination of MK-8669 and MK-2206 was more effective than either MK-8669 (p&lt;0.05) or MK-2206 (p&lt;0.01) alone. Biomarker studies indicated that the combination therapy resulted in a more dramatic inhibition of tumor cell proliferation (as assessed by Ki67) and angiogenesis (as assessed by CD31 staining) than single agents alone in both models. In addition, treatment with MK-2206 abolished the MK-8669-induced AKT activation in vivo, suggesting the inhibition of the feedback loop between mTOR and AKT being a potential underlying mechanism for the enhanced anti-tumor effect observed with the combination therapy. Our results provide a preclinical rationale for future clinical investigation of this combination in basal-like breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2861. doi:1538-7445.AM2012-2861
Abstract 2887: Nanoconstructs for the efficient delivery of siRNA molecules against Aquaporin-1 for anti-angiogenic therapies
Authors: Stigliano Cinzia , Ananta Jeyarama , Acharya Swetadrinadha , Mackeyev Yuri , Wilson Lon , Nicchia Grazia Paola , Svelto Maria , Decuzzi Paolo 
Published: August 2012

Abstract
Aquaporins (AQPs) are water-specific, membrane-channel proteins expressed in diverse tissues. In particular, AQP1 has been reported to be specifically and strongly expressed in most tumor microvascular endothelial cells. Angiogenesis and tumor progression have been dramatically impaired, in AQP1-null mice [Saadoun et al. Nature 434:2005]. These findings support the notion that AQP1 could be considered as a specific target for the treatment of various neoplasias. The AQP1 proteins can be specifically blocked by using small interference RNA molecules (siRNAs). However, despite the considerable potential of RNA interference for the treatment of cancer, the proper systemic delivery of exogenous siRNA molecules is still a challenge. The most significant obstacle is ensuring specific and effective delivery of siRNAs to the cytoplasm of the target cell, limiting toxic effects and serum degradation by RNAses. The use of nanoparticles, as intravascular delivery vehicles, has potential in supporting the efficient, effective and safe systemic delivery of siRNAs. Herein, multiple nanotechnological platforms (nanoconstructs) are used to deliver siRNAs against AQP1. The performance of the different nanoconstructs is assessed in vitro using HeLa cells, transfected to express AQP1 molecules. Three nanoconstructs are studied: fullerenes (C60), poly(lactic-co-glycolic acid) (PLGA) nanospheres and hydrogel-template nanoparticles. Positively charged fullerenes are sub-nanometer spheres (diameter ∼ 0.71 nm) that complex with the negatively charged siRNA molecules forming a stable compound under physiological conditions (pH = 7.4). Differently, the PLGA nanospheres and hydrogel-template nanoparticles are loaded with siRNA molecules during their synthesis process. The silencing performance of the three different nanoconstructs is assessed in vitro at multiple time points, over a period of 6 days post incubation. The loading efficiency, the release rate, the cell-entry mechanisms and potential cytotoxic response are analyzed. The performance of the nanoconstructs is compared with traditional delivery systems based on the use of transfection agents (oligofectamine). AQP1 is here used as a model system, and the optimized nanoconstructs could be utilized also for other siRNA therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2887. doi:1538-7445.AM2012-2887
Abstract 3014: Expression of hypoxia-inducible factors (HIF-1alpha) mediates Matrix Metalloproteinases (MMP) in colorectal carcinomas progression
Authors: Ahmed Maqbool , Hussain Azhar R. , Bavi Prashant , Bu Rong , Al-Janadi Sahar M A , Al-Dayel Fouad , uddin Shahab , Al-Kuraya Khawla S. 
Published: August 2012

Abstract
Hypoxia-inducible factors (HIFs) are transcription factors that respond to changes in available oxygen in the cellular environment, specifically, to decreases in oxygen, or hypoxia. Most, if not all, oxygen-breathing species express the highly-conserved transcriptional complex HIF-1, which is a heterodimer, composed of an alpha and a beta subunit. HIF-1 transcription factor has been shown to promote pathogenesis of several malignancies. We have shown previously using a large cohort of CRC samples in a tissue micro array (TMA) format found that HIF-1α was expressed in the majority of CRC samples. HIF-1α over expression was found to be associated with MMP-2, and MMP-9. In the current study we investigated whether down regulation of HIF-1α by YC-1 a pharmacological inhibitor and gene silencing with specific HIF-1α siRNA leads to inhibition of cell proliferation and inhibition of apoptosis using a panel of CRC cell lines. Treatment of CRC cell lines with YC-1, inhibitor of HIF-1α resulted in inhibition of cell viability via induction of apoptosis. This apoptosis was initiated via loss of mitochondrial potential leading to the release of cytochrome c that resulted in sequential activation of caspases-9, and -3 and cleavage of PARP. Interestingly, pharmacological inhibition of HIF-1α also down-regulated expression of MMP-2, and MMP-9 in CRC cell lines. This data was further validated by siRNA knockdown strategy where expression of siRNA against HIF-1α also down-regulated the expression of HIF-1α, MMP-2 and MMP-9. Altogether, these data suggests that HIF-1α and its associated signaling pathway play a critical role in CRC tumorigenesis, therefore targeting of HIF-1α expression may be a viable therapeutic intervention for treatment of these cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3014. doi:1538-7445.AM2012-3014
Abstract 3042: Glypican-1 (GPC1) promotes S-phase entry and DNA replication in human glioma cells
Authors: Qiao Dianhua , Meyer Kristy , Friedl Andreas 
Published: August 2012

Abstract
Glypican-1 (GPC1), the most ubiquitously expressed member of the glypican family of heparan sulfate proteoglycans (HSPGs), is highly expressed in the developing brain and gliomas. In gliomas, GPC1 is overexpressed in both tumor blood vessel endothelial cells (ECs) and the neoplastic cells. Prior work by us in ECs indicates that GPC1 is overall mitogenic and essential for cell cycle progression and proliferation, implying a role in glioma angiogenesis. The present study focused on the role of GPC1 in glioma cells to explore potential roles in tumorigenesis and growth. The expression of GPC1 in U87 cells, a human glioma cell line with a relatively low basal level of GPC1, was titrated by adenoviral transduction. BrdU pulse-labeling showed a robust induction of S-phase entry and DNA replication by expression of GPC1 in a dose-dependent manner. GPC1 overexpression ultimately led to DNA re-replication and aneuploidy as well as enlarged nuclei and cell rounding. Consistent with these cell cycle effects, ectopic expression of GPC1 significantly induced downregulation of pRb, p21Cip1 and p27Kip1 and upregulation of cyclin E, CDK2 and E2F transactivation activity. These cellular and molecular activities of GPC1 were independent of serum concentrations in the growth medium, suggesting that they do not require exogenous growth factors. This activity required intact GPC1 as neither unglycanated GPC1 core protein nor isolated GPC1 HS chains induced the cell cycle and molecular alterations seen after intact GPC1 was added. The more general relevance of our observation to other cell types and the HS-dependency of the GPC1 activity were confirmed by GPC1 transduction of wild-type and HS synthesis-defective CHO cells. Overexpression of GPC1 induced dramatic S-phase entry in wild-type but not in HS-deficient mutant CHO cells. In summary, this work reveals a potent S-phase promoting activity of GPC1 in glioma cells, which may lead to accelerated cell growth and/or increased genomic instability and, therefore, implies a role for GPC1 in glioma tumorigenesis and growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3042. doi:1538-7445.AM2012-3042
Abstract 3054: P1446A-05: a new oral cyclin-dependent kinase inhibitor with potent preclinical antitumor activity
Authors: Joshi Kalpana S. , Padgaonkar Amol , Rathos Maggie , Wagh Vilas , Manohar Sonal , Bhatia Dimple , Damre Anagha , Sivakumar Meenakshi , Sharma Somesh 
Published: August 2012

Abstract
Cell cycle deregulation is one of the first steps that transform normal cells into tumor cells. Cyclin-dependent kinases (Cdks) related alterations such as overexpression and amplification of cell-cycle activators or inactivation of cell cycle inhibitors are among the most common genetic changes in human tumors. The pursuit for drugs that inhibit Cdks has been an intense area of research for more than 15 years. A number of Cdk inhibitors are being evaluated in clinical trials for the treatment of cancer. P1446A-05 has been identified as a Cdk4-D1, Cdk1-B and Cdk9-T inhibitor. P1446A-05 exhibited greater selectivity to Cdk4-D1 and Cdk1-B that are involved in the G1 and G2/M phase of the cell cycle respectively. The IC50 values were 0.09 and 0.025 μM for Cdk4-D1 and Cdk1-B respectively. P1446A-05 also inhibited Cdk9-T, which plays a role in transcription, with an IC50 of 0.022 μM. P1446A-05 was inactive against many non-Cdks with an IC50 of more than 50 μM. In cytotoxicity assay using 30 human cancer cell lines P1446A-05 showed IC50 in the range of 0.5 to 3.9 μM, whereas the cytotoxicity for unstimulated normal human PBMNCs was &gt; 10 μM. P1446A-05 arrested cell cycle progression at G1 and G2 phases and induced apoptosis in human cancer cell lines such as non-small-cell lung cancer (H-460), colorectal carcinoma (HCT-116) and prostate cancer (PC-3) in a dose and time dependent manner. Furthermore, P1446A-05 affected the proteins involved in cell cycle and apoptosis. It down-regulated cyclin D1, inhibited Cdk4 specific phosphorylation (ser780 of retinoblastoma), induced the tumor suppressor protein p53, and reduced the levels of the anti-apoptotic protein Bcl-2. Pharmacokinetic studies revealed that P1446A-05 exhibited an absolute oral bioavailability of 82.48% in mice and 79.07% in rats. It showed dose-dependent increase in 1446A-05 levels in plasma of mice and rats. In in vivo efficacy studies, orally administered P1446A-05 significantly (p&lt;0.001) inhibited the tumor growth in two xenograft models that of colon cancer (Colo-205) and non-small cell lung cancer (H-460) in SCID mice. These data demonstrated that P1446A-05 is an orally active inhibitor of Cdk with a unique target profile that may have therapeutic potential in human malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3054. doi:1538-7445.AM2012-3054
Abstract 3060: DYRK2-mediated phosphorylation of c-Jun and c-Myc is requisite for proper control of the G1/S transition
Authors: Taira Naoe , Mimoto Rei , Miki Yoshio , Yoshida Kiyotsugu 
Published: August 2012

Abstract
Transcription factors c-Jun and c-Myc are indispensable regulators for the G1/S transition and their expressions were tightly regulated at transcriptional and post-translational levels. Dysregulation of these expressions leads to tumor development and progression. Degradation of c-Jun/c-Myc, a critical event for the G1/S transition, is triggered by sequential phosphorylations by unknown priming kinase(s) and GSK3-beta. Here we show that DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2) functions as a priming kinase for c-Jun/c-Myc and modifies its expression at the by post-translational level. In the absence of priming phosphorylation, c-Jun and c-Myc escape from GSK-3-mediated sequential phosphorylation and Fbw-7-mediated ubiquitination. Therefore, depletion of DYRK2 results in aberrant expression of c-Jun and c-Myc. Furthermore, in DYRK2 knockdown cells, up-regulated c-Jun and c-Myc facilitate cell proliferation and shorten the length of the G1 phase and prompts the G1/S transition. Furthermore, DYRK2 inactivation contributes to cell proliferation and tumor progression in vitro and in vivo. Pathological analysis demonstrated that DYRK2 expression is decreased in multiple cancerous tissues. Taken together, DYRK2 controls cell cycle progression at G1/S phase via phosphorylation of c-Jun and c-Myc
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3060. doi:1538-7445.AM2012-3060
Abstract 3118: The proteasome inhibitor Bortezomib rescues clinically identified unstable missense variants of the DNA mismatch repair protein Msh2
Authors: Arlow Tim , Gammie Alison 
Published: August 2012

Abstract
Msh2 is required for DNA mismatch repair in eukaryotes. Deleterious mutations in human MSH2 account for approximately half of the alleles associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch Syndrome. Previously, we characterized clinically-identified MSH2 missense mutations, using yeast as a model system and found that the most common cause of defective DNA mismatch repair was low levels of the variant Msh2 proteins. Here, we measured the half-lives of the Msh2 variants and found that increased protein turnover was responsible for the low cellular levels. Additionally, restoring levels with increased gene dosage fully restored mismatch repair function in 10 of the 21 variants in a DNA polymerase proofreading defective strain background in which mismatch repair is essential. Using immunoprecipitation, we detected high molecular weight ubiquitinated species of unstable Msh2 variants when over-expressed. Additionally, genetic and chemical inhibition of the proteasome stabilized low-level Msh2 missense variants. We identified San1, an ubiquitin ligase known to target misfolded nuclear proteins, as responsible for targeting the MSH2 missense variants. Deletion of San1 restored protein levels for all but one variant, but did not elevate wild-type Msh2 levels. Additionally, mismatch repair function was significantly improved when the Msh2 variants that had displayed high-copy restoration of function were expressed in a san1α strain. Taken together, these results indicate that the ubiquitin-mediated proteasome degradation pathway is the major mechanism for increased turnover of the clinically identified Msh2 variants. Human MutSα, comprised of Msh2 and Msh6, is also regulated by the ubiquitin-mediated pathway, underscoring the conservation of regulation as well as function for mismatch repair in eukaryotes. Additionally, it is well established that mismatch repair defective tumors are resistant to standard chemotherapeutic regimens. Of therapeutic significance, the clinically approved drug Bortezomib partially restored levels and mismatch repair function in two different msh2 missense variants. In this regard, Bortezomib may prove to be a valuable adjuvant chemotherapeutic for individuals with particular alleles of MSH2. Our results provide the foundation for an innovative therapeutic regime for certain mismatch repair defective cancers that are refractory to conventional chemotherapies. Currently we are testing the rescue phenotype in human cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3118. doi:1538-7445.AM2012-3118