bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1638: Potent anticancer actions of the Hsp90 inhibitor STA-9090 in wild-type EGFR models of lung cancer
Authors: Acquaviva Jaime , Sang Jim , Sequeira Manuel , Smith Donald , Zhang Chaohua , Lovly Christine , Wada Yumiko , Blackman Ronald K. , Proia David A. 
Published: June 2012

Abstract
Non-small cell lung cancer (NSCLC) is a heterogeneous disease that can be sub-classified based on the specific alterations in oncogenes that drive it. While EGFR and KRAS are most often implicated in the molecular epidemiology of NSCLC, aberrations in several other genes have been shown to contribute to oncogenesis. These include mutation and/or amplification of MET, mutation in BRAF or chromosomal rearrangements involving ALK. Targeted therapy against these kinases has shown signs of therapeutic success; however, acquired drug resistance universally develops.
Heat Shock Protein 90 (Hsp90) is a molecular chaperone that mediates the post-translational stability of its protein substrates, many of which are validated oncogenes. Hsp90 is emerging as an important target in cancer therapy because its inactivation results in the abrogation of multiple signaling pathways simultaneously, irrespective of the mutational status of its substrate. STA-9090 is a second-generation, synthetic, small-molecule Hsp90 inhibitor that has shown potent and selective activity preclinically and is currently in Phase 2 trials in a number of indications.
We show here that in the presence of STA-9090, upregulation of the MET pathway, either through transient stimulation by its ligand, HGF, or through amplification of MET itself, is incapable of maintaining survival in EGFR-inhibitor-resistant NSCLC. To identify additional genetic lesions sensitive to Hsp90 inhibition, we screened a panel of wild-type EGFR NSCLC cell lines for viability in the presence of STA-9090. All the cell lines assayed, driven by mutations in genes such as PDGFRα, BRAF, PI3K and EML4-ALK or amplification of wild-type EGFR, were sensitive to STA-9090, with IC50 values between 10 and 150 nM. Further analysis demonstrated that STA-9090 potently destabilized the oncogenic driver for each cell line. In vivo, STA-9090 showed strong single-agent activity in xenograft models of human NSCLC carrying either a BRAF mutation or EML4-ALK fusion, in accordance with the sensitivity of these client proteins to the effects of STA-9090 action.
Inhibition of Hsp90 activity therefore presents a promising approach for combating NSCLC induced by mutations in genes other than EGFR, as well as by compensatory pathways upregulated in the context of EGFR-inhibitor resistance.
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 1638. doi:10.1158/1538-7445.AM2011-1638
Abstract 1640: Notch pathway mediates post-treatment repopulation of lung squamous cell carcinoma cells
Authors: Day Chi-Ping , Esposito Dominic , Mahesh Cynthia R. , Merlino Glenn 
Published: June 2012

Abstract
Conventional adjuvant therapies, such as chemotherapy and radiotherapy, usually take intermittent schedule, allowing the recovery of the normal tissues. However, during the recovery period, tumors may resume growth to replenish the lost cells. This phenomenon, known as repopulation, is an important mechanism to mediate post-treatment recurrence. In this study, we examined murine Lewis Lung Carcinoma (LLC) with a panel of subtype markers of non-small cell lung cancer (NSCLC), and characterized it as a murine lung squamous cell carcinoma (SCC), one of the major NSCLC subtypes. To recapitulate post-treatment repopulation, LLC cells were treated with the first-line NSCLC chemotherapeutic agent, paclitaxel, at IC50 dose for 24 hours, and allowed to recover in normal culture medium. Expression of genes involved in Notch pathway and markers of airway epithelial stem cell (basal cell) in LLC cells are upregulated during the recovery phase instead of treated period. Notch pathway inhibitor, DAPT, has no significant effect on growth of LLC cells as single agent or in combination with paclitaxel. However, sequential treatment of paclitaxel for 24 hours followed by DAPT for another 24 hours delays growth of LLC cells during recovery phase, suggesting that Notch pathway mediates the post-treatment repopulation. Moreover, using different labeling markers to track cell growth, we found paclitaxel-treated LLC cells in recovery phase can stimulate the growth of healthy LLC cells in co-culture, while conditioned medium from the culture of treated cells had no significant effect. These results implied that direct contact between damaged and healthy cells is required for repopulation, thus cell-surface Notch ligand such as Jagged-1 may be involved in this mechanism. Here we suggested that treatment of Notch pathway inhibitor following chemotherapy may prevent post-treatment recurrence of lung SCC.
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 1640. doi:10.1158/1538-7445.AM2011-1640
Abstract 1651: Targeting Vav3 oncogene enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia
Authors: Nomura Takeo , Hirai Kenichi , Yamasaki Mutsushi , Sato Fuminori , Mimata Hiromitsu 
Published: June 2012

Abstract
Introduction and Objective: We previously reported that chronic hypoxic condition (1% oxygen for over six months) induced Vav3 oncogene expression with androgen-independent growth and malignant behavior in LNCaP cells. And overexpression of Vav3 oncogene promoted the growth of LNCaP cells with increased invasion and migration under normoxic condition. The objective of this study was to examine the effect of Vav3 siRNA on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxic condition.
Methods: We analyzed the sensitivity of docetaxel in LNCaP cells under normoxic and chronic hypoxic conditions by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-1) and flow cytometric analyses. The effects of Vav3 siRNA on cell growth and apoptosis were examined under chronic hypoxia with or without docetaxel treatment. To seek a molecular understanding of Vav3 siRNA induced apoptosis, we analyzed alterations in the growth signaling components in the PI3K/Akt and ERK mediated pathways by immunoblot analysis.
Results: Overexpression of Vav3 was observed in LNCaP cells under chronic hypoxia compared with its expression under normoxia. Although the growth rates were reduced in a dose- and time-dependent manner by docetaxel in LNCaP cells under both normoxic and chronic hypoxic conditions, these effects were significantly decreased in LNCaP cells under chronic hypoxia. In addition, we found that docetaxel induced apoptosis following activation of caspase-3 and cleaved poly (ADP-ribose) polymerase, and that the interrupting the Vav3 signaling pathway using siRNA enhanced docetaxel sensitivity of LNCaP cells under chronic hypoxia and led to apoptosis. A profound activation of PI3K/Akt pathway was observed under chronic hypoxic condition. Treatment with Vav3 siRNA showed weak inhibition of Akt phosphorylation and treatment with Vav3 siRNA plus docetaxel strongly inhibited this signaling.
Conclusions: Our results showed that Vav3 siRNA enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia and that targeting Vav3 oncogene may have important practical implications for managing hormone refractory prostate 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 1651. doi:10.1158/1538-7445.AM2011-1651
Abstract 1661: Knockdown of Nrf2 in cancer cells suppresses tumor growth: implication for the inhibitory role in HIF-1α and ErbB2 signaling
Authors: Kwak Mi-Kyoung , Hur Eu-gene , Kim Tae-Hyoung , Manandhar Sarala , Choi Bo-Hyun , Ryu In-geun 
Published: June 2012

Abstract
Nuclear factor-erythroid 2 (Nrf2) is the transcription factor regulating multiple antioxidant proteins and phase 2 detoxifying enzymes, and plays a crucial role in the cytoprotection against oxidative stress-associated damages. However, a potential role of Nrf2 in cancer biology has been emerged recently. In our mouse xenografts study, a stable knockdown of Nrf2 in cancer cells from the colon (HCT116 and HT29) and ovary (SKOV-3) strongly suppressed tumor growth. As an underlying mechanism, it was observed that a vessel formation and vascular endothelial growth factor (VEGF) expression were suppressed in Nrf2-inhibited colon cancer tumors. Suppressive effect of Nrf2 knockdown on angiogenesis was further evidenced by the chicken embryo chorioallantoic membrane assay and endothelial tube formation assay. The subsequent mechanism studies revealed that Nrf2-inhibited HT29 cells failed to accumulate HIF-1α protein under 1% O2 hypoxia, resulting in the limitation of the expression of HIF-1α target genes for angiogenesis. Whereas, a tumor growth suppression shown in SKOV-2 cells was associated with repressed expression of ErbB2 and the consequent increase in p27. Further experimental demonstrations showed that the expression of ErbB2 is inversely related with Nrf2 in other types of cancer cell lines; therefore, the cell growth is attenuated in these Nrf2-inhibited cancer cells. Taken together, our current study suggests that a stable Nrf2 inhibition in cancer cells suppresses tumor growth through the alterations in HIF-1α and ErbB2 signaling. Hence, Nrf2 may be a promising target to control cancer cell growth and chemoresistance.
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 1661. doi:10.1158/1538-7445.AM2011-1661
Abstract 1667: In vitro and in vivo validation of CSE1L/hCAS as a potential molecular target in pancreatic cancer
Authors: Husain Kazim , Coppola Domenico , Centeno Barbara , Helm Richard , Dung-Tsa Chen , Sebti Said , Malafa Mokenge 
Published: June 2012

Abstract
Background: The human cellular apoptosis susceptibility protein (hCAS) is a Ran- binding protein playing a role as mitotic spindle checkpoint regulator and as nuclear export factor. hCAS expression is frequently altered in metastatic cancers. To date the role of hCAS in pancreatic cancer is unknown. Therefore this study aimed to investigate the role of hCAS in human pancreatic cancer in vitro and in vivo.
Methods: The hCAS protein expression was determined using Western immunoblotting in human pancreatic cancer cell lines (AsPc-1, BxPc-3, Capan-2, MiaPaCa-2, Panc-1, and SW1990) and immortalized normal human pancreatic ductal epithelial cell (HPNE) and HPNE-Kras. siRNA induced hCAS knockdown pancreatic cancer cells were compared to scrambled siRNA cells with regard to proliferative (MTT assay), cell death, cell cycle (Trypan blue and Flow cytometry), malignant transformation (colony formation assay) and protein expression (Western and confocal microscopy). hCAS KD MiaPaCa-2 cells were xenografted in SCID nude mice. Tumor growth, expression of hCAS, proliferation index (Ki-67), and caspase-3 were immunostained in tumor tissues and compared with scr siRNA MiaPaCa-2 cells. Expression of hCAS was determined in human pancreatic tumor tissues using immunohistochemical stain.
Results: hCAS protein expression was low in HPNE cells compared to HPNE-Kras. Lowest expression of hCAS noted in BxPc-3 cells compared to other pancreatic cancer cells. When compared to Scr-MiaPaCa-2, KD-MiaPaCa-2 cells demonstrated lower proliferation, G2/M phase cell cycle arrest, increased apoptosis, as well as inhibition of malignant transformation. Pancreatic ductal carcinomas (PCA) were hCAS strongly positive. Normal pancreatic ducts (ND) were hCAS weakly positive. hCAS KD-MiaPaCa-2 tumor growth was retarded in mice compared to Scr-MiaPaCa-2 tumors. hCAS KD-MiaPaCa-2 tumors showed hCAS depletion, lower proliferative index, increased caspase-3 immunostaining and PARP1 cleavage.
Conclusion: This is the first report of hCAS expression in human pancreatic cancer. Our data suggest that hCAS is a regulator of cell proliferation, cell cycle regulation and apoptosis. hCAS may represent a potential chemopreventive and therapeutic target for human pancreatic 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 1667. doi:10.1158/1538-7445.AM2011-1667
Abstract 1677: Expression of lysophosphatidic acid acyltransferase-beta in human pancreatic ductal adenocarcinoma
Authors: Blaskovich Michelle A. , Coppola Domenico , Helm James , Sebti Said , Springett Gregory M. 
Published: June 2012

Abstract
Lysophosphatidic acid acyltransferase beta (LPAAT-β) is a new therapeutic target and prognostic marker in human cancer. The enzymatic function of LPAAT- β is to convert Lysophosphatidic Acid (LPA) to Phosphatidic Acid (PA), a lipid second messenger that functions to regulate the proliferation, adhesion, migration and survival of cancer cells. PA is an essential cofactor needed by the oncogenes c-Raf, BRAF, PKC-ζ and mTOR for their enzymatic and growth promoting activities in cancer. LPAAT-β protein over expression has been detected in tumors compared to normal tissue in ovarian, endometrial, breast and lung cancers. The over expression of LPAAT-β in ovarian tumors is associated with poor clinical outcome.
Methods: In this study we determined LPAAT-β expression in paired specimens of pancreatic ductal adenocarcinoma and adjacent non-malignant pancreas obtained from 102 patients who underwent pancreatectomy with curative intent (stage IA-IIB). Formalin-fixed, paraffin-embedded core sections in a tissue microarray were immunostained using the avidin-biotin-peroxidase method with rabbit anti- LPAAT-β antibody. A semi-quantitative measure of LPAAT-β expression was determined as the product of immunostain intensity and percentage of cells stained, where intensity and percentage were each scored on a scale of 0 to 3, with 3 being maximal.
Results: LPAAT-β expression (product score) in 57% (58/102) of pancreatic cancers was lower than in paired non-malignant pancreas, equal in 20% (20/102) of cancers, and greater in 23% (24/102) of cancers as compared to non-malignant pancreas. LPAAT-β expression in cancer (median product score = 3) was less than in non-malignant pancreas (median score = 4) (Wilcoxon signed-rank test, p &lt; 0.0001).
Conclusions: Low LPAAT-β expression in pancreatic cancer as compared to non-malignant pancreas stands in contrast to previous studies showing increased LPAAT-β expression in several other cancers. This finding indicates that there may be tissue-specific differences in the biologic activity of LPAAT-β.
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 1677. doi:10.1158/1538-7445.AM2011-1677
Abstract 1681: Synergistic induction of Mek1/2 and Nox-1 by histone deacetylase inhibitors leads to differential induction of reactive oxygen species for mediating selective apoptosis of oncogenic H-Ras-expressing cells
Authors: Choudhary Shambhunath , Rathore Kusum , Sood Shilpa , Wang Hwa-Chain Robert 
Published: June 2012

Abstract
The goal of this study was to investigate roles of the ERK pathway and Nox-1 in the pro-apoptotic ability of oncogenic H-Ras to enhance histone deacetylase inhibitor (HDACI)-induced cell death. Oncogenic induction of the ras genes is widely involved in human cancers. Our previous studies revealed that expression of oncogenic H-Ras increases susceptibility of human and mouse cells to HDACIs, such as FK228 and trichostatin A, for inducing selective apoptosis. In this study, we used the mouse embryo fibroblast 10T1/2-TR-H-ras cell system, in which ectopic expression of oncogenic H-Ras(V12) is controlled by addition of tetracycline into cultures, and paired oncogenic H-Ras-expressing and parental human epithelial cells. We pursued the roles of Mek1/2 activation, Nox-1 elevation, and reactive oxygen species (ROS) production in FK228-induced selective cell death of oncogenic H-Ras-expressing cells versus counterpart cells. We verified that Nox-1 elevation and ROS played essential roles in oncogenic H-Ras-induced cell proliferation and morphological transformation. We also detected that FK228 treatment and expression of oncogenic H-Ras synergistically induced Mek1/2 activation, leading to differentially elevated Nox-1 and ROS and contributing to induction of selective apoptosis of oncogenic H-Ras-expressing cells versus counterpart cells. FK228 treatment also resulted in mitochondrial ROS production, and mitochondrial ROS contributed to Mek1/2 activation, bypassing Raf, to induce Erk1/2 activation for elevating Nox-1 and ROS, leading to apoptosis. Accordingly, Mek1/2 and Nox-1 played important pro-apoptotic roles in ROS-mediated cell death. Thus, Mek1/2 and Nox-1 should be considered as potential targets in designing therapeutic protocols using FK228 in ROS-mediated cell killing to treat cancer cells acquiring Ras activation.
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 1681. doi:10.1158/1538-7445.AM2011-1681
Abstract 1689: The combination treatments using siRNA and CDDP are effective therapeutic options for cancers
Authors: Kokuryo Toshio , Yokoyama Yukihiro , Senga Takeshi , Nagino Masato , Hamaguchi Michinari 
Published: June 2012

Abstract
Background: RNA interference technology has been developed as potential therapeutic options for several diseases, including cancer. Short interfering RNA (siRNA) is the best candidate for cancer therapy because of its specificity and efficiency in gene-specific silencing. We reported that the efficiency of siRNA as novel therapeutic agents for several cancers, such as cholangiocarcinoma, breast cancer and colorectal cancer.
Methods: We examined the effect of a combination treatment using Nek2 (NIMA related kinase 2) siRNA with anti cancer agent, CDDP (Cisplatin) on xenograft colorectal cancer mouse model. We next examined the effect of a combination treatment using Tlk1 (Tousled like kinase 1) siRNA with CDDP on MTT assay and TUNEL assay on cholangiocarcinoma cell lines.
Results and Discussion: The combination treatment using Nek2 siRNA and CDDP suppressed the tumor growth in colorectal cancer model, more efficiently than negative control siRNA and CDDP. It was more effective than the treatment with Nek2 siRNA alone. The combined administration of Tlk1 siRNA and CDDP strongly induced apoptosis in comparison with negative control siRNA and CDDP on cholangiocarcinoma cell lines. Tlk1 siRNA enhanced DNA damage induced by CDDP treatment. The combination of siRNA and CDDP was effective therapeutic options in colorectal cancer and cholangiocarcinoma.
Conclusions: Our data provides a strong rationale for the further investigation concerning the combination of both siRNA and anti cancer drug as a new cancer strategy, holding the potential to provide regression of multiple human malignancies.
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 1689. doi:10.1158/1538-7445.AM2011-1689
Abstract 1693: Mrp7 as a breast cancer resistance factor
Authors: Domanitskaya Natalya , Jacobs Joely , Paulose Chelsy , Hopper-Borge Elizabeth 
Published: June 2012

Abstract
Breast cancer is the most common cancer and the second leading cause of cancer deaths in American women. Breast cancer kills more than 40,000 women every year in the United States. Taxanes and epothilone B are used to treat breast cancer, but cellular resistance to chemotherapeutic agents is a major obstacle. Therapy-induced overexpression of ATP-binding cassette (ABC) drug efflux pumps promotes resistance in many drug-treated cancers. While early studies focused on overexpression and activity of the P-glycoprotein (Pgp) pump, a structurally distinct group of ABC efflux pumps, known as the Multidrug Resistance Proteins (MRPs), have been gaining increasing attention as alternative sources of resistance. There are 9 MRP family members (MRP1-9), with each family member preferentially transporting somewhat overlapping groups of substrates. We have previously shown that MRP7 is distinct from other MRPs because MRP7 confers resistance to a wide variety of anticancer agents including taxanes, vinca alkaloids and nucleoside-based analogs. We also have evidence that Mrp7 null mice are sensitized to taxanes (submitted). We bred a mammary tumor model to our Mrp7 null mouse to investigate Mrp7's in vivo activities regarding breast cancer resistance mechanisms. To better understand the resistance mechanisms of MRP7 the expression level of Mrp7 and expression levels of other transporters was determined in these cell lines using qRT-PCR. In addition, cell lines derived from mammary tumors are being evaluated to determine the impact Mrp7 has on sensitization to agents used in the treatment of breast cancer: epothilone B, docetaxel and paclitaxel. Further, the growth properties of these mammary tumor cell lines will be characterized. Lastly, to better understand the physiological role of this efflux pump, MRP7 cellular localization and polarity are being investigated.
Further research into previously mentioned aims and specific MRP7 inhibitors will aid in combating cellular resistance to chemotherapeutic agents.
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 1693. doi:10.1158/1538-7445.AM2011-1693