bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1710: Expression of erbB3 upregulates Survivin via transcription-independent mechanism in erbB2-overexpressing breast cancer cells to confer Paclitaxel resistance
Authors: Wang Shuiliang , Huang Xiaoping , Lee Choon-Kee , Liu Bolin 
Published: June 2012

Abstract
The erbB2 receptor is often activated via dimerization with another erbB receptor, such as EGFR or erbB3. Studies show that co-expression of erbB3 and erbB2 is frequently observed in breast cancer; and erbB2 requires erbB3 to stimulate breast cancer cell proliferation. Increased resistance to therapeutic agents such as paclitaxel is one of the mechanisms by which erbB2 contributes to breast tumorigenesis. While several molecular mechanisms contributing to paclitaxel resistance have been proposed, a series studies demonstrate that overexpression of erbB2 inhibits paclitaxel-induced apoptosis in breast cancer cells. However, the role of erbB3 in paclitaxel resistance remains unclear. Our current studies focus on determining the role(s) of erbB3 in erbB2-mediated paclitaxel resistance in breast cancer cells.
Overexpression of exogenous erbB3 via either stable or transient transfection in erbB2-overexpressing, but not EGFR-expressing, breast cancer cells significantly decreases paclitaxel-induced growth inhibition and apoptosis. Consistently, knockdown of erbB3 expression with a specific shRNA in breast cancer cells with coexpression of both erbB2 and erbB3 enhances paclitaxel-induced apoptosis evidenced by increased DNA fragmentation, PARP cleavage, and activation of caspase-3, and -8. Furthermore, while forced overexpression of erbB3 increases, specific knockdown of erbB3 decreases the protein but not mRNA expression levels of Survivin only in the erbB2-overexpressing breast cancer cells. Targeting Survivin with specific shRNA overcomes paclitaxel resistance without effect on the expression levels of either erbB2 or erbB3. Mechanistic studies indicate that the specific PI-3K, Akt, and mTOR inhibitors, but not the MEK inhibitor, not only abrogate erbB3-mediated upregulation of Survivin, but also reinforce the erbB2/erbB3-coexpressing breast cancer cells to paclitaxel-induced growth inhibition.
Our studies demonstrate that heterodimerization of erbB2/erbB3 results in paclitaxel resistance in breast cancer cells via PI-3K/Akt/mTOR signaling pathway. Elevated expression of erbB3 upregulates Survivin through transcription-independent mechanism in erbB2-overexpressing cancer cells, suggesting that novel strategies targeting erbB3 or Survivin protein translation may enhance the efficacy of chemotherapeutic agents against breast cancer with erbB2-overexpressing tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1710. doi:10.1158/1538-7445.AM2011-1710
Abstract 1717: SATB1 expression increases resistance of bladder cancer cells to cisplatin
Authors: Choudhary Shilpa , Voznesensky Olga , Pilbeam Carol , Taylor John A. 
Published: June 2012

Abstract
Background: SATB1 (special AT-rich sequence binding protein-1) is a nuclear protein involved in chromatin organization and gene regulation. Increased expression of SATB1 in breast and hepatocellular cancer cells has been shown to promote metastasis and multidrug resistance. We explored the effects of SATB1 expression in the high grade human bladder cancer cell line, HTB-5.
Methods: HTB-5 cells were transfected with an shRNA construct for SATB1 or a non-silencing (NS) control. Nuclear protein and mRNA expression were measured by Western analysis and real-time PCR, respectively. Cells were counted on days 2-6 of culture, and DNA replication was measured by thymidine incorporation (TdR) on day 3. Cell cycle distribution and cell viability were analyzed by propidium iodide-Annexin V FITC flow cytometry in 3 independent experiments. Cells were treated with cisplatin (6 μM) for 3 days.
Results: SATB1 mRNA and protein expression levels were 28-fold and 5-fold higher, respectively, in HTB-5 cells compared to UROtsa cells, a benign transformed human urothelial cell line. Expression of SATB1 was reduced 80% or more in shRNA transfected HTB-5 cells. Cell counts and TdR were decreased 20-23% (p&lt;0.01) in SATB1 knockdown cells compared to NS controls. SATB1 knockdown was associated with a significant increase of 15% in G1/G0 and decrease of 18% in S-phase. There was no significant difference in cell viability between SATB1 knockdown cells and NS controls. However, cisplatin treatment resulted in a decrease in live cells from 61.9 ± 4.6% to 39.5 ± 5% (p&lt;0.01) and an increase in apoptotic cells from 33.1 ± 4.4% to 56.1 ± 4.0% (p&lt;0.01) in SATB1 knockdown cells compared to NS controls.
Conclusions: SATB1 expression was higher in a malignant compared to benign urothelial cell line and was associated with increased proliferation and increased resistance to chemotherapy.
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 1717. doi:10.1158/1538-7445.AM2011-1717
Abstract 1718: Exploring temozolomide resistance in glioblastoma using a combinatorial zinc-finger library approach
Authors: Narayanan Radhakrishnan , Levin Benjamin S. , Maeder Morgan L. , Joung J Keith , Nutt Catherine L. , Louis David N. 
Published: June 2012

Abstract
Recent therapeutic advances have improved control of glioblastomas, with a significant fraction of tumors responding to initial therapies. Unfortunately, all glioblastomas recur and lead to patient death. In an effort to better understand therapeutic resistance, we have explored high-dimensional profiling studies to understand mechanisms of therapeutic resistance and to identify novel therapeutic targets. Temozolomide (TMZ) is an alkylating chemotherapeutic agent that is used to treat all glioblastomas. Recurrent glioblastomas, however, become resistant to the effects of TMZ through a mechanism associated with inactivation of MSH6, a member of the mismatch repair gene family; MSH6-deficient glioblastomas grow more rapidly during TMZ therapy. To explore pathways of therapeutic resistance, we have designed an unbiased drug resistance selection screen to create TMZ-resistant human glioblastoma cell lines using combinatorial zinc-finger transcription factors (ZTFs). The combinatorial ZTF library enables activation of a gene or a set of genes that will be selected for resistance to TMZ. We have isolated resistant clones in the TMZ-sensitive A172 and Gli36 cell lines and present molecular profile analysis of these clones. By comparative gene expression profile analysis of novel ZTF-induced TMZ resistant glioblastoma cell lines, we expect to identify molecular pathways that confer TMZ resistance. In doing so, we also aim to identify possible biomarkers for TMZ resistance in recurrent glioblastomas.
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 1718. doi:10.1158/1538-7445.AM2011-1718
Abstract 1720: Tyrosine phosphorylation of HSC70 located in the cell membrane may regulate methotrexate transportation in murine L1210 leukemia cells
Authors: Liu Tuoen , Rios Zech , Sheridan Peter P. , Bhushan Alok , Lai James C.K. , Daniels Christopher 
Published: June 2012

Abstract
Bhushan and co-workers previously described an alteration in an unidentified 66-68 kDa membrane-associated, tyrosine-phosphorylated, methotrexate (MTX)-binding protein in the L1210 murine leukemia cell line. This protein was absent, at least in the tyrosine phosphorylated form, in cisplatin-resistant, methotrexate cross-resistant L1210/DDP cells. The 66-68 kDa protein was isolated by affinity chromatography, first on MTX-agarose followed by purification using an anti-phosphotyrosine immunoaffinity column. Amino acid sequence analysis identified the protein as heat shock cognate protein 70 encoded by the HSPa8 gene. The HSPa8 gene was found to be transcribed in both sensitive and resistant cell lines by RT-PCR and the sequence of the HSPa8 gene was identical in both cell lines. Western blot analysis showed that HSC70 was also expressed in both cell lines. A binding pull-down assay with MTX-agarose beads, followed by western blotting for HSC70, showed HSC70 to be present in cell lysates and in the MTX-binding fraction. Fractionation of cell homogenates into membrane and cytosolic fractions showed that HSC70 was found in both fractions but was not detected in the MTX-binding assay with the membrane fraction from the L1210/DDP cells, suggesting HSC70 located in the membrane fraction may be controlling MTX transport in the sensitive cells. Comparing the tyrosine phosphorylation status between L1210/0 and L1210/DDP cells, a band around 70 kDa was observed in the membrane fraction of L1210/0 cell but was not present in the L1210/DDP cells. Additionally, immunoprecipitation with anti-phosphtyrosine (PY20) agarose beads and detection of HSC70 by western blot showed little to no PY-HSC70 in the membrane fraction from the L1210/0 cells. Thse results suggest that HSC70 is a putative MTX binding protein, and HSC70 associated with the cell membrane may regulate methotrexate uptake. Tyrosine phosphorylation may contribute to the function of HSC70 in the cross-resistance mechanism in the murine L1210 cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1720. doi:10.1158/1538-7445.AM2011-1720
Abstract 1726: Overcoming multi-drug resistance with Paclitaxel-loaded polymer nanoparticles
Authors: Lee Yeonju , Graeser Ralph , Kratz Felix , Geckeler Kurt Ernst 
Published: June 2012

Abstract
Multi-drug resistance against chemotherapeutic agents is a major problem in the treatment of cancer. It is primarily mediated by over-expression of P-glycoprotein (P-gp) encoded by the MDR-1 gene by the tumor cells. Most of the promising anticancer drugs such as doxorubicin, docetaxel, paclitaxel, and mitoxantrone are P-gp substrates. Thus, various ways for overcoming the multi-drug resistance, e.g. combination of an anticancer drug and a P-gp inhibitor or the formulation of nanoparticles in conjunction with anticancer drugs as well as the P-gp inhibitor, have been studied. Anticancer drug-loaded nanoparticles, such as paclitaxel-loaded polymer nanoparticles, are excellent candidates to overcome multi-drug resistance due to their enhanced therapeutic efficacy induced by increased cellular accumulation and sustained intracellular drug delivery.
In this work, we developed an ampholytic copolymer that can encapsulate paclitaxel, and the resulting nanoparticles were found to have good water-solubility. In addition, in contrast to native paclitaxel, the paclitaxel-loaded nanoparticles were able to reverse multi-drug resistance in MCF7/ADR and MT-3/ADR cell lines, resulting in drug sensitivities comparable to the parental MCF7 and MT3 cell lines. P-gp expression was confirmed in both ADR cell lines by Western blotting, and its functionality was verified using a rhodamine accumulation and efflux assay. The nanoparticles were taken up by endocytosis in both cell lines and their enhanced therapeutic efficacy is probably due to the different mode of entry into the cell that may avoid the P-gp efflux pump. As a consequence higher concentrations of paclitaxel reach the nucleus and induce cell killing.
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 1726. doi:10.1158/1538-7445.AM2011-1726
Abstract 1730: Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer
Authors: Yano Seiji , Donev Ivan S. , Wang Wei , Li Qi , Takeuchi Shinji , Yamada Tadaaki 
Published: June 2012

Abstract
Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show favorable response to EGFR mutant lung cancer. However, the responders acquire resistance almost without exception. We recently reported that hepatocyte growth factor (HGF) induces EGFR-TKI resistance by activating MET which restores downstream MAPK-ERK1/2 and PI3K-Akt signaling. The purpose of this study was to determine whether inhibition of PI3K, a downstream molecule of both EGFR and MET, could overcome HGF-mediated EGFR-TKI resistance in EGFR mutant lung cancer cells, PC-9 and HCC827. Experimental Design: We explored therapeutic effect of a class I PI3K inhibitor PI-103 on HGF-induced EGFR-TKI resistance in vitro and in vivo. Results: Unlike gefitinib or erlotinib, continuous exposure with PI-103 inhibited proliferation of PC-9 and HCC827 cells, even in the presence of HGF. On the other hand, in gefitinib-resistant xenograft model using PC-9 cells mixed with HGF high producing fibroblasts, PI-103 monotherapy did not inhibit tumor growth. However, PI-103 combined with gefitinib successfully regressed gefitinib-resistant tumor. In vitro experiments considering short half life of PI-103 reveal that transient exposure of PI-103 combined with gefitinib caused sustained inhibition of Akt phosphorylation, but not ERK1/2 phosphorylation, resulting in induction of tumor cell apoptosis even in the presence of HGF. Conclusions: These results indicate that transient blockade of PI3K-Akt pathway by PI-103 and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis, further suggesting usefulness of double blockade of PI3K-Akt signaling at upstream (EGFR) and downstream (PI3K) for more successful treatment of EGFR mutant lung 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 1730. doi:10.1158/1538-7445.AM2011-1730
Abstract 1731: TAK-701, a humanized monoclonal antibody to HGF, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation
Authors: Okamoto Wataru , Okamoto Isamu , Tanaka Kaoru , Arao Tokuzo , Nishio Kazuto , Fukuoka Masahiro , Jänne Pasi , Nakagawa Kazuhiko 
Published: June 2012

Abstract
Most non-small cell lung cancer (NSCLC) tumors with an activating mutation of the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib but ultimately develop resistance to these drugs. Hepatocyte growth factor (HGF) induces EGFR-TKI resistance in NSCLC cells with such a mutation. We investigated strategies to overcome gefitinib resistance induced by HGF. Human NSCLC cells with an activating EGFR mutation (HCC827 cells) were engineered to stably express HGF (HCC827-HGF cells). HCC827-HGF cells secreted large amounts of HGF and exhibited resistance to gefitinib in vitro to an extent similar to that of HCC827 GR cells, in which the gene for the HGF receptor MET is amplified. A MET-TKI reversed gefitinib resistance in HCC827-HGF cells as well as in HCC827 GR cells, suggesting that MET activation induces gefitinib resistance in both cell lines. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib inhibited the phosphorylation of MET, EGFR, ERK, and AKT in HCC827-HGF cells, resulting in suppression of cell growth and indicating that autocrine HGF-MET signaling contributes to gefitinib resistance in these cells. Combination therapy with TAK-701 and gefitinib also markedly inhibited the growth of HCC827-HGF tumors in vivo. The addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation.
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 1731. doi:10.1158/1538-7445.AM2011-1731
Abstract 1786: Improved survival with gemcitabine and CTLA-4 blockade in a murine model of prostate cancer
Authors: Ariyan Charlotte E. , Quezada Segio , Corse Emily , Montalvo Welby , Allison James 
Published: June 2012

Abstract
Introduction: Immunotherapy with CTLA-4 blockade has resulted in dramatic responses in patients with advanced melanoma and prostate cancer. However, only 10-30% of patients have a response, therefore there is a need to increase the efficacy of CTLA-4 blockade. In this work we tested the hypothesis that combinatorial approaches incorporating tumor destruction with conventional chemotherapy and CTLA-4-blockade would synergize to significantly increase anti-tumor activity in vivo.
Experimental Procedure: Mice with a transplantable prostate tumor (TRAMPC2) were treated with 5 doses of gemcitabine alone, or followed by immunotherapy with CTLA-4 blockade. Control mice were treated with isotype antibody. Tumor growth was measured by calipers and mice were sacrificed when tumors reached 15mm. Progression was followed over time and CD8 T cell responses to the tumor specific antigen SPAS were examined by tetramer staining and functional assays ex vivo.
Data: Mice treated with the combination gemcitabine and α-CTLA-4 had improved survival over mice treated with gemcitabine alone. The majority of mice treated with control Hamster Ig or CTLA-4 blockade died (median survival 59 days for both groups). The median survival of mice treated with gemcitabine was 72 days with 50% having long-term survival. The addition of α-CTLA-4 to gemcitabine treatment increased median survival to &gt; 125 days with 65% of mice with long term survival (p&lt;0.05 for survival of gemcitabine versus gemcitabine + α-CTLA-4). The additive effect of α-CTLA-4 was lost when CD8 T cells were depleted. Analysis of draining lymph nodes revealed a reduced number of T regulatory T cells and myeloid suppressor cells with gemcitabine treatment. Mice receiving combination treatment had increased accumulation of tetramer positive CD8 cells for the SPAS peptide in the spleen and tumor draining lymph node. In addition, the combination treated mice had increased IFNγ production by ELISPOT in response to SPAS peptide re-stimulation ex vivo (p&lt;0.05 for gemcitabine versus gemcitabine and α-CTLA-4).
Conclusion: Combination chemo- and immunotherapy with gemcitabine and α-CTLA-4 improves survival. This is associated with an accumulation of CD8 cells that are tumor specific. Depletion of CD8 cells reduces the efficacy of this treatment. This study supports further investigation into the additive effects of chemotherapy with CTLA-4 blockade.
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 1786. doi:10.1158/1538-7445.AM2011-1786
Abstract 1787: ImmTACs: Bi-functional reagents for redirected tumour cell killing
Authors: Paston Samantha J. , Ashfield Rebecca , Liddy Nathaniel , Bossi Giovanna , Adams Katherine , McCormack Emmet , Lissina Anna , Mahon Tara , Hassan Namir , Gavarret Jessie , Bianchi Frayne , Pumphrey Nick , Ladell Kristin , Gostick Emma , Sewell Andrew K. , Lissin Nikolai , Molloy Peter , Li Yi , Cameron Brian , Sami Malkit , Baston Emma , Harper Jane , Johnson Andrew , Vuidepot Annelise , Todorov Penio , Dennis Rebecca , Kalos Michael , June Carl , Price David A. , Williams Daniel , Jakobsen Bent K. 
Published: June 2012

Abstract
The human immune system can theoretically identify malignant cells by inspecting cell surface Class I HLA -peptide complexes for the presence of disease-associated epitopes. Indeed, many cancer patients generate CD8 cyto-toxic T cell responses to tumour-associated antigens; the majority of patients, however, fail to clear tumours since T cell avidity for self-antigens tends to be weak, and cancer cells employ escape mechanisms for avoiding destruction by T cells. To overcome these issues, we have engineered novel, bi-functional protein therapeutics termed ImmTACs (Immune Mobilising mTCR Against Cancer) which re-direct the immune system to target and destroy tumour cells with a high degree of potency and specificity. An ImmTAC comprises a high affinity ‘monoclonal’ T cell Receptor (mTCR) targeting a cancer-associated HLA-peptide complex, fused to an anti-CD3 scFv domain which activates an anti-tumour T cell response.
We demonstrate that ImmTACs against a number of different cancer-associated antigens can target and kill tumour cells expressing as few as 10-20 epitopes per cell with pico-Molar potency. ImmTACs preferentially activate effector memory CD8 T cells, resulting in secretion of multiple cytokines and tumour cell killing; a single activated T cell can kill multiple antigen positive tumour cells. Furthermore, we demonstrate that the reagents are able to inhibit tumour growth in mouse xenograft models. In vitro ImmTAC potency translates to a dose of less than 1mg in humans, representing a significant advance over existing targeted anti-cancer therapies. Currently we are conducting a phase I dose-escalation trial and Phase 0 exploratory trial using ImmTAC-gp100 in late stage melanoma patients. In summary, ImmTACs offers a novel therapeutic approach for the treatment of various cancers with the potential to provide major benefits over current treatments including reduction in dose to sub-mg quantities and an improved safety profile.
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 1787. doi:10.1158/1538-7445.AM2011-1787