bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3745: Optimization of an assay for the detection of phosphorylated FAK by immunohistochemistry in formalin-fixed, paraffin-embedded human tissue and cell lines
Authors: Dauffenbach Lisa M. , Sia Gela C. , Cash Patricia A. , Girees Sherif K. , Lim Ryan S. , Zheng Jianping , Olsen Eric P. , Richeh Rana , Kerfoot Christopher A. 
Published: May 2015

Abstract
Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase with elevated expression in most human cancers, most notably in invasive metastasis. FAK is involved in cell adhesion, motility, and apoptosis, and it is a target for oncology therapeutics. FAK activation occurs by phosphorylation at Tyr397 in response to integrin clustering caused by cell adhesion. The development of a sensitive and specific immunohistochemical assay for phosphorylated FAK (pFAK) is important for pharmacodynamic biomarker studies. The purpose of this study was to investigate 4 commercially available anti-pFAK antibodies in human tissues and cell lines. Antibodies included 3 rabbit monoclonals (EP2160Y, 141-9, and 31H5L17) and 1 rabbit polyclonal. Antibody specificity was evaluated in a variety of cell lines (BxPC3, HCT-116, LOVO, MDA-MB-231, and MiaPaca2) treated with 2 FAK inhibitors: TAE226 (NVP-TAE226) and PF-562271. Decreased immunohistochemical staining for pFAK was observed in post-treatment samples of cell lines with baseline pFAK expression. TAE226 was more potent at inhibiting pFAK staining. Membrane staining was observed with the rabbit polyclonal and rabbit clone EP2160Y only. Each of the 4 antibodies was tested in human breast cancer tissues using tissue microarrays created by Mosaic Laboratories. The percentage of breast cancer samples that were pFAK positive was 96% with clone EP2160Y, 83% with clone 141-9, 92% with clone 31H5L17 and 96% with the polyclonal. The percentage of cells that were positive within each breast cancer sample ranged from 63% to 83%, depending on the antibody used (standard deviations between 30% and 44%). Immunohistochemistry with the polyclonal and clone EP2160Y antibodies demonstrated membrane and cytoplasmic staining, while clones 141-9 and 31H5L17 demonstrated primarily cytoplasmic staining. Based on reduction of pFAK staining in treated cells and acceptable performance in human cancer tissues, pFAK immunohistochemistry is “fit for purpose” for evaluation of FAK inhibitor activity in pre- and post-treatment clinical trial tissue biopsies.
Citation Format: Lisa M. Dauffenbach, Gela C. Sia, Patricia A. Cash, Sherif K. Girees, Ryan S. Lim, Jianping Zheng, Eric P. Olsen, Rana Richeh, Christopher A. Kerfoot. Optimization of an assay for the detection of phosphorylated FAK by immunohistochemistry in formalin-fixed, paraffin-embedded human tissue and cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3745. doi:10.1158/1538-7445.AM2014-3745
Abstract 3751: The potential role of CXCR4 in cisplatin associated resistance in esophageal carcinoma
Authors: Zhao Yue , Wang Yan , Bruns Christiane 
Published: May 2015

Abstract
Introduction
CXC chemokine receptor 4 was found dys-regulated in many different types of human cancers and correlated with poor prognosis of tumor metastasis and resistance to chemotherapy. Limited data show the effect of CXCR4 on the esophageal carcinoma cells, especially with influence of chemotheraputuc reagent-cisplatin.
Methods
CXCR4 was detected by FACs analysis in esophageal cell lines OE19, OE21, OE33, PT1590 and LN1590. Corronsponding cisplatin resistant cells were established after selection of cisplatin treatment and further confirmed by IC50 and ERCC1. SDF-1α and AMD3100 were used as CXCR4 stimulattion or inhibition. Subcutanous model of OE19 injection in Balb/c nude mice was established and followed by treatment with cisplatin twice a week via i.p injection. Tumors were collected for the further evaluation.
Results
Esophageal cell line OE19, PT1590 and LN1590 have detetable amount of CXCR4+ subpopulation cells as high as 2.8%±0.9, 0.7%± 0.9 and 1.0%±0.6, respectively. OE19, PT1590 and LN1590 cisplatin resistant subline displayed increased IC50 value of 48h cisplatin treatment from 6.0±1.3 to 12.2±1.0, 1.4±0.7 to 9.1±0.7 and 1.4±0.6 to 7.2±0.6 ug/ml along with a significant overexpression of ERCC1. Interestingly only OE19 and LN1590 cisplatin resistant cell lines showed a significant enreichment of CXCR4+ cells ( 12.1%± 2.5 Vs 2.8%±0.9; 4.2%± 1.1 Vs1.0%±0.6, p&lt;0.05) as compared to parental cells. Meanwhile, side population cells were also increased in those cisplatin resistant variants. There is no difference on tumor weight in control group and cisplatin treatment group in vivo. The relative expression of CXCR4 will be further evaluated by realtime PCR on mRNA level and IHC on protein level.
Conclusion
Overexpression of CXCR4 is significantly associated with cisplatin-based chemotherapy resistance and might be a prognostic factor in esophageal cancer. Inhibition of CXCR4 might be a strategy to address the chemoresistance of EAC cell lines.
Citation Format: Yue Zhao, Yan Wang, Christiane Bruns. The potential role of CXCR4 in cisplatin associated resistance in esophageal carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3751. doi:10.1158/1538-7445.AM2014-3751
Abstract 3755: Restoring sensitivity to cisplatin or TRAIL by targeting drug resistance master regulators in endometrial cancer
Authors: Meng Xiangbing , Yang Shujie , Wang Xinjun , Jia Yichen , Zhang Yuping , Leslie Kimberly K. 
Published: May 2015

Abstract
Understanding the molecular mechanisms of drug resistance is vital to enhance the efficacy of current therapeutic regimens. In particular, metadherin (MTDH) and FOXM1 overexpression has been independently demonstrated to have a critical role in chemoresistance. Overexpression of MTDH correlates with poor clinical outcome in many cancers, including endometrial cancer. Our previous study showed that endometrial cancer cells are sensitive to the combination treatment of tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) with histone deacetylase (HDAC) inhibitor LBH589, an effect that could be enhanced by depletion of MTDH. In this study, we focused on the therapeutic strategies to restore sensitivity to chemotherapeutic agent cisplatin or apoptosis-inducing TRAIL by disrupting drug resistance genes FOXM1 or MTDH. CUDC907 is a novel investigational dual inhibitor designed to target PI3K and HDACs. The high frequency of PI3K /PTEN/AKT pathway dysregulation in endometrial cancer suggests that CUDC907 will also be effective in this disease. Indeed, CUDC907 potently induced apoptosis when combined with TRAIL in MTDH-depleted endometrial cancer cells. Cisplatin is a frontline treatment for advanced endometrial cancers. However, drug resistance causes treatment failure. Although the detailed mechanisms of drug resistance are still elusive, gradual induction of FOXM1 and its downstream target gene network may be involved in the development of resistance to cisplatin. We found that co-treatment with cisplatin and the Nedd8 conjugation system inhibitor MLN4924 restored sensitivity to cisplatin by down-regulating drug resistant gene FOXM1. These findings imply that simultaneously depleting drug resistant master genes, such as MTDH and FOXM1, is a potentially novel avenue for reversing therapeutic resistance to current chemotherapy and targeted therapies in patients with endometrial cancer.
Citation Format: Xiangbing Meng, Shujie Yang, Xinjun Wang, Yichen Jia, Yuping Zhang, Kimberly K. Leslie. Restoring sensitivity to cisplatin or TRAIL by targeting drug resistance master regulators in endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3755. doi:10.1158/1538-7445.AM2014-3755
Abstract 3757: Vacuolar ATPase ‘a’ subunit mediates platinum resistance in ovarian cancer
Authors: Kulshrestha Arpita , Katara Gajendra K. , Pamarthy Sahithi , Gilman-Sachs Alice , Beaman Kenneth D. 
Published: May 2015

Abstract
Development of resistance to platinum compounds significantly hinders successful ovarian cancer treatment. Understanding the molecular alterations in chemo-resistance is important for developing therapeutic strategies for reversal of resistance. Vacuolar-H + −ATPases (V-ATPases) are multi-subunit proton pumps that play key roles in regulating cytosolic/extracellular pH and drug tolerance in tumor cells. The present study begins to decipher the role of V-ATPase `a’ subunit isoforms (major pH sensing unit) in cisplatin resistance. For this, cisplatin resistant human ovarian cancer cell lines A2780 and TOV112D were generated in lab by stepwise increase in drug pressure. Comparative expression profiling revealed that V-ATPase `a` subunit levels correlated with cisplatin resistance and each of the a1,a2 and a3 isoforms were significantly up regulated in the resistant lines. Isoform-specific shRNAs were employed to selectively and stably reduce mRNA levels for VATPase ‘a’ subunit in cisplatin resistant cell lines and determine their effect on cisplatin/carboplatin sensitivity, DNA damage and apoptosis. V-ATPase a2 or a3 isoform knocked down resistant lines exhibited sensitization to cisplatin and carboplatin. In vitro effects showed increased DNA damage by forming platinum DNA adducts which led to higher levels of apoptosis. In conclusion, inhibition of V-ATPase `a` subunit expression by monoclonal antibodies or V-ATPase inhibitors could serve as a therapeutic strategy to overcome cisplatin resistance and has a potential as a combination therapy along with platinum drugs for treatment of chemo-resistant ovarian carcinoma.
Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Sahithi Pamarthy, Alice Gilman-Sachs, Kenneth D. Beaman. Vacuolar ATPase ‘a’ subunit mediates platinum resistance in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3757. doi:10.1158/1538-7445.AM2014-3757
Abstract 3758: Inhibition of ATR, but not ATM, sensitizes gynecologic cancer cells to cisplatin
Authors: Teng Pang-Ning , Bateman Nicholas W. , Hamilton Chad A. , Maxwell G. Larry , Bakkenist Christopher J. , Conrads Thomas P. 
Published: May 2015

Abstract
Resistance to platinum-based therapies remains a major hurdle in the management of gynecologic (GYN) cancer especially in ovarian cancer. Platinum such as cisplatin damages DNA by inducing DNA crosslinks that stalls DNA replication forks where significant accumulation of single-stranded DNA from persistently stalled replication forks could ultimately lead to double strand breaks and activation of apoptosis. Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR) are two main DNA damage response (DDR) protein kinases that recognize genotoxic stress and function to initiate cell cycle arrest and DNA repair mechanisms. We hypothesized by combining genotoxic stress with inhibition of DDR kinases ATR and/or ATM, therapeutic response of GYN cancer cells to platinum-based chemotherapy could be improved. To test our hypothesis, we assessed cell survival of multiple GYN cell lines including ovarian (A2780, A2780-CP20, OVCAR3), endometrial (KLE, HEC1B), and cervical (HELA, SIHA) carcinoma cells exposed to cisplatin along with ATR inhibitor (ETP-46464) and/or ATM inhibitor (KU55933). We observed inhibition of ATR significantly enhanced cisplatin induced cell death in all seven cell lines tested, resulting in 65 - 96% increased sensitivity to cisplatin. Inhibition of ATM did not sensitize GYN cancer cells to cisplatin and cells were not further sensitized by co-inhibition of ATM and ATR beyond that observed by inhibition of ATR alone. DDR signaling was assessed by immunoblotting in cells exposed to cisplatin with or without the presence of ETP-46464 and/or KU55933 where elevated levels of phospho-ATM (Ser1981), phospho-Chk2 (Thr68) and phospho-Chk1 (Ser345) observed in cisplatin treated cells were attenuated in cells that were co-treated with cisplatin and ETP-46464. In addition, increased levels of cleaved PARP1 and caspase 3 were observed in cisplatin-treated, ATR-inhibited cells, suggesting the enhancement of cisplatin induced cell death with ATR inhibition occurs through elevated apoptosis. Further, no differential effect was observed in GYN cancer cells harboring wild type (A2780, OVCAR3, HELA, SIHA) or mutant (CP20, KLE, HEC1B) TP53. These data support further investigation of pharmacologic inhibitors of ATR in combination with existing platinum based therapeutics for treating GYN cancer.
Citation Format: Pang-Ning Teng, Nicholas W. Bateman, Chad A. Hamilton, G. Larry Maxwell, Christopher J. Bakkenist, Thomas P. Conrads. Inhibition of ATR, but not ATM, sensitizes gynecologic cancer cells to cisplatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3758. doi:10.1158/1538-7445.AM2014-3758
Abstract 3759: Identification of novel carboplatin resistance gene in ovarian cancer
Authors: Wei Han , She Yun , Lu Tao 
Published: May 2015

Abstract
Ovarian cancer (OC) is the most lethal gynecology cancer in the world. Although carboplatin is one of the major drugs used to treat OC, resistance to carboplatin remains a major barrier to successful treatment. To date, the mechanisms of carboplatin resistance are still poorly understood. The purpose of this study is to use the novel validation-based insertional mutagenesis (VBIM) technique to identify carboplatin resistance gene in A2780 OC cells. A2780 cells were infected with VBIM virus to cause the overexpression of drug resistance genes, then were further selected under carboplatin treatment. Targeted gene was then identified by using VBIM specific primers. In a preliminary screen, we identified the novel carboplatin resistance gene 1 (NCR1). Overexpression of NCR1 increased carboplatin resistance in A2780 OC cells, while knocking it down with shRNA had the opposite effect. In an attempt to investigate the molecular mechanism that underlying NCR1-mediated carboplatin resistance, we found that NCR1 is a potential NF-κB activator. In summary, we conclude that using a novel VBIM technique, we discovered a previously unknown carboplatin resistance gene NCR1, which may mediate drug resistance via NF-κB signaling pathway. This study is of extreme importance by identifying a potential novel therapeutic target NCR1 in carboplatin resistance. Development of small chemical inhibitors targeting NCR1 could ultimately lead to novel therapeutic approach for ovarian cancer treatment.
Citation Format: Han Wei, Yun She, Tao Lu. Identification of novel carboplatin resistance gene in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3759. doi:10.1158/1538-7445.AM2014-3759
Abstract 3761: Nanoliposomal c-MYC-siRNA inhibits in vivo tumor growth of cisplatin-resistant ovarian cancer
Authors: Reyes-González Jeyshka M. , Armaiz Guillermo N. , Mangala Lingegowda S. , Valiyeva Fatma , Pradeep Sunila , Sood Anil K. , Vivas-Mejía Pablo E. 
Published: May 2015

Abstract
Ovarian cancer is the deadliest of gynecological cancers in the United States. With fewer than 15% of cases diagnosed early, ovarian cancer continues to be characterized by late-stage presentation. Treatment for ovarian cancer usually involves surgical cytoreduction followed by platinum-based chemotherapy. Unfortunately, despite initial respond, more than 70% of ovarian cancer patients develop cisplatin resistance, relapse and therapeutic failure. Therefore, there is a need of novel therapies focused on targets within cancer cell survival pathways for advanced stage drug resistant ovarian cancer. Evidence indicates that activation of the oncogenic transcription factor c-MYC is involved in drug resistance. Our previous findings indicate that cisplatin-resistant ovarian cancer cells express higher c-MYC protein levels when compared to their sensitive counterparts. Importantly, targeting c-MYC with small interfering RNA (siRNA) in the cisplatin-resistant ovarian cancer cell line, A2780CP20, induced a significant cell growth arrest and inhibition of cell proliferation. Apoptosis and arrest of cell cycle progression were also observed after siRNA-based silencing of c-MYC. These results were confirmed by Western blot analysis. Furthermore, in vivo delivery of c-MYC-siRNA in a murine xenograft model of cisplatin-resistant ovarian cancer was achieved by using DOPC/PEG-2000-based nanoliposomes. A single weekly injection of nanoliposomal c-MYC-siRNA, during a four week period, decreased tumor weight and number of tumor nodules compared with a liposomal-negative control siRNA. These data propose c-MYC as a potential therapeutic target for cisplatin-resistant ovarian cancer.
Citation Format: Jeyshka M. Reyes-González, Guillermo N. Armaiz, Lingegowda S. Mangala, Fatma Valiyeva, Sunila Pradeep, Anil K. Sood, Pablo E. Vivas-Mejía. Nanoliposomal c-MYC-siRNA inhibits in vivo tumor growth of cisplatin-resistant ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3761. doi:10.1158/1538-7445.AM2014-3761
Abstract 3765: Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, γ radiation, and cisplatin
Authors: Vareki Saman Maleki , Rytelewski Mateusz , Figueredo Rene , Chen Di , Ferguson Peter J. , Vincent Mark , Min Weiping , Zheng Xiufen , Koropatnick James 
Published: May 2015

Abstract
Indoleamine 2,3-dioxygenase-1 (IDO) is an immunosuppressive molecule expressed by most human tumors. IDO levels correlate with poor prognosis in cancer patients and IDO inhibitors are under investigation to enhance endogenous anticancer immunosurveillance. Little is known of immune-independent functions of IDO relevant to cancer therapy. We show, for the first time, that IDO mediates human tumor cell resistance to a PARP inhibitor (olaparib), γ radiation, cisplatin, and combined treatment with olaparib and radiation, in the absence of immune cells. Antisense-mediated reduction of IDO, alone and (in a synthetic lethal approach) in combination with antisense to the DNA repair protein BRCA2 sensitizes human lung cancer cells to olaparib and cisplatin. Antisense reduction of IDO decreased NAD+ in human tumor cells. NAD+ is essential for PARP activity and these data suggest that IDO mediates treatment resistance independent of immunity and at least partially due to a previously unrecognized role for IDO in DNA repair. Furthermore, IDO levels correlated with accumulation of tumor cells in G1 and depletion of cells in G2/M of the cell cycle, suggesting that IDO effects on cell cycle may also modulate sensitivity to radiation and chemotherapeutic agents. IDO is a potentially valuable therapeutic target in cancer treatment, independent of immune function and in combination with other therapies.
Supported by grants to JK and WM from the Canadian Institutes of Health Research (CIHR).
Citation Format: Saman Maleki Vareki, Mateusz Rytelewski, Rene Figueredo, Di Chen, Peter J. Ferguson, Mark Vincent, Weiping Min, Xiufen Zheng, James Koropatnick. Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, γ radiation, and cisplatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3765. doi:10.1158/1538-7445.AM2014-3765
Abstract 3766: The response of cervical cancer cells to chemotherapeutic agents depends on endogenous ROS levels as well as the drug-induced ROS profile
Authors: Filippova Maria 
Published: May 2015

Abstract
Worldwide, cervical cancer is the second most common cancer in women; approximately 400,000 new cases of this disease are diagnosed each year, of which approximately half will lead to death. Treatment of advanced and relapsed cervical cancer is frequently ineffective, due in large part to chemoresistance. To examine the pathways responsible, we employed the cervical carcinoma-derived SiHa and CaSki cells as cellular models of resistance and sensitivity, respectively, to treatment with chemotherapeutic agents. In particular, CaSki cells are much more sensitive than are SiHa cells to cell death induced by doxorubicin and cisplatin. In this study, we compared the proteomic profiles of SiHa and CaSki cells, and identified pathways with the potential to contribute to the differential response. Based on the results from this proteomic analysis, we hypothesized that pathways involved in the regulation of reactive oxygen species (ROS) levels might contribute in to the observed difference in how these two cell lines respondse to chemotherapy. We then extended these findings by analyzing and comparing the expression level of genes involved in reactive oxygen species (ROS) metabolism through the use of an RT PCR array, and. We found outdiscovered that cells resistant and sensitive cells to drug treatment had displayed different expression levels of expression of pro- and anti-oxidant enzymes. Decreasing or increasing oxidative stress led to protection or sensitization, respectively, to drug-induced cell death, supporting the idea that cellular levels of oxidative stress affect responsiveness to treatment. Interestingly, the two agents tested, doxorubicin and cisplatin, induced different profiles of ROS, and these differences appear to contribute to the differential sensitivity displayed by cervical cancer cells to treatment. Overall, our findings demonstrate that cervical cancer cells display variable profiles with respect to their redox-generating and -adaptive systems, and that these different profiles have the potential to contribute to their differential responses to treatments with chemotherapeutic agents.
Citation Format: Maria Filippova. The response of cervical cancer cells to chemotherapeutic agents depends on endogenous ROS levels as well as the drug-induced ROS profile. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3766. doi:10.1158/1538-7445.AM2014-3766