bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2036: Overcoming platinum-resistance in ovarian cancer via targeting basonuclin1 (BNC1).
Authors: Wu Sherry Y. , Unruh Anna K. , Rupaimoole Rajesha , Ivan Cristina , Ruder Dennis , Pradeep Sunila , Sehgal Vasudha , Rodriguez-Aguayo Cristian , Pecot Chad , Miyake Takahito , Lopez-Berestein Gabriel , Ram Prahlad , Baggerly Keith A. , Sood Anil K. 
Published: August 2014

Abstract
Purpose This study aims to interrogate if basonuclin1 (BNC1), a key gene identified through integrative TCGA-based functional genomic analysis, is a relevant target for overcoming chemo-resistance in high-grade serous ovarian cancer (HGS-OvCa). BNC1 is a transcription factor which can regulate ribosomal biogenesis and cell proliferation. Methods TCGA mRNA expression and clinical response data were used to systematically identify genes associated with chemo-resistance in patients with HGS-OvCa. Gene-specific effects were subsequently studied for selected targets in vitro. BNC1 targeted siRNA was used to study the functional role of BNC1 in chemo-resistance. Apoptosis and cell cycle analyses were carried out following BNC1 silencing in ovarian cancer cell lines with or without the presence of cisplatin. The in vivo effects of silencing BNC1 on the chemosensitivity were tested using an orthotopic mouse model (A2780CP20) of ovarian cancer. Results The expression of BNC1 was found to be increased by more than two-fold (Agilent platform; p&lt;0.001) in chemo-resistant tumors in the TCGA dataset. A 5-fold increase in its expression level was also observed in cisplatin-resistant A2780-CP20 and IGROV-CP20 cells compared to parental cell lines. BNC1 silencing increased the sensitivity of A2780CP20 cells to cisplatin treatment (IC50) with a 30% increase in the percentage of apoptotic cells present at 72 hours following cisplatin treatment, when compared to cells treated with control siRNA. Profound G2-cell cycle arrest was also noted following combined siBNC1 and cisplatin (IC30) treatment (68% vs. 28%; siBNC1 plus cisplatin vs. siControl plus cisplatin; p&lt;0.0001). Importantly, combinational treatment of siBNC1 and cisplatin resulted in a 90% reduction in tumor burden in chemo-resistant A2780CP20 orthotopic mouse model when compared to control siRNA plus cisplatin treatment group (p&lt;0.01). Conclusion Collectively, BNC1 represents an important target for enhancing chemosensitivity in ovarian tumors and its down-regulation could lead to better clinical outcome.
Citation Format: Sherry Y. Wu, Anna K. Unruh, Rajesha Rupaimoole, Cristina Ivan, Dennis Ruder, Sunila Pradeep, Vasudha Sehgal, Cristian Rodriguez-Aguayo, Chad Pecot, Takahito Miyake, Gabriel Lopez-Berestein, Prahlad Ram, Keith A. Baggerly, Anil K. Sood. Overcoming platinum-resistance in ovarian cancer via targeting basonuclin1 (BNC1). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2036. doi:10.1158/1538-7445.AM2013-2036
Abstract 2040: Indication switching of the FDA-approved anticancer tyrosine kinase inhibitors to treat metabolic diseases.
Authors: Sun Jiazhi , Yang Lun , Li Minghua , Wang Zhixin , Haynes Amy , Wang Qian , Raplee Isaac , Melchisedek Jean , Prasad Anand , Sneed Kevin B. , He Lin , Zhou Shufeng 
Published: August 2014

Abstract
Drug switching is a unique way to identify and extend new indications for approved drugs in drug discovery & development. Tyrosine kinase inhibitors (TKIs) are used in biologically targeted cancer therapy and so far 12 TKIs have been approved by FDA. We hypothesize that these TKIs act on other molecular targets in addition to tyrosine kinases and may manage metabolic diseases given that there is a complex network of kinases that work together to regulate a number of important cellular processes. Employing a comprehensive docking method with our established chemical-protein interactome (CPI) and 11 FDA-approved TKIs, we have discovered301 PDB-deposited proteins corresponding to 353 ligand binding pockets among a total of 1,780 PDB-deposited human protein entries. Notably, sorafenib, dasatinib and crizotinib had a CPI binding score (ZZ_score) of -1.2903, -1.0278 and -1.5384 against histone deacetylase 7A, respectively. In addition, those TKIs achieved high ZZ scores against B-Raf, PPAR and VDR, suggesting a high binding affinity of sorafenib, dasatinib and crizotinib with these proteins. Our preliminary studies have showed that the acetylated-lysine in α-tublin and oncogenic Akt and Raf-signaling was inhibited significantly in human multiple melanoma cells by these TKIs. Interestingly, dasatinib increased VDRE and HDLR luciferase reporter activity in the human lung adenocarcinoma A-549 cells, and dasatinib and crizotinib induced autophage by activated LC3 in vitro. Furthermore, the erlotinib and sorafenib decreased glucose levels in Wistar STZ-D rats. These TKIs are predicted to act on a series of therapeutics targets associated with metabolic diseases (such as PPAR and Sirt1). Collectively, FDA-approved TKIs may be switched to become a “magic bullet” concurrently targeting tyrosine kinase, HDAC, PPAR, VDR and B-Raf, shedding a light for future anti-metabolic disorder and anticancer drug discovery & development. Further validation of additional “hot targets” besides tyrosine kinase such as HDAC, B-Raf, PPAR, Sirt1, Akt and VDR, and in vivo evaluation of anti-metabolic disorder by TKIs are undergoing at our laboratory. These findings suggest that drug switching may represent a new and effective approach to expanding the application of existing drugs.
Citation Format: Jiazhi Sun, Lun Yang, Minghua Li, Zhixin Wang, Amy Haynes, Qian Wang, Isaac Raplee, Jean Melchisedek, Anand Prasad, Kevin B. Sneed, Lin He, Shufeng Zhou. Indication switching of the FDA-approved anticancer tyrosine kinase inhibitors to treat metabolic diseases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2040. doi:10.1158/1538-7445.AM2013-2040
Abstract 2047: Discovery and molecular characterization of AGS-15/SLITRK6 as a novel target for antibody-mediated therapeutic development in bladder cancer.
Authors: Shostak Yuriy , Said Suzanne , Russell Deanna L. , Mattie Michael D. , Chang Mi Sook , Christensen Ashley , Morrison Karen , Morrison Kendall , Stover David , Challita-Eid Pia 
Published: August 2014

Abstract
Discovery efforts utilizing suppression subtractive hybridization identified AGS-15/SLITRK6 as a differentially expressed gene in bladder cancer. SLITRK6 encodes a cell surface type I transmembrane protein, a member of the SLITRK family of factors with neuronal function activities. Comprehensive SLITRK6 RNA expression analysis in patient specimens revealed limited restricted normal tissue expression and high frequent expression in bladder cancers, as well as expression in subsets of breast, lung and several other cancer types. Tissue immunohistochemical analysis validated SLITRK6 protein limited expression in normal tissues and high expression levels in cancers. SLITRK6 expression profiling in cancer cell lines and Agensys proprietary patient-derived xenografts (PDXs) identified model systems in relevant cancer indications for further target characterization and antibody therapeutics development. Genomic analyses, including whole exome next generation sequencing, chromosomal aberrations and gene copy number assessments, were performed to evaluate SLITRK6 gene status in model cell lines and PDXs. Thus, we discovered and characterized AGS-15/SLITRK6 as a novel target with high levels and selective expression in tumors, particularly in bladder cancer. This cell surface antigen's attractive expression profile is a major determinant of AGS-15/SLITRK6 as a suitable and preferential candidate for antibody drug conjugate therapeutic targeting in bladder cancer treatment and, potentially, in several other cancer indications.
Citation Format: Yuriy Shostak, Suzanne Said, Deanna L. Russell, Michael D. Mattie, Mi Sook Chang, Ashley Christensen, Karen Morrison, Kendall Morrison, David Stover, Pia Challita-Eid. Discovery and molecular characterization of AGS-15/SLITRK6 as a novel target for antibody-mediated therapeutic development in bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2047. doi:10.1158/1538-7445.AM2013-2047
Abstract 2049: A novel, potent, Cyp17 inhibitor with favorable pharmacokinetics and oral bioavailability for potential treatment of human castration resistant prostate cancer (CRPC).
Authors: Feng Ying , Wang Bing , Chu Daniel , Post Leonard , Shen Yuqiao 
Published: August 2014

Abstract
Cytochrome P450 17α-hydroxylase/C17,20-lyase (CYP17) is a key enzyme in androgen bio-synthesis in adrenals and testes. It has been validated clinically as an effective target for CRPC through successful clinical trials with abiraterone acetate. Abiraterone acetate is a selective, potent inhibitor of Cyp17, and was recently approved as a treatment for CRPC. We have designed a novel Cyp17 inhibitor, BMN680, with improved pharmacokinetic (PK) profile and oral bioavailability while maintaining potent Cyp17 inhibition. BMN680 inhibits Cyp17 lyase activity with IC50 of 0.8 nM and reduces testosterone production in human adrenal cancer cell line H295R cells with IC50 of 3.87 nM. in vitro metabolic stability studies indicate that BMN680 has a half-life of 5-hr in human liver microsome and 8-hr half-life in human hepatocytes. Animal PK profiling in rats and monkeys demonstrated BMN680 has in vivo half-life of &gt;4 hr and oral bioavailability of &gt;30%. Single oral dosing of BMN680 at 10 mg/kg in normal, intact, Cynomolgus monkeys resulted in suppression of plasma testosterone level for up to 24 hour. Pharmacodynamic (PD) effect of single and multi-day oral dosing of BMN680 in monkey will be presented. In human liver microsome Cyp panel screen, BMN680 exhibited IC50 greater than 1.5 uM for all Cyp enzymes tested including 1A2, 2C9, 2C19, 2D6, 3A4, indicating low potential of drug-drug interaction. In conclusion, BMN680 is a potent Cyp17 inhibitor with low interaction with Cyp450 isoforms, and desirable PK and oral bioavailability. BMN680 can effectively suppress testosterone production in vivo, and will be further evaluated in preclinical development.
Citation Format: Ying Feng, Bing Wang, Daniel Chu, Leonard Post, Yuqiao Shen. A novel, potent, Cyp17 inhibitor with favorable pharmacokinetics and oral bioavailability for potential treatment of human castration resistant prostate cancer (CRPC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2049. doi:10.1158/1538-7445.AM2013-2049
Abstract 2059: Kinase library siRNA screen identifies KSR1 as a synergistic therapeutic target in combination with TIC10.
Authors: Allen Joshua E. , El-Deiry Wafik S. 
Published: August 2014

Abstract
Apo2L/TRAIL is an endogenous antitumor protein that possesses efficacy-limiting properties such as short serum half-life, stability, cost, and limitations in delivery when used as a recombinant protein therapeutic. TIC10 is a first-in-class small molecule inducer of the human TRAIL gene that improves these unfavorable drug properties to ultimately increase the efficacy and utility of TRAIL. TIC10 upregulates TRAIL gene transcription by activating the pro-apoptotic transcription factor Foxo3a, which is achieved through dual inhibition of Akt and MEK/ERK. We conducted a siRNA screen using a kinase library to identify kinases that affect TIC10 response in cancer cells assayed by cell viability assays to gain mechanistic insight into the molecular mechanisms of TIC10 and potentially identify a combinatorial target to improve the activity of TIC10. Execution and validation of the siRNA screen revealed 4 kinases (DGKD, SGKL, STK23, KSR) that improved the therapeutic response to TIC10 upon siRNA-mediated knockdown at 36 hours, but not 12 hours, post-treatment in HCT116 human colon cancer cells. We next assayed the effect of knocking down these 4 kinases on cancer cell cytotoxic response to recombinant human TRAIL. These studies revealed no effect with kinase knockdowns, suggesting that the mechanisms of sensitization lie upstream of TIC10-mediated TRAIL production. Network analysis of the “hit” kinases and the previously described mechanism of TIC10 revealed rational overlap of signaling pathways and kinetics. Among the 4 identified kinases, KSR1 possessed the most direct connection to the putative mechanism of TIC10 that involves the dual inhibition of Akt and the MAPK pathway. KSR1 is a MAPK scaffold protein that positively regulates the MAPK signaling pathway. Based on these observations, we are testing the hypothesis that inhibiting KSR1 in combination with TIC10 cooperatively inhibits MAPK signaling to increase TRAIL production. Together, these results suggest that KSR1 is a key player in the cytotoxic response to TIC10 and that combining TIC10 and an inhibitor of KSR1 may result in improved therapeutic response.
Citation Format: Joshua E. Allen, Wafik S. El-Deiry. Kinase library siRNA screen identifies KSR1 as a synergistic therapeutic target in combination with TIC10. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2059. doi:10.1158/1538-7445.AM2013-2059
Abstract 2081: Evaluation of Src as a therapeutic target in biliary tract cancer using bosutinib, a c-Src/Abl kinase inhibitor.
Authors: Nam Ah-Rong , Min Ahrum , Han Sae-Won , Song Sang-hyun , Oh Do-Youn , Im Seock-Ah , Kim Tae-You , Bang Youg-Jue 
Published: August 2014

Abstract
Background: Src is a nonreceptor tyrosine kinase involved in the crosstalk and mediation of many signaling pathways that promote cell proliferation, invasion and angiogenesis. Elevation of Src activity has been reported in many types of cancers including biliary tract cancer (BTC). In BTC, no molecular therapeutic target has been validated so far. Therefore, the prognosis of advanced BTC is limited and there is a huge unmet medical need in this area. The purpose of this study is to evaluate of Src as a therapeutic target in BTC and to elucidate the therapeutic potential and action mechanism of bosutinib, an orally active small molecule c-Src/Abl kinase inhibitor, alone or in combination with chemotherapy for the treatment of BTC.
Methods: Experiments were conducted using 8 human biliary tract cancer cell lines (SNU-245, 308, 478, 869, 1079, 1196, HuCCT1, TFK1). MTT assay, colony formation assay and 3D culture were done for determining growth inhibitory effect of bosutinib, alone or in combination with chemotherapeutic agents (gemcitabine, cisplatin). Cell cycle distribution was analyzed by FACS Calibur flow cytometer. Matrigel invasion assay and wound healing assay were done. The methods described by Chou and Talalay were used to determine whether a synergistic effect existed between drug combination.
Results: pSrc was highly expressed in most BTC cells. Bosutinib inhibited the growth of BTC cells, especially SNU308, SNU478 and HuCCT1 (IC50, 0.6-0.8 μmol/L). Bosutinib induced G1 arrest (decrease of cyclin D, cyclin E, cyclin A, cyclin B and increase of p27) in SNU308 and SNU478. It decreased pSrc, pFAK, pAKT and pERK in these cells. Bosutinib also inhibited the cell migration and invasion in parallel with decrease of snail, not only in SNU308, SNU478 cells but also in several other cells. Interestingly, bosutinib showed synergistic antiproliferative effects (Combination Index value &lt;1) with gemcitabine in 4 out of 8 BTC cells. Bosutinib was downregulated TS (thymidine synthase) expression, one of resistance mechanisms to gemcitabine. Bosutinib also showed synergistic anti-invasion activity in combination of gemcitabine or cisplatin.
Conclusion: Taken together, these preclinical evaluations reveal that Src could be a potential therapeutic target in biliary tract cancer and support clinical development of bosutinib alone or in combination with chemotherapy in biliary tract cancer.
Citation Format: Ah-Rong Nam, Ahrum Min, Sae-Won Han, Sang-hyun Song, Do-Youn Oh, Seock-Ah Im, Tae-You Kim, Youg-Jue Bang. Evaluation of Src as a therapeutic target in biliary tract cancer using bosutinib, a c-Src/Abl kinase inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2081. doi:10.1158/1538-7445.AM2013-2081
Abstract 2098: Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells.
Authors: Wempe Stacy L. , Gamarra-Luques Carlos D. , Telleria Carlos M. 
Published: August 2014

Abstract
We have previously shown that the antiprogestin/antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided because of a compensatory activation of the PI3K/Akt survival pathway.To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. Mifepristone-induced growth arrest of ovarian cancer cells was associated with phosphorylation of Akt (Ser473), which was prevented by treatment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of anti-apoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in two dimensional cell cultures was recapitulated in organized, tri-dimensional spheroids. This study demonstrates that mifepristone and LY294002, when used individually cause cell growth arrest, yet when combined, they cause lethality. This work further provides proof-of-concept that in combination, targeted cytostatic therapies can be an efficient tool to engage cancer cells in a death program.
Citation Format: Stacy L. Wempe, Carlos D. Gamarra-Luques, Carlos M. Telleria. Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2098. doi:10.1158/1538-7445.AM2013-2098
Abstract 2112: The role of reactive oxygen species (ROS) in cell death induced by thymidylate synthase inhibitors.
Authors: Ozer Ufuk , Barbour Karen W. , Berger Franklin G. 
Published: August 2014

Abstract
Thymidylate synthase (TS) catalyzes the reductive transfer of a methyl group from N5,N10-methylenetetrahydrofolate (CH2H4PteGlu) to dUMP, forming dTMP and dihydrofolate (H2PteGlu). It is generally accepted that inhibition of the enzyme leads to a deficiency of dTMP, followed by genome damage and programmed cell death. As such, TS has long been viewed as an important target of anti-neoplastic agents, such as 5-fluorouracil (FUra) and ratitrexed (RTX), which function as inhibitors of the enzyme. Oxidative stress is well-recognized as having a central role in cellular response to a number of DNA damaging agents, and may be a proximate cause of therapy-induced cell death. Despite such recognition, little detail exists on the origin and regulation of reactive oxygen species (ROS) during TS-directed chemotherapy. We have undertaken a detailed examination of the origin, nature, and role of ROS in cell death mediated by TS inhibitors. In colon tumor cell line HCT116, fluorescence detection of H2O2 and O2•− (using H2DCFDA and DHE, respectively) showed that profound increases in ROS levels occur during drug exposure. These increases are attenuated by treatment with the antioxidant N-acetylcysteine (NAC), by addition of thymidine to the medium and by TS overproduction, indicating that it is indeed TS inhibition and the resulting dTMP deficiency that is responsible. Oxidative damage to DNA, as indicated by 8-oxo-guanine formation, is elevated in drug-treated cells. Apoptotic indices, as measured by TUNEL assays, parallel changes in ROS levels, i.e., they are induced in response to drug, and are inhibited by NAC, thymidine, and TS overproduction. We have identified NADPH oxidase (NOX) as the primary source of increased ROS following exposure to TS-directed agents, as indicated by observing decreased ROS production apoptotic indices in cells treated with NOX inhibitors. We have found that in response to TS inhibitors, NOX enzyme activity increases in association with induction of the transcript for p67phox, which specifically regulates the NOX2 isoform. These effects were reduced by thymidine and by TS overproduction. Based on these results, we conclude that augmentation of NOX2 activity via induction of p67phox mRNA expression is the proximate cause of programmed cell death elicited by dTMP deficiency.
Citation Format: Ufuk Ozer, Karen W. Barbour, Franklin G. Berger. The role of reactive oxygen species (ROS) in cell death induced by thymidylate synthase inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2112. doi:10.1158/1538-7445.AM2013-2112