bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1780: Identification and characterization of L524-0366 as a small molecule inhibitor that disrupt TWEAK-Fn14 signaling in glioblastoma
Authors: Dhruv Harshil D. , Loftus Joseph C. , Narang Pooja , Petit Joachim L. , Chow Donald , Yin Holly , Berens Michael , Meurice Nathalie , Tran Nhan L. 
Published: May 2015

Abstract
Deregulation of the TWEAK-Fn14 signaling pathway is observed in many diseases including inflammation, autoimmune diseases, and cancer, notably glioblastoma. Activation of Fn14 signaling by TWEAK binding triggers glioma cell invasion and survival and therefore represents an attractive pathway for therapeutic intervention. Based on structural studies of the TWEAK-binding cysteine rich domain of Fn14, several homology models of TWEAK were built to investigate plausible modes of TWEAK-Fn14 interaction. Two promising models, centered on different anchoring residues of TWEAK [Tyrosine 176 (Y176) and Tryptophan 231 (W231)], were prioritized using a data-driven strategy. Site-directed mutagenesis of TWEAK at Y176, but not W231, resulted in the loss of TWEAK binding to Fn14 substantiating Y176 as the anchoring residue. Importantly, mutation of TWEAK at Y176 did not disrupt TWEAK trimerization, but failed to induce Fn14 mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The validated structural models were utilized in a virtual screen to design a targeted library of small molecules predicted to disrupt the TWEAK-Fn14 interaction. 129 small molecules were screened iteratively, with identification of molecules producing up to 37% inhibition of TWEAK-Fn14 binding. One specific compound, L524-0366 binds specifically to the Fn14 receptor and disrupt TWEAK-Fn14 interaction. Treatment of L524-0366 suppresses TWEAK-induced cell migration and survival in glioblastoma cells. In summary, we present a data-driven in silico study revealing key structural elements of the TWEAK-Fn14 interaction, followed by experimental validation, serving as a guide for the design of small molecule inhibitors of the TWEAK-Fn14 ligand-receptor interaction. Our results provide the foundation for further exploration utilizing L524-0366 as a small molecule inhibitor to the TWEAK-Fn14 signaling axis.
Citation Format: Harshil D. Dhruv, Joseph C. Loftus, Pooja Narang, Joachim L. Petit, Donald Chow, Holly Yin, Michael Berens, Nathalie Meurice, Nhan L. Tran. Identification and characterization of L524-0366 as a small molecule inhibitor that disrupt TWEAK-Fn14 signaling in glioblastoma. [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 1780. doi:10.1158/1538-7445.AM2014-1780
Abstract 1783: Puupehenol natural product inhibits STAT3 signaling and induces antitumor cell effects in vitro against human glioblastoma cells
Authors: Hilliard Tyvette S. , Chock Christopher , Williams Philip , Turkson James 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is a malignant brain tumor that lacks effective therapeutics and has a high mortality rate. Constitutively-activated signal transducer and activator of transcription 3 (STAT3) protein is prevalent and implicated in GBM phenotype and represents a valid anti-GBM target. To discover novel STAT3 inhibitors suitable for GBM therapy, natural product extracts were investigated. Whole extracts from marine organisms were first screened for effects against cell viability using the human glioma model line, U251MG that harbors aberrantly-active STAT3 and normal fibroblasts that do not. The screening campaign identified the puupehenol, CC-1-2 from the whole extracts of leiodermatium sp as a bioactive compound that suppressed U251MG cell viability, with an IC50 4.1±0.1 µM, compared to an IC50 value of 7.3±0.3 µM against normal NIH3T3 mouse fibroblasts. Western blot analysis showed pSTAT3 levels in U251MG cells substantially decreased in a time-dependent manner in response to CC-1-2. Decreased pSTAT3 in treated cells occurred in parallel with partial suppression of both phospho- Janus kinase (Jak) 2 and pSrc levels and no induction of protein tyrosine phosphatase, PTP1B. Phosphorylated extracellular signal-regulated kinase (Erk) 1/2 levels also decreased in time-dependent manner, while pAkt remained unchanged in U251MG cells under the same treatment conditions. Furthermore, treatment of U251MG cells with CC-1-2 led to dramatic morphological changes that occurred in a dose- and time-dependent manner, compared to minimal changes observed for similarly-treated MCF-7 breast cancer cells that do not harbor aberrantly-active STAT3. Colony survival assay of U251MG cells revealed single treatment with 1-10 µM CC-1-2 decreased colony sizes and numbers in a dose-dependent manner, compared to moderate effects on MCF-7. In vitro wound-healing assay further showed reduced U251MG cell migration into the denuded area in response to CC-1-2 treatment. CC-1-2 further induced apoptosis in U251MG cells in a dose-dependent manner and suppressed the expression of c-Myc, Cyclin D1, and Bcl-2 levels, which are known STAT3-regulated genes. Studies together identify CC-1-2 as a natural product inhibitor of STAT3 that preferentially induces antitumor cell effects against human glioblastoma cells.
Citation Format: Tyvette S. Hilliard, Christopher Chock, Philip Williams, James Turkson. Puupehenol natural product inhibits STAT3 signaling and induces antitumor cell effects in vitro against human glioblastoma cells. [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 1783. doi:10.1158/1538-7445.AM2014-1783
Abstract 1786: Development and pharmacological properties of PEGylated glucuronide-auristatin linkers
Authors: Burke Patrick J. , Hamilton Joseph Z. , Hunter Joshua H. , Jeffrey Scott C. , Doronina Svetlana O. , Okeley Nicole M. , Meyer David W. , Senter Peter D. , Lyon Robert P. 
Published: May 2015

Abstract
Antibody-drug conjugates (ADCs) are an emerging therapeutic modality for the treatment of cancer, exemplified by the recent clinical success of brentuximab vedotin and ado-trastuzumab emtansine. The majority of ADCs currently in development include functionalities that are hydrophobic, resulting in increased plasma clearance. Consequently, there has been significant interest in generating new linkers that compensate for this potential liability. In an attempt to mitigate the pharmacokinetic impact of monomethylauristatin E (MMAE) when conjugated to an antibody, we prepared drug-linkers incorporating a polyethylene glycol (PEG) polymer. Initial work demonstrated that incorporation of a discrete PEG24 polymer into the cleavable β-glucuronide-MMAE linker system could either increase or decrease the plasma clearance of the resulting ADCs, depending upon the configuration of the PEG. When inserted into the drug-linker as a stretcher unit between the maleimide and the cleavage site, PEG24 elicited increased ADC plasma clearance. Conversely, incorporation of the PEG24 as a side chain from a modified lysine residue adjacent to the maleimide resulted in ADCs with slower clearance. These differences in ADC pharmacokinetics translated into corresponding differences in antitumor activity in two xenograft models. Thus, incorporation of PEG24 into ADC linkers impacts both pharmacokinetics and activity in a structure-dependent manner.
Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Joshua H. Hunter, Scott C. Jeffrey, Svetlana O. Doronina, Nicole M. Okeley, David W. Meyer, Peter D. Senter, Robert P. Lyon. Development and pharmacological properties of PEGylated glucuronide-auristatin linkers. [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 1786. doi:10.1158/1538-7445.AM2014-1786
Abstract 179: Presence of primary cilia in cancer cells correlates with prognosis of pancreatic ductal adenocarcinoma
Authors: Emoto Katsura , Masugi Yohei , Yamazaki Ken , Effendi Kathryn , Tsujikawa Hanako , Kitago Minoru , Itano Osamu , Kitagawa Yuko , Sakamoto Michiie 
Published: May 2015

Abstract
Primary cilia are microtubule-based organelles that protrude from basal bodies and are involved in cell differentiation, sensory functions, and planar cell polarity. Especially, primary cilia have become popular as the place for signal transduction pathways including sonic hedgehog, Wnt, and platelet-derived growth factor pathways. Although there are many studies examining the roles of primary cilia in the fields of embryology and physiology, few such studies have been carried out in the field of oncology, and the role of primary cilia in cancer cells is poorly understood especially in human samples. In this study, we identified primary cilia by immunofluorescence analysis in which primary cilia were visualized as green rods labeled with anti-acetylated α-tubulin adjacent to basal bodies detected as red dots labeled with anti-γ-tubulin. Primary cilia were found in human pancreatic cancer cell lines (PANC-1 and CFPAC-1) and the number of them increased in the condition of serum starvation. As for clinical samples, primary cilia were found in cancer cells in 25 of 100 pancreatic ductal carcinoma patients [1-109 (median 8) primary cilia / 3 field pictures]. Most primary cilia in cancer tissue were observed in areas showing well differentiated glandular structures in clinical samples. Patients whose cancers were primary cilia positive had a higher frequency of lymph node metastasis than those whose cancers were primary cilia negative (p = 0.016). Univariate analysis demonstrated that tumor size (p = 0.009), tumor grade (p = 0.001), lymph node metastasis (p = 0.008), and the presence of primary cilia (p = 0.002) correlated with overall survival. Multivariate analysis found that tumor grade (p &lt; 0.001) and the presence of primary cilia (p = 0.001) were independent prognostic indicators. In summary, we showed that pancreatic cancer cells can form primary cilia and that the presence of primary cilia is significantly associated with the prognosis of pancreatic ductal adenocarcinoma. The presence of primary cilia has the potential to become a new diagnostic tool and therapeutic target.
Citation Format: Katsura Emoto, Yohei Masugi, Ken Yamazaki, Kathryn Effendi, Hanako Tsujikawa, Minoru Kitago, Osamu Itano, Yuko Kitagawa, Michiie Sakamoto. Presence of primary cilia in cancer cells correlates with prognosis of pancreatic ductal adenocarcinoma. [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 179. doi:10.1158/1538-7445.AM2014-179
Abstract 1798: Mechanistic study of NVP-CGM097: a potent, selective and species specific inhibitor of p53-Mdm2
Authors: Valat Thérèse , Masuya Keiichi , Baysang Frédéric , Albrecht Geneviève , Buschmann Nicole , Erdmann Dirk , Furet Pascal , Gabriel Tobias , Gessier François , Hofmann Francesco , Holzer Philipp , Kallen Joerg , Pissot-Solderman Carole , Stutz Stefan , Chène Patrick , Jeay Sébastien 
Published: May 2015

Abstract
An effective strategy to restore p53 activity in cancer cells containing wild type p53 is to inhibit the Mdm2-p53 protein-protein interaction (PPI). NVP-CGM097 is a novel PPI inhibitor under evaluation in a Phase I clinical trial. It binds to the p53 binding-site of the Mdm2 protein, disrupting the interaction between both proteins, leading to an activation of the p53 pathway.
The main biophysical and biochemical inhibitory characteristics of NVP-CGM097 are presented here. These include an affinity constant for Mdm2 in the nanomolar range and a selectivity of 3 orders of magnitude vs. Mdm4. The binding kinetics of NVP-CGM097 to Mdm2 are characterized by a high association rate constant (Kon =37 x 106 M-1.s-1) and a moderate dissociation rate constant (Koff =0.071 s-1). Additionally, NVP-CGM097 exhibits an 8-fold greater affinity for Mdm2 over Nutlin-3 due to a longer residence time of the Mdm2-inhibitor complex.
Moreover, biochemical studies have revealed the species specificity of NVP-CGM097 with human Mdm2 being inhibited more strongly than the dog, mouse or rat forms of the protein. This was confirmed in cellular assays where NVP-CGM097 treatment resulted in induction of p53 target gene expression (p21, PUMA and Mdm2) only in human, but not in dog, mouse or rat cell lines.
Citation Format: Thérèse Valat, Keiichi Masuya, Frédéric Baysang, Geneviève Albrecht, Nicole Buschmann, Dirk Erdmann, Pascal Furet, Tobias Gabriel, François Gessier, Francesco Hofmann, Philipp Holzer, Joerg Kallen, Carole Pissot-Solderman, Stefan Stutz, Patrick Chène, Sébastien Jeay. Mechanistic study of NVP-CGM097: a potent, selective and species specific inhibitor of p53-Mdm2. [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 1798. doi:10.1158/1538-7445.AM2014-1798
Abstract 1802: Small molecule compound NCI-8 induces mutant p53 degradation via inhibition of the MDM2-Hsp90 axis
Authors: Zhang Shengliang , Zhou Lanlan , Kline Christina Leah B. , Dicker David T. , El-Deiry Wafik S. 
Published: May 2015

Abstract
The tumor suppressor p53 prevents cancer development via regulating cell cycle arrest, cell death, or repair processes. Over 50% of human cancers harbor mutant p53. Mutations in p53 not only abrogate its tumor suppressor function, but also endow mutant p53 with a gain-of-function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression and chemotherapeutic resistance. Thus, targeting mutant p53 to restore wild-type p53 pathway signaling is an attractive strategy for cancer therapy. We previously reported a novel small molecular compound, NCI-8, which not only restores wild-type p53 signaling, but also depletes mutant p53 protein (Zhang S, Zhou L, Hong B, et al. Cancer Res 2013;73(8 Suppl):Abstract 2171). In this study, we further elucidate the mechanism of the small molecular compound NCI-8-mediated degradation of mutant p53 protein. We found that the small molecule NCI-8 induces mutant p53 protein degradation via the MDM2-ubiquitin-proteasome pathway. NCI-8 exposure leads to phosphorylation of p53 at Thr55. Dephosphorylation of p53 at Thr55 rescues mutant p53 protein from degradation in cells treated with Apigenin, suggesting that phosphorylation at Thr55 is required for mutant p53 protein degradation induced by NCI-8. Hsp90 and hsp70 are two molecular chaperones that stabilize mutant p53 protein by affecting the MDM2 mediated turnover of mutant p53, therefore, we investigated the effect of NCI-8 on the MDM2-hsp chaperone axis. We found that less HSP90 but more MDM2 were bound to mutant p53 in cells treated with NCI-8, suggesting that NCI-8 induces mutant p53 protein degradation through disturbing the MDM2-hsp chaperone axis. Correlated to the degradation of mutant p53 protein, the p73 pathway was activated in response to NCI-8 treatment specifically in mutant p53-expressing colorectal cancer cells. Our results provide a possible mechanism of NCI-8-mediated p73-dependent restoration of the p53 pathway via mutant p53 protein degradation.
Citation Format: Shengliang Zhang, Lanlan Zhou, Christina Leah B. Kline, David T. Dicker, Wafik S. El-Deiry. Small molecule compound NCI-8 induces mutant p53 degradation via inhibition of the MDM2-Hsp90 axis. [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 1802. doi:10.1158/1538-7445.AM2014-1802
Abstract 1804: New insights in the induction of cell death by the imidazolium based compound YM155
Authors: Danielpour David , Shankar Eswar , Corum Sarah L. 
Published: May 2015

Abstract
The inhibitor of apoptosis protein (IAP) Survivin is robustly over-expressed in a variety of cancers including prostate carcinomas, and has been shown to play pivotal roles in cancer progression and resistance to chemotherapy. The imidazolium based small molecule YM155, which was first identified as a robust suppressor of the Survivin promoter of PC-3 prostate carcinoma and under clinical investigation for the treatment of multiple cancers, is a potent apoptosis inducer of castration-resistant prostate cancer (CRPC) cells. However, the mechanisms by which it inhibits the expression of Survivin and kills cancer cells remain unclear. Here we studied early signaling responses to YM155 in a panel of prostate and kidney cancer cell lines in standard cell culture conditions and showed that YM155 rapidly decreases the expression of cyclin Ds 1, 2 and 3, and activates the retinoblastoma protein (Rb), leading to the downregulation of the Survivin promoter. However, despite the robust lost of cyclin Ds, YM155 promotes an S-phase arrest rather than arrests cells at either G1 or G2/M. This suggests cell killing by YM155 involves S-phase arrest, consistent with a DNA damage response. In addition, we show that YM155 also downregulates the expression of the anti-apoptotic protein Mcl-1 and induces the expression of proapoptotic proteins Bad and Bim followed by the activation of caspases -3 and -8. Moreover, early time course experiments show that YM155 induces rapid (10 - 60 min) but transient activation of Akt and Erk1/2 followed by a marked suppression by 4 to 8 h likely via the induced expression of phosphatases 1 and 5 (DUSP1 and 5). Taken together we suggest YM155 induces apoptosis of prostate epithelial cells through a complex mechanism involving Akt, Erk1/2, DUSPs, cyclin Ds, Rb, S-phase arrest, Bim, Bad, Mcl-1,Survivin, and activation of caspases -3 and -8.
Citation Format: David Danielpour, Eswar Shankar, Sarah L. Corum. New insights in the induction of cell death by the imidazolium based compound YM155. [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 1804. doi:10.1158/1538-7445.AM2014-1804
Abstract 1805: Characterization of pyoluteorin derivatives as Mcl-1 antagonists
Authors: Doi Kenichiro , Gowda Krishne , Liu Qiang , Sung Shen-Shu , Lin Jyh Ming , Amin Shantu , Loughran Thomas P. , Wang Hong-Gang 
Published: May 2015

Abstract
The evasion of apoptosis is considered to be a hallmark of cancers and a cause of resistance to anti-cancer therapies. Consistently, aberrant overexpression of anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xL, Mcl-1) is associated with tumorigenesis and increased resistance to chemotherapy in multiple malignancies. To date, several small-molecule Bcl-2 inhibitors that bind the BH3-binding pocket of the protein have entered clinical trials. These BH3 mimetics are known to induce apoptosis by disrupting the interactions between pro- and anti-apoptotic Bcl-2 family proteins. The most well characterized selective agents are the Bcl-2 inhibitor ABT-737 and its orally active analog ABT-263 which inhibit Bcl-2 and Bcl-XL but not Mcl-1. Consequently, cancers with elevated Mcl-1 do not respond to these drugs. Moreover, Mcl-1 is frequently upregulated in cancer cells and compensates for the inhibition of Bcl-2 function by ABT-737, thereby mediating resistance to the drug. Thus, there is an urgent need to develop Mcl-1-specific inhibitors for the treatment of Mcl-1-dependent human cancers. We have recently identified and characterized the natural product marinopyrrole A (maritoclax) as a novel Mcl-1 inhibitor, which induces apoptosis by targeting Mcl-1 for proteasomal degradation without significant effects on mRNA levels. To determine the pharmacophore of maritoclax, we systematically altered or removed portions of the molecule to identify regions essential for inhibition of Mcl-1 and induction of apoptosis. To date, we synthesized over 40 derivatives of maritoclax and evaluated their inhibitory actions toward Mcl-1 and cytotoxicity in cell lines of human hematological malignancies. As a result, we have identified several pharmacophore sites in maritoclax that are required for biological activity and two pyoluteorin derivatives, KS04 and KS18, which bind to a similar site(s) in Mcl-1 as maritoclax, as determined by NMR titration experiments. Like maritoclax, KS04 or KS18 markedly reduced the half-life of Mcl-1 protein, induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells, and acted synergistically with ABT-737 to enhance apoptosis in ABT-737 resistant HL60 cells. Moreover, the combination treatment of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL60 xenografts in nude mice. Thus, further studies are warranted to develop pyoluteorin derivatives as a novel class of Mcl-1 inhibitors.
Citation Format: Kenichiro Doi, Krishne Gowda, Qiang Liu, Shen-Shu Sung, Jyh Ming Lin, Shantu Amin, Thomas P. Loughran, Hong-Gang Wang. Characterization of pyoluteorin derivatives as Mcl-1 antagonists. [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 1805. doi:10.1158/1538-7445.AM2014-1805
Abstract 1821: HER3 activation by MET contributes to trastuzumab resistance in HER2-positive breast cancer
Authors: Hashimoto Kenji , Macaulay Valentine , Kong Anthony 
Published: May 2015

Abstract
Background: Trastuzumab is a standard therapy for HER2-positive breast cancer patients. Majority of the patients treated with trastuzumab in metastatic disease experience relapse. MET has been reported as one possible candidate of trastuzumab resistance however, detailed mechanism is unclear.
Methods: Using panel of HER2-positive cell lines, pHER3 level was assessed with trastuzumab treatment by western blot. Co-immunoprecipitation and siRNA knockdown were used to assess the interaction between HER3 and MET.
Results: Phospho-HER3 as well as pAKT levels were decreased after trastuzumab treatment in trastuzumab sensitive cell lines, while there were no deactivation in the resistant cell lines. In the primary trastuzumab resistant cell lines, 5 of 6 cells expressed MET while only one of 4 cells expressed MET in the sensitive cell lines. BT474 cells were found to have increased MET level when the cells acquired resistance to trastuzumab. HCC1954 cells, MET overexpressing and primary trastuzumab cell line, were sensitized to trastuzumab when MET was knocked down. MET knockdown led to a decrease of phosphor-HER3 level in HCC1954, BT474, and BT474 trastuzumab resistant (BT-TR) cells. The paraffin-embedded tumor samples from BT474 xenograft treated with trastuzumab and HER2-positive breast cancer patients will be stained for MET expression to assess its prognostic and predictive values sin HER2 positive breast cancer.
Conclusion: MET may play a key role in maintaining HER3 phosphorylation during trastuzumab treatment and resistance in HER2 positive breast cancer.
Citation Format: Kenji Hashimoto, Valentine Macaulay, Anthony Kong. HER3 activation by MET contributes to trastuzumab resistance in HER2-positive breast 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 1821. doi:10.1158/1538-7445.AM2014-1821