bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3860: The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma
Authors: Simbulan-Rosenthal Cynthia M. , Dakshanamurthy Sivanesan , Gaur Anirudh , Chen You-Shin , Shimizu Rena , AbdusSumad Maryam , Zhou Hengbo , Zapas John , Calvert Valerie , Petricoin Emaneul F. , Atkins Michael B. , Byers Stephen W. , Rosenthal Dean S. 
Published: July 2016

Abstract
Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that MBZ binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of dabrafenib-resistant BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation in vivo. RPPA and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were downregulated, consistent with S phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, an off-patent approved drug with no major side effects, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.
Citation Format: Cynthia M. Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Rena Shimizu, Maryam AbdusSumad, Hengbo Zhou, John Zapas, Valerie Calvert, Emaneul F. Petricoin, Michael B. Atkins, Stephen W. Byers, Dean S. Rosenthal. The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3860.
Abstract 3861: Ruxolitinib inhibits STAT-3 activation in glioblastoma
Authors: Fehling Samuel , McFarland Braden , Benveniste Etty 
Published: July 2016

Abstract
Glioblastoma (GBM), a primary Grade IV astrocytoma, is the most aggressive primary brain cancer in humans. Despite combined radiotherapy and chemotherapy, the median survival is 14 months. We and others have validated that levels of phosphorylated JAK1/2 and STAT-3 are increased in GBM tissues. When stimulated with IL-6 family members, JAK1/2 recruits and phosphorylates STAT-3. Phosphorylated STAT-3 dimerizes and translocates to the nucleus where it regulates genes involved in proliferation, angiogenesis, anti-apoptotic activity and immunosuppression. Elevated JAK/STAT activation is generated through an increase in IL-6 family cytokines as well as a decrease in JAK/STAT-3 negative regulators. To therapeutically inhibit the JAK/STAT-3 pathway in GBM we employed ruxolitinib, an FDA approved JAK1/JAK2 inhibitor. Human GBM cell lines U87-MG and U251-MG, as well as patient derived GBM xenograft lines JX6 and JX12, were treated with ruxolitinib in doses ranging from 0.01 to 10 μM. Ruxolitinib was observed to inhibit STAT-3 activation in a dose-dependent manner. Pre-treatment of U87-MG and U251-MG cells with ruxolitinib inhibited stimulus-induced STAT-3 activation and downstream gene expression in a dose-dependent manner. Future studies will examine ruxolitinib effects on migration, invasion, apoptosis and proliferation in vitro. Collectively, these data indicate the potential for ruxolitinib therapy for GBM patients.
Citation Format: Samuel Fehling, Braden McFarland, Etty Benveniste. Ruxolitinib inhibits STAT-3 activation in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3861.
Abstract 3863: Cancer immunotherapy: Could TK1 be used as a target for colon cancer
Authors: Townsend Michelle H. , Weagel Evita G. , Meng Wei , Chandler Craig , Robison Richard A. , O’Neill. Kim L. 
Published: July 2016

Abstract
The aim of this study is to determine whether Thymidine Kinase 1 (TK1) would be a suitable target for future immunotherapeutic treatment of colon cancer. The salvage pathway enzyme TK1 has been shown to be upregulated in cancer patients due to active proliferation of cancer cells and the resulting high demand for nucleotides. Present in both the cytosol and the serum of cancer patients, TK1 levels can be used to not only predict cancer occurrence, but also to predict tumor aggressiveness and future remission. While serum levels of TK1 have been established, surface expression of the enzyme have not been fully characterized. In colon cancer cells, TK1 has been shown to strongly associate with the plasma membrane. In this project we explored the presence of TK1 on the surface of colon cancer cells (HT29 and SW620 cell lines) using flow cytometry, confocal microscopy, scanning electron microscopy, membrane separation, and cytoplasmic staining. Using fluorescent antibodies conjugated to FITC, expression levels as high as 19% are observed in HT29's and 12% in SW620's in comparison to sodium potassium ATPase surface levels of 11% and 6% respectively. Confocal microscopy images revealed direct overlap between cells stained with a rhodamine red membrane dye and with a FITC conjugated anti-TK1 antibody which indicates a direct relationship between TK1 and the cellular surface of cancer cells. To further confirm surface expression, TK1 levels were assessed using gold labeling and scanning electron microscopy. Gold levels indicate the physical location of the TK1 on the surface of the colon cancer cells and their relative abundance. TK1 surface levels in colon cancer cells corresponded with the surface expression levels of sodium potassium ATPase and share relatively the same abundance. These results strongly indicate a direct relationship between TK1 and the surface of colon cancer cells, and suggests TK1 as a potential target for future immunotherapeutic treatment.
Citation Format: Michelle H. Townsend, Evita G. Weagel, Wei Meng, Craig Chandler, Richard A. Robison, Kim L. O’Neill. Cancer immunotherapy: Could TK1 be used as a target for colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3863.
Abstract 3868: Aggressiveness niche within BRCA1-IRIS/TNBC tumors is supported by reciprocal interactions with the microenvironment
Authors: Sinha Abhilasha , ElShamy Wael M. 
Published: July 2016

Abstract
Introduction: Bi-directional interactions with stromal cells promote metastasis from breast tumors. We aimed at determining the role these bi-directional interactions between BRCA1-IRIS-overexpression (IRISOE) tumor cells and stromal cells in generating aggressive triple negative breast cancers.
Experimental Procedures: We used co-culturing assay, immunohistochemistry, in vitro invasion assay with or without cytokines neutralization, ELISA, western blot analysis, exposure to hypoxic conditions, cytokines receptor inactivation, in vivo orthotopic tumor formation assay, analysis of publically available data sets for the association of selected factors with overall survival, distant metastasis free survival and recurrent free survival to define the role of these bi-directional interactions in enhancing IRISOE tumors aggressiveness.
Results: Here we show formation of an aggressiveness niche within IRIS overexpressing triple negative breast cancers (IRISOE/TNBCs) defined as the necrotic/hypoxic core. To this niche, metabolically stressed IRISOE/TNBC cells attract mesenchymal stem cells (MSCs) to the aggressiveness niche through secreting high levels of IL-1β. IL-1R-negative MSCs are induced to express the receptor upon exposure to medium conditioned by IRISOE/TNBCs. Activated by IL-1β, IL-1R activates AKT, MAPK and NF-κB signaling in MSCs to which they respond by releasing inflammatory cytokines, such as CXCL1. Inhibiting IL-1β signaling utilizing neutralizing antibody attenuates MSCs recruitment and CXCL1 secretion, in vitro and in vivo. CXCL1 receptor; CXCR2 is expressed on IRISOE/TNBCs only and thus CXCL1 acts in a paracrine fashion to entrain IRISOE/TNBCs. Mechanistically, MSCs-entrained IRISOE/TNBCs secrete CCL2 and VEGF that activate and attract tumor associated macrophages (TAMs) and endothelial cells (ECs), respectively to the vicinity of IRISOE/TNBCs in the aggressiveness niche. S100A8 and IL-8 secreted from IRISOE/TNBCs-activated TAMs and ECs, respectively in concert with CXCL1 enhance IRISOE/TNBCs aggressiveness. In pre-clinical model, IRISOE cells co-injected with MSCs (10:1 ratio) developed faster and bigger orthotopic mammary tumors containing more TAMs and ECs compared to IRISOE/TNBCs injected alone. These tumors progressed to develop spontaneous lymph-node or distant metastases (e.g., bone, lung and/or brain).
Conclusion: We propose that in concert with an anti-BRCA1-IRIS drug, inhibitors to the reciprocal interactions between IRISOE/TNBCs and their surrounding stromal cells could be exploited as a viable therapy for IRISOE/TNBCs and their metastases.
Citation Format: Abhilasha Sinha, Wael M. ElShamy. Aggressiveness niche within BRCA1-IRIS/TNBC tumors is supported by reciprocal interactions with the microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3868.
Abstract 3872: Quantification of mutant SPOP proteins in prostate cancer using targeted proteomics
Authors: Wang Hui , Barbieri Christopher , He Jintang , Gao Yuqian , Wu Chaochao , Schepmoes Athena , Fillmore Thomas , Shi Tujin , Chae Sung-Suk , Huang Dennis , Mosquera Juan Miguel , Qian Wei-Jun , Smith Richard , Srivastava Sudhir , Kagan Jacob , Camp David , Rodland Karin , Rubin Mark , Liu Tao 
Published: July 2016

Abstract
Speckle-type POZ protein (SPOP) is an E3 ubiquitin ligase adaptor protein that functions as a potential tumor suppressor, and SPOP mutations have been identified in ∼10% of human prostate cancers. However, it remains unclear if mutant SPOP proteins can be utilized as biomarkers for diagnosis, prognosis or targeted therapy of prostate cancer. To address this issue, selected reaction monitoring (SRM) and PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing) -SRM mass spectrometry assays have been developed for quantifying mutant SPOP proteins.
SRM assays for wild-type SPOP protein and 11 prostate cancer-derived mutations were developed. The presence of multiple lysine residues in the mutation regions precludes the use of conventional tryptic digestion. Arg-C was selected instead due to its superior performance in generating mutation site(s) containing SPOP peptides that are more suitable for SRM analysis comparing to other proteases (e.g., Asp-N). Although the resulting Arg-C peptides are longer and more hydrophobic than typical tryptic peptides, all the SRM assays showed a linear dynamic range of more than two orders of magnitude. The limits of quantification for the mutation site(s) containing peptides range from 10 to 100 fmol/μg of total protein in the cell lysate. Applying these SRM assays to analyze 293T cells with and without expression of the three most frequent SPOP mutations in prostate cancer (Y87N, F102C or F133V) led to confident detection of all three SPOP mutations in corresponding positive cell lines but not in the negative cell lines. Expression of the F133V mutation and wild-type SPOP was at much lower levels compared to that of F102C and Y87N mutations, which agrees with RT-PCR results. It is unknown if this is related to activity of the SPOP protein. PRISM-SRM assays have shown further improvement in sensitivity.
SRM enables multiplexed, isoform-specific detection of mutant SPOP proteins in cell lysates, which holds great potential in biomarker development for prostate cancer.
Citation Format: Hui Wang, Christopher Barbieri, Jintang He, Yuqian Gao, Chaochao Wu, Athena Schepmoes, Thomas Fillmore, Tujin Shi, Sung-Suk Chae, Dennis Huang, Juan Miguel Mosquera, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, David Camp, Karin Rodland, Mark Rubin, Tao Liu. Quantification of mutant SPOP proteins in prostate cancer using targeted proteomics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3872.
Abstract 3878: Proteomic approach to identify biomarkers for invasive cervix cancer: a prospective pilot study
Authors: Mysona David P. , Pyrzak Adam , Allen Jennifer , Sharma Ashok , Weinberger Paul , Rungruang Bunja , She Jin-Xiong , Ghamande Sharad 
Published: July 2016

Abstract
Objectives: Cervical cancer is the second most common cancer of women worldwide. In this prospective study, we attempted to identify a set of serum biomarkers, which could identify patients who have invasive cervical cancer and possibly help monitor disease status (recurrence, remission).
Methods: Luminex bead array was used to measure serum protein concentrations of 19 different, promising proteins in cervical cancer patients (n = 23) compared to women with precancerous lesions (CIN2-3) (n = 20), and patients with normal cervical cytology (n = 20) in this IRB approved prospective study. Cervical cancer (adenocarcinoma and squamous carcinoma) patients had blood samples drawn within 30 days of diagnosis and repeat blood samples taken on follow up visits after completing therapy. These results were correlated to clinical data and outcomes. Protein expression was confirmed by immunohistochemistry in patient samples.
Results: CIN and controls have very similar levels of serum proteins. Six proteins (CA153, OPG, CEA, IGFBP7, IGFBP4, and MMP-7) had significantly different levels in cervical cancer patients compared to controls and CIN (p &lt; 0.05) with Area Under the Curve values of 0.74, 0.77, 0.79, 0.83, 0.84, and 0.98 respectively. IGFBP4 had a sensitivity of 75% at 95% specificity for correctly identifying invasive disease. MMP-7 had a sensitivity of 92% at 95% specificity. MMP-7 was confirmed by IHC in patient specific cervical cancer tissue. ProteinAUCP valueSensitivity at 95% SpecificityMMP70.98 (0.96-0.99)5.29E-1392.11IGFBP40.84 (0.8-0.89)2.36E-0775IGFBP70.83 (0.78-0.87)6.23E-0757.89CEA0.79 (0.74-0.84)1.30E-0542.11OPG0.77 (0.72-0.82)3.80E-0535.14CA1530.74 (0.69-0.8)2.50E-047.89
Conclusions: Several serum proteins are significantly altered in cervical cancer patients compared to controls and CIN, and are worth studying for further clinical utility. MMP-7 may prove to be an important mediator of cervical cancer.
Citation Format: David P. Mysona, Adam Pyrzak, Jennifer Allen, Ashok Sharma, Paul Weinberger, Bunja Rungruang, Jin-Xiong She, Sharad Ghamande. Proteomic approach to identify biomarkers for invasive cervix cancer: a prospective pilot study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3878.
Abstract 3880: Quantitative human secretome: a technology to measure the expression levels of thousand of secreted proteins
Authors: Huang Ruo-Pan , Mao Yingqing , Huang RuoChun , Yen Haw-Han 
Published: July 2016

Abstract
The secretome constitutes an increasingly important category of proteins which are involved in a multitude of biological, physiological and pathological processes, and are thus a clinically relevant source for biomarkers and therapeutic targets. The development of cancer often leads to alterations in growth-stimulatory autocrine and paracrine signals which change the expression levels of secreted proteins such as growth factors, cytokines, chemokines, and angiogenic factors. There is thus an urgent need to develop high-content and high-throughput approaches to profile the secretome. Using a sandwich-based ELISA format, we have developed an antibody array technology which can quantitatively measure expression levels of 1000 secreted proteins. Most of the target proteins are detectable at pg/ml levels. We have also developed a multi-layered normalization process (including positive controls, standard curves, and reference samples) which significantly enhances the performance of the platform and may be used for accurate measurement of protein concentrations in a variety of samples, including serum, plasma, tissue lysates, and other fluids. This platform is also high throughput, allowing hundreds of samples to be assayed daily. We have analyzed several hundred serum samples (both normal and cancer patients) using this system. Our results demonstrate that our technologies provide a powerful approach for delineating candidate biomarkers with potential clinical significance and may be broadly applicable to cancer and other human diseases.
Citation Format: Ruo-Pan Huang, Yingqing Mao, RuoChun Huang, Haw-Han Yen. Quantitative human secretome: a technology to measure the expression levels of thousand of secreted proteins. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3880.
Abstract 3892: Unique pleural vs peritoneal mesothelioma exosomal signature: does mesothelial cell susceptibility to asbestos matter
Authors: Shukla Arti , Munson Phillip , Thompson Joyce K. , Dragon Julie , MacPherson Maximilian B. , Peinado Hector 
Published: July 2016

Abstract
Malignant mesothelioma (MM) is a cancer of mesothelial cells of the pleura or peritoneum caused exclusively by asbestos exposure. It is a deadly cancer which is only diagnosed at terminal stages, possibly due to the long latency period of development and lack of biomarkers for early diagnosis. Both pleural and peritoneal mesothelial cells can develop MM in response to asbestos, however, pleural MM (85%) is more common than peritoneal MM (15%). To get an insight of this difference we first isolated exosomes from pleural (Hmeso, H2373) and peritoneal (ORT) MM cells and performed proteomic analysis. We found that 45 proteins are common and specific to MM cells derived from pleural cavity (Hmeso/H2373) while 86 proteins are specific to ORT cells lines derived from peritoneal cavity. On the other hand, the non-transformed mesothelial cell line, LP9, showed a completely different profile with 269 proteins secreted in exosomes not shared with MM models. This led us to hypothesize that mesothelial cells of two different locations may have different susceptibility to asbestos, accounting for differences observed in pleural and peritoneal MM. To test this hypothesis we exposed human primary pleural and peritoneal mesothelial cells to asbestos for 8 h, and performed massively parallel sequencing on the RNA. Gene expression analysis performed on the RNA-Seq data showed a higher magnitude of responses from pleural mesothelial cells as compared to peritoneal mesothelial cells for the same genes. In addition, at a p&lt;0.05 and 2-fold threshold, unique genes expressed in pleural mesothelium were pro-inflammatory genes known to be involved in MM tumorigenesis. Taken together, results from our study suggest that exosomal cargo from pleural and peritoneal MM cells bear unique signatures which may be due to the different responses of pleural and peritoneal mesothelial cells to asbestos. Future directions involve assessing miRNA cargo from exosomes of pleural and peritoneal MM cells and identifying potential biomarker candidates. This work is supported by grants from NIH (RO1 ES021110), DoD (W81XWH-14-1-0199) and the University of Vermont Cancer Center/Lake Champlain Cancer Research Organization.
Citation Format: Arti Shukla, Phillip Munson, Joyce K. Thompson, Julie Dragon, Maximilian B. MacPherson, Hector Peinado. Unique pleural vs peritoneal mesothelioma exosomal signature: does mesothelial cell susceptibility to asbestos matter. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3892.
Abstract 3896: Novel in vivo pan-Hsp90 family protein inhibitor, Panvotinib-401, showed potent anticancer activities without HSF1 activation
Authors: Kang Byoung Heon 
Published: July 2016

Abstract
Hsp90 family proteins are implicated in tumorigenesis and many inhibitors have been developed as cancer therapeutics. The inhibitors showed potent inhibitory activities against purified Hsp90 family proteins, Grp94 and TRAP1, as well as Hsp90 in vitro. The mitochondrial TRAP1, however, is not inactivated in vivo due to insufficient drug accumulation in the mitochondria. Here, we showed that simultaneous inactivation of Hsp90 family proteins in different compartments can augment anticancer activity of the Hsp90 inhibitors. When simultaneously inhibited, cytoplasmic calcium elevation and activation of calcineurin inhibited HSF1 triggering heat shock responses such as cytoprotective Hsp70 induction. To improve anticancer efficacy of Hsp90 inhibitors, we developed a small molecule (∼380 Da) mitochondrial inner membrane-permeable Hsp90 inhibitor, and named it as Panvotinib-401, briefly Pan-401. Pan-401 showed much improved cancer-selective cytotoxic activity compared with Hsp90 inhibitors or mitochondria-targeted (accumulating) inhibitor, gamitrinib. Collectively, with improved subcellular distribution, cancer-specific cytotoxic activity of Hsp90 inhibitors can be further enhanced.
Citation Format: Byoung Heon Kang. Novel in vivo pan-Hsp90 family protein inhibitor, Panvotinib-401, showed potent anticancer activities without HSF1 activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3896.