tbuckley/cabot-search huggingface dataset:
Abstract 1269: Enhanced cytotoxicity in primary human metastatic melanoma cells via inhibition of the transient receptor potential melastatin-2 (TRPM2) channel
Authors: David W. Koh, Steven D. Blake, Daniel P. Powell
Journal: Cancer Research (2016)

Abstract The transient receptor potential melastatin-2 (TRPM2) cation channel was previously identified as a potential target in various cancers, where its pharmacologic inhibition caused increased DNA damage and the selective eradication of cancer cells. In this study, we utilized several human primary metastatic melanoma cell lines, in which we analyzed TRPM2 and its isoforms, and evaluated the ability of TRPM2 inhibition to modulate cell death. As TRPM2 is known to exist as a plasma membrane cation channel in noncancerous cells, we investigated the localization of TRPM2 in melanoma cells. In three lines of primary human metastatic melanoma cells, TRPM2 was localized in the nucleus, as compared to an extra-nuclear localization in noncancerous primary epidermal keratinocyes. Because TRPM2 exists in several isoforms in cancer cells, we investigated the cellular localization of these isoforms. Subcellular fractionations demonstrated that only full-length TRPM2 was localized to the nucleus in primary human metastatic melanoma cells, whereas two smaller isoforms were localized exclusively in the cytoplasmic fraction. Treatment with the TRPM2 inhibitor, clotrimazole, caused decreased proliferation in all three lines of primary human metastatic melanoma cells. Further, treatment with the DNA alkylating agent, temozolomide (TMZ), led to increased levels of cell death in melanoma cells pretreated with clotrimazole, but not in noncancerous primary epidermal keratinocyes after pretreatment. Similar increases in cell death were observed after RNAi silencing of TRPM2 followed by TMZ treatment. Taken together, this study demonstrated that TRPM2 inhibition selectively increases cell death in primary human metastatic melanoma cells. Further, the data suggests that, similar to our previous results in breast adenocarcinoma cells, full-length TRPM2 appears to have a novel role in melanoma cell growth and survival. The results therefore suggest that TRPM2 is a potential target in melanoma, where its inhibition may cause the selective eradication of metastatic melanoma. Citation Format: David W. Koh, Steven D. Blake, Daniel P. Powell. Enhanced cytotoxicity in primary human metastatic melanoma cells via inhibition of the transient receptor potential melastatin-2 (TRPM2) channel. [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 1269.
Abstract 2776: The relationship between UHRF1 overexpression and LINE-1 hypomethylation in esophageal squamous cell carcinoma
Authors: Kenichi Nakamura, Yoshifumi Baba, Keisuke Kosumi, Kazuto Harada, Hironobu Shigaki, Keisuke Miyake, Junji Kurashige, Takatsugu Ishimoto, Masaaki Iwatsuki, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2016)

Abstract Background: Global DNA hypomethylation contributes to oncogenesis through multiple mechanism. The level of long interspersed nucleotide element-1 (LINE-1) methylation is regarded as a surrogate marker of global DNA methylation, and is drawing interest as a good indicator for predicting cancer prognosis. However, the mechanism by which LINE-1 (global DNA) methylation is controlled in cancer cells remains to be fully explored. Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) plays an essential role in DNA methylation. Previous studies have demonstrated that UHRF1 overexpression might be a mechanism of underlying DNA hypomethylation in hepatocellular carcinoma, and contribute to poor prognosis. Nonetheless, the epigenetic role of UHRF1 in esophageal squamous cell carcinoma (ESCC) remains unclear. Methods: Using 16 frozen tissues (matched pairs of cancer and normal epithelium), and 160 curatively resected esophageal cancer specimens, we analyzed the relationship between UHRF1 expression, LINE-1 methylation levels and patient outcome. We measured UHRF1 expression by real-time PCR and immunohistochemistry, and LINE-1 methylation levels by bisulfite- pyrosequencing technology. In addition, to investigate the relationships between UHRF1 expression and LINE-1 methylation level (i.e., global DNA methylation level) using UHRF1 overexpression vector and siRNA for UHRF1 with ESCC tissues and ESCC cell lines. Results: In ESCC tissues, UHRF1 expression were significantly associated with LINE-1 methylation levels, and UHRF1 overexpression correlated with poor prognosis in our cohort of 160 ESCC patients. Furthermore, UHRF1 vector-mediated overexpression caused LINE-1 (global DNA) hypomethylation, and conversely, UHRF1 knockdown using siRNA increased DNA methylation in ESCC cell lines. Conclusion: These results may suggest that UHRF1 is an epigenetic key regulator of DNA methylation, moreover, can be applicable to attractive cancer therapies. Citation Format: Kenichi Nakamura, Yoshifumi Baba, Keisuke Kosumi, Kazuto Harada, Hironobu Shigaki, Keisuke Miyake, Junji Kurashige, Takatsugu Ishimoto, Masaaki Iwatsuki, Naoya Yoshida, Hideo Baba. The relationship between UHRF1 overexpression and LINE-1 hypomethylation in esophageal squamous cell carcinoma. [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 2776.
Abstract 1116: Contribution of miR-199a to subtype switching of the SW13 adrenocortical carcinoma cell line
Authors: Tracy Gerona, McKale Davis, Elizabeth Hull
Journal: Cancer Research (2016)

Abstract The human adrenocortical carcinoma SW13 cell line has two subtypes that are phenotypically distinct. The SW13- subtype is highly proliferative and epithelial-like, while the SW13+ subtype is slow growing, motile, and mesenchymal-like. These differences are mediated in part by the post-transcriptional regulation of BRM, which is expressed in SW13+ cells, and not detectable in SW13- cells. While treatment with histone deacetylase inhibitors (HDACi) can force cells to transition from SW13- to SW13+, the epigenetic mechanisms involved in the subtype switch are unknown. Recently, it was shown that miR-199a is a potent negative regulator of BRM expression in many epithelial tumor cell lines. Given this, we examined the expression of miR-199a in the two SW13 subtypes, and indeed found that miR-199a expression was significantly higher in the BRM-deficient SW13- cells than the BRM-expressing SW13+ cells. To begin to further assess the involvement of miR-199a in the SW13 subtype switch, SW13+ and SW13- cells were treated with either a miR-199a mimic or miR-199a inhibitor, respectively and assessed for differences in BRM mRNA and protein expression, as well changes in cell-type morphology. Our results indicate that although miR-199a can mediate differences in BRM expression, miR-199a alone is not sufficient to induce a full subtype conversion as evidenced by retention of subtype morphology following miR-199a inhibition and over-expression. We are currently investigating the role of miR-199a in HDACi mediated subtype conversion, as well as the expression of other miRNA and their targets that are differentially expressed between the two SW13 subtypes. Citation Format: Tracy Gerona, McKale Davis, Elizabeth Hull. Contribution of miR-199a to subtype switching of the SW13 adrenocortical carcinoma cell line. [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 1116.
Abstract 4772: Addiction to chaperones: Investigating the role of HSP70 isoforms in cancer
Authors: Lorna AB Suckling, Marissa Powers, Swee Sharp, Paul Workman
Journal: Cancer Research (2016)

Abstract The heat shock protein 70kDa (HSP70) family of molecular chaperones are critical for the survival of cancer cells due to their antiapoptotic activity and role in protein homeostasis. Our laboratory has previously shown that silencing two members of this family (HSP72 and HSC70) causes tumour cell specific apoptosis and also sensitises cancer cells to HSP90 inhibitors. HSP70 has therefore become an appealing therapeutic target. The human HSP70 family comprises 17 genes and the individual roles of the isoforms in cancer are poorly understood. Here we use a systematic approach to determine the importance of HSP70 isoforms, and a selection of HSP70 binding partners, for the growth of cancer cells under stress. It was hypothesised that cancer cells are more dependent on HSP70 proteins when under stressed conditions, as encountered in the tumour environment. We used RNA interference (RNAi) to determine the effect of silencing HSP70 isoforms and binding partners on cancer cell viability, as measured by CellTiter-Blue®. The siRNA screens were carried out in human colon (RKO) and breast (BT474) cancer cells under serum deprivation, oxidative stress and hypoxia. The silencing of several HSP70 genes, including the HSP70 isoform HSPA5 (also known as BiP/Grp78), were found to cause a reduction in cancer cell viability under stress. Detailed validation of hits has been carried out to confirm their importance for cancer cell survival and validated hits may provide potentially important therapeutic targets for cancer drug discovery. Citation Format: Lorna AB Suckling, Marissa Powers, Swee Sharp, Paul Workman. Addiction to chaperones: Investigating the role of HSP70 isoforms in 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 4772.
62P 89ZR-Bevacizumab Pet Imaging in Primary Breast Cancer
Authors: S.B.M. Gaykema, A.H. Brouwers, H. Timmer-Bosscha, M.N. Lub-de Hooge, S. van der Meulen, J. Bart, L. Jansen, J. de Vries, E.G.E. de Vries, C.P. Schröder
Journal: Annals of Oncology (2012)
Abstract 1876: Reduced Pak1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition
Authors: Olga Villamar-Cruz, Tatiana Prudnikova, Neil Johnson, Jonathan Chernoff, Luis E. Arias Romero
Journal: Cancer Research (2016)

Abstract Cells that are deficient in homologous recombination, such as those that have mutations in any of the Fanconi Anemia (FA)/BRCA pathway genes, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, FA/BRCA-deficient tumors represent only a small fraction of breast cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. p21-activated kinase 1 (Pak1) is a serine/threonine protein kinase located in the chromosome 11q13 and is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors. This enzyme controls many cellular processes by phosphorylating its downstream substrates; in addition to its role in the cytoplasm, Pak1 also affects gene transcription due to its nuclear localization and association with chromatin. It is now recognized that Pak1 activation is a component of the DNA damage response. Here, we show that depletion or inhibition of Pak1 down-regulated the expression of several genes involved in the FA/BRCA pathway and compromised the ability of cells to repair DNA by homologous recombination, induced cell cycle arrest, promoted apoptosis and resulted in reduced colony formation. Combined inhibition of Pak1 and PARP in pak1 amplified breast cancer cells had a synergistic effect, enhanced apoptosis, resulted in reduced colony formation and delayed tumor growth in a xenograft setting. Inhibition of Pak1 did not sensitize non-transformed or Pak1 non-amplified cells to inhibition of PARP. Because reduced Pak1 activity impaired FA/BRCA function and consequently, repair by homologous recombination, inhibition of this kinase in pak1 amplified and/or overexpressing breast cancer cells represents a plausible strategy for expanding the utility of PARP inhibitors to FA/BRCA-proficient cancers. Citation Format: Olga Villamar-Cruz, Tatiana Prudnikova, Neil Johnson, Jonathan Chernoff, Luis E. Arias Romero. Reduced Pak1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition. [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 1876.
Noncoronary Measures Enhance the Predictive Value of Cardiac CT Above Traditional Risk Factors and CAC Score in the General Population
Authors: Amir A. Mahabadi, Nils Lehmann, Stefan Möhlenkamp, Noreen Pundt, Iryna Dykun, Ulla Roggenbuck, Susanne Moebus, Karl-Heinz Jöckel, Raimund Erbel, Hagen Kälsch, Martin Nixdorf, Jur Gerhard Schmidt, D. Grönemeyer, R. Seibel, U. Slomiany, E.M. Beck, A. Öffner, S. Münkel, M. Bauer, S. Schrader, R. Peter, H. Hirche, K. Lauterbach, T. Meinertz, C. Bode, P.J. de Feyter, B. Güntert, F. Gutzwiller, H. Heinen, O. Hess, B. Klein, H. Löwel, M. Reiser, M. Schwaiger, C. Steinmüller, T. Theorell, S.N. Willich, C. Bode, K. Berger, M. Dichgans, H.R. Figulla, C. Hamm, P. Hanrath, W. Köpcke, E.B. Ringelstein, C. Weimar, A. Zeiher
Journal: JACC. Cardiovascular imaging (2016)
Abstract 3771: Discovery of a covalent inhibitor of ERK docking-interactions that inhibits A375 melanoma cells proliferation
Authors: Tamer S. Kaoud, William H. Johnson, Nancy D. Ebelt, Andrea Piserchio, Mangalika Warthaka, Micael Cano, Rachel Sammons, Qiantao Wang, Pengyu Ren, Ranajeet Ghose, Kevin N. Dalby
Journal: Cancer Research (2016)

Abstract Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Several ERK inhibitors have already entered clinical trials. Most of the available ERK inhibitors are reversible inhibitors that either act through an allosteric mechanism, or by targeting the ATP binding site. Taking advantage of our understanding of ERK-docking interactions we tried to discover an irreversible substrate-selective inhibitor that targets the protein-binding site of ERK. Here, we report the discovery of a covalent inhibitor of ERK that targets its protein-docking site. Protein NMR, Mass spectroscopy, mutagenesis and molecular docking studies indicate a covalent interaction of the inhibitor with a conserved cysteine residue, Cys-159. Extensive biochemical studies provide an estimate of its kinetic parameters and its kinase-selectivity profile. The new ERK inhibitor inhibits ERK activation, as well as its ability to phosphorylate downstream substrates (e.g. p90RSK and Elk-1) in HEK293T and A375 melanoma cells. The targeting of ERK in HEK293T cells was confirmed using a chemical-genetic approach where the ERK2 C159A mutant was used to rescue the effects of this compound on ERK2 signaling and cell proliferation. Currently, we are testing the effect of the compound on tumor growth inhibition in an A375 melanoma cancer xenografts model. This covalent inhibitor represents a potentially valuable lead molecule whose development may result in a novel class of pharmacologically useful ERK inhibitors for targeting resistant forms of melanoma. Citation Format: Tamer S. Kaoud, William H. Johnson, Nancy D. Ebelt, Andrea Piserchio, Mangalika Warthaka, Micael Cano, Rachel Sammons, Qiantao Wang, Pengyu Ren, Ranajeet Ghose, Kevin N. Dalby. Discovery of a covalent inhibitor of ERK docking-interactions that inhibits A375 melanoma cells proliferation. [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 3771.
Abstract 604: A multi-layered, hydrogel system for automated 3D high throughput drug screening of cancer-stromal cell co-cultures
Authors: Pamela E. Constantinou, Brian J. Engel, Lindsey K. Sablatura, Nathaniel J. Doty, Daniel D. Carson, Mary C. Farach-Carson, Daniel A. Harrington, Thomas I. Zarembinski
Journal: Cancer Research (2016)

Abstract Pre-clinical drug screens, involving culturing well-annotated cancer cell lines on two-dimensional (2D) tissue culture plastic, poorly recapitulate in vivo tumor characteristics and yield candidate drugs which fail clinical trials. We created a multi-layer, hyaluronic acid (HA)-based hydrogel system that incorporates three layers: an acellular cushion layer; an encapsulated cancer cell layer for growth in three dimensions (3D); and a collagen-containing layer that supports the growth of stromal cells on top of the hydrogel (2.5D). Utilizing high-throughput robotic delivery coupled with automated advanced imaging, this formulation provides a highly reproducible system for spheroid culture of prostate (C4-2B) or endometrial (Ishikawa) cancer cell lines in mono- or co-culture with matched stromal cells (HS27a or ESS-1, respectively). Both culture systems provided high cancer cell viability over one week of culture. Cells were treated with drugs from a panel of chemotherapeutic compounds. Cells cultured in our 3D multi-layer HA-based system responded to cytotoxic drugs distinctly from cells grown in 2D and 3D-aliginate, and better predicted the efficacy of chemotherapeutics in clinical trials. We have also successfully incorporated cells derived from patient derived xenograft (PDX) models in our 3D culture system. Wider adoption of 3D automated screening has the potential to speed drug discovery and increase success of drugs in clinical trials. Citation Format: Pamela E. Constantinou, Brian J. Engel, Lindsey K. Sablatura, Nathaniel J. Doty, Daniel D. Carson, Mary C. Farach-Carson, Daniel A. Harrington, Thomas I. Zarembinski. A multi-layered, hydrogel system for automated 3D high throughput drug screening of cancer-stromal cell co-cultures. [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 604.
Abstract 769: Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/â-catenin /STAT3 axis signalling pathway in human non-small cell lung carcinomas
Authors: Wen-Chien Huang.
Journal: Cancer Research (2016)

Abstract Innate or acquired drug resistance and consequently, tumor relapse in lung cancer patients have been linked to the activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that Garcinol, a polyisoprenylated benzophenone isolated from the fruiting bodies of Garcinia indica, possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory and anticancer activities, modulates the activities of lung cancer stem cells (LCSCs) and their associated aggressiveness. Here, we demonstrated the inhibitory effect of Garcinol on LCSC phenotype of human NSCLC cells by using the analytical drug cytotoxicity or cell viability, flow-cytometric and functional assay approach. Garcinol significantly diminished the ability of NSCLC cell lines, H441 and A549 to form spheres. In parallel assays, Garcinol inhibited differentiated lung cancer cell and LCSCs viability in a dose-dependent manner. Consistent with these observations, Flow cytometric data showed that Garcinol reduced putative LCSC pool, evidenced by the dose-dependent decreased proportion of side-population (SP) cells and associated ALDH activity in Garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that Garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, Garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In same assay, Garcinol downregulated â-catenin, Dvl2, Axin2, and Cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/â-catenin signalling pathway. Put together, we demonstrated here that Garcinol modulates the LCSC phenotype via regulation of the Wnt/â-catenin signalling and inactivation of STAT3, thus, presenting Garcinol as a putative novel anti-LCSC therapeutic agent. Keywords - Garcinol, non-small cell lung cancer, cancer stem cells, Wnt/â-catenin signalling pathway, anti-cancer therapy, STAT3 Citation Format: Wen-Chien Huang. Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/â-catenin /STAT3 axis signalling pathway in human non-small cell lung carcinomas. [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 769.
Analysis of DNA mismatch repair (MMR) and clinical outcome in stage III colon cancers from patients (pts) treated with adjuvant FOLFOX +/- cetuximab in the PETACC8 and NCCTG N0147 adjuvant trials.
Authors: Aziz Zaanan, Qian Shi, Julien Taieb, Steven R. Alberts, Thomas C. Smyrk, Catherine Julie, Ayman Zawadi, Josep Tabernero, Enrico Mini, Richard M. Goldberg, Gunnar Folprecht, Jean L. Van Laethem, Karine Le Malicot, Daniel J. Sargent, Pierre Laurent-Puig, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2015)

3506 Background: The prognostic impact of deficient (d) MMR, including sporadic and familial types, in stage III colon cancer pts receiving standard adjuvant FOLFOX therapy remains unknown. We examined the association of MMR status with clinical outcome in two phase III clinical trials of adjuvant FOLFOX +/- cetuximab. Methods: Prospectively collected tumors from both studies were separately analyzed for MMR protein (MLH1, MSH2, MSH6) expression and mutations in BRAF (V600E). Loss of any MMR protein indicated dMMR. Methylation of the MLH1 gene promoter was studied in tumors with loss of MLH1 and wild-type (WT) BRAF. Associations of MMR status with time-to-recurrence (TTR), disease-free survival (DFS) and overall survival (OS) were analyzed using a stratified Cox proportional hazards model. Multivariate models were adjusted for treatment and covariates (age, sex, tumor grade, T/N stage, tumor location, ECOG PS, BRAF/KRAS). Results: The frequency of dMMR in the overall cohort was 10.7% (499/ 4674). 3-year (yr) DFS for dMMR vs proficient (p) MMR pts was 75% vs 74% (HR = 0.87; 95% CI, 0.71-1.07; padustedj = .196). Among pts with complete biomarker data (N = 4339), there were 405 dMMR tumors of which 265 (65.4%) were categorized as sporadic (BRAF mutation or WT with MLH1 methylation) and 140 (34.6%) as familial (BRAF WT and unmethylated MLH1 or loss of MSH2 or MSH6). DFS rates of pts with sporadic and familial dMMR tumors were similar (HR, 1.15; 95% CI, 0.73-1.81; padjusted = .54). Pts with dMMR tumors had similar DFS rates as did pts with pMMR tumors without BRAF or KRAS mutations (Table). Consistent results were found for biomarkers and TTR and OS. Conclusions: In this large cohort of stage III colon cancer pts enrolled in two adjuvant trials testing FOLFOX +/- cetuximab, MMR status was not prognostic. Similar outcomes were found for sporadic and familial dMMR cases, and when each of these dMMR subtypes was compared to pMMR tumors WT for both BRAF and KRAS genes. Clinical trial information: NCT00079274. Variable N 3-yr DFS % HR (95% CI) Adjusted P value WT KRAS, WT BRAF, pMMR, 2205 78.1 Ref --- Sporadic dMMR 265 77.3 0.99 (0.73,1.32) 0.9263 Familial dMMR 140 77.6 0.86 (0.58,1.26) 0.4342