bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C187: Salicylates suppress tumor growth via inhibition of HMGB1.
Authors: Napolitano Andrea , Pellegrini Laura , Jube Sandro , Jennings Cormac J. , Flores Erin G. , Larson David , Negi Vishal S. , Pagano Ian , Tanji Mika , Powers Amy , Pastorino Sandra , Pass Harvey I. , Bianchi Marco E. , Carbone Michele , Yang Haining 
Published: August 2014

Abstract
High-Mobility Group Box 1 (HMGB1) is a chromatin-associated protein critically involved in nucleosome assembly. During cell necrosis, HMGB1 is first translocated from the nucleus to the cytoplasm, and then passively released to the extracellular space, where it initiates and propagates the inflammatory response. Immune cells (e.g. macrophages) and cancer cells are also able to actively secrete HMGB1. Extracellular HMGB1 is therefore considered a crucial molecule for both chronic inflammation and cancer development, and a promising therapeutic target.
In this study, using a malignant mesothelioma (MM) model, we tested the hypothesis that the known anti-cancer effects of aspirin (acetyl salicylic acid), the most widely used anti-inflammatory drug, and salicylic acid, its major metabolite, could be due to HMGB1 inhibition.
In vitro, we analyzed the effects of salicylates on HMGB1-induced MM cell proliferation, wound healing, migration, invasion and anchorage-independent colony formation. Moreover, using a MM xenograft model, we tested whether in vivo suppression of HMGB1 signaling by salicylates or BoxA, a specific HMGB1 inhibitor, resulted in reduced MM growth and increased survival.
Our results demonstrated that salicylates, at doses normally used in clinical practice (≤1 mM), significantly suppress HMGB1-induced in vitro pro-tumorigenic effects on MM cells and inhibits in vivo MM growth, significantly extending mice survival.
Our findings are critically relevant to the understanding of the poorly known anti-cancer effects of salicylates. From this perspective, they apply to more than 50 million people in the USA alone currently taking aspirin. Finally, these preclinical results could be translated to improve the current treatment of the usually lethal MM, and of other HMGB1-related malignancies as well.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C187.
Citation Format: Andrea Napolitano, Laura Pellegrini, Sandro Jube, Cormac J. Jennings, Erin G. Flores, David Larson, Vishal S. Negi, Ian Pagano, Mika Tanji, Amy Powers, Sandra Pastorino, Harvey I. Pass, Marco E. Bianchi, Michele Carbone, Haining Yang. Salicylates suppress tumor growth via inhibition of HMGB1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C187.
Abstract C231: Novel, fully-human GrB-containing constructs targeting the Fn14 receptor for TWEAK on solid tumor cells.
Authors: Zhou Hong , Migliorini Mary , Hittelman Walter , Ekmekcioglu Suhendan , Tran Nhan , LoBello Janine , Winkles Jeffrey A. , Rosenblum Michael G. 
Published: August 2014

Abstract
The TNFR superfamily member Fn14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), has emerged as a potentially clinically valuable target for cancer therapy. Fn14 expression was relatively low in normal tissues but was found to be elevated in various human solid tumor types, including brain, breast and melanoma, and can be a negative prognostic indicator. TMAs of melanoma patient tumors found elevated Fn14 expression in 173/190(92%) of primary specimens and 86/150(58%) of metastases. Studies are underway examining expression vs survival. Studies are also underway examining TNBC microarrays for expression as well. To target the Fn14 receptor, we constructed a novel chimeric protein designated granzyme B (GrB)-TWEAK, using the human TWEAK receptor-binding domain as a targeting moiety and the human Granzyme B as a cytotoxic domain. In addition, we developed a high mw(160kDa) fusion protein composed of a single-chain anti-Fn14 scFv and GrB(designated scIGB). Both fusion construct was expressed in mammalian cells and purified to homogeneity. BiaCore analysis of TWEAK, GrB-TWEAK and scIGB binding to the Fn14 extracellular domain indicated that these proteins bound to Fn14 with similar affinities(Kds of ∼ 3-8 nM). Confocal immunofluoresence studies showed that GrB-TWEAK and scIGB specifically and rapidly (within 3 hrs) internalized into Fn14-expressing MDA-MB-231 breast cancer and HT-29 colorectal adenocarcinoma cells. Against a panel of 26 human cancer cell lines in culture, GrB-TWEAK demonstrated impressive and selective cytotoxicity to Fn14-expressing cells in the low nanomolar range (IC50 ranged from 0.4 nM-330 nM) and were 6 to 1117 fold more potent than free GrB. Treatment of cells expressing the multidrug resistance protein MDR1 showed no cross-resistance to the fusion construct in vitro. Mechanistic studies demonstrated that GrB-TWEAK activated caspase cascades and cytochrome C related pro-apoptotic mechanisms in keeping with the known intracellular functions of GrB in target cells. Preliminary mouse xenograft tumor model studies are ongoing.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C231.
Citation Format: Hong Zhou, Mary Migliorini, Walter Hittelman, Suhendan Ekmekcioglu, Nhan Tran, Janine LoBello, Jeffrey A. Winkles, Michael G. Rosenblum. Novel, fully-human GrB-containing constructs targeting the Fn14 receptor for TWEAK on solid tumor cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C231.
Abstract C292: Inhibition of carbonic anhydrase (9 and 12) decreases cell proliferation and gene expression in human glioblastoma cell.
Authors: Teixeira Silvia A. , Pezuk Julia A. , Brassesco Maria S. , Carlotti Carlos G. , Tone Luiz G. , Scrideli Carlos A. 
Published: August 2014

Abstract
Propose: Glioblastoma (GB) is the most common and lethal malignant primary brain tumor, representing up to 50% of all primary brain gliomas, and carries the poorest prognosis. An important factor for tumor progression is the acidification of the environment that is promoted by carbonic anhydrases (CAs) 9 and 12, directing to the acquisition of metastatic phenotype and chemoresistance to anticancer drugs. Indisulam is a novel anticancer drug with potent inhibition of CAs. It has in vitro and in vivo activity and prevents cell cycle progression in tumor cells, downregulates genes involved in cytotoxic drug resistence and cell proliferation. The aim this study was to evaluate the expression and the effects of inhibition of the 9/12 CAs by indisulam in proliferation and in gene expression of GB cell lines subjected to normoxia or hypoxia.
Materials and Method: The U87-MG, U251, U138-MG, U343-MG-a adult GB cell lines were cultured in conditions of hypoxia or normoxia. Functional studies of cell proliferation and clonogenic capacity were performed in triplicate with Indisulan at different concentrations during 24, 48 and 72h. Gene expression of CA9, CA12, VEGF and HIF1α was assessed using qRT-PCR. Statistical analysis was made by one-way ANOVA and Bonferoni post-hoc.
Results: Indisulam displayed inhibitory characteristics to hypoxia induced CA9/CA12 expression in the four GBM cell lines. All experiments showed that the inhibition of CA9/12 with indisulam were dose- and time-dependent (p&lt;0.05) and caused a decreased on cell proliferation and the capacity clonogenic. The evaluation of gene expression in conditions of hypoxia (1%) compared to normoxia (preliminary experiments) showed increased expression to the genes CA9, CA12, HIF-1α and VEGF with decreased expression when the cells were treated with Indisulam.
Conclusion: Our results indicate antiproliferative and inhibitory effect of the indisulam in GB cell line on condition of normoxic and hypoxic. It suggests that indisulam may be an interesting candidate for the development antitumor therapies based on the inhibition of tumor-associated carbonic anhydrase.
Financial Support: FAPESP
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C292.
Citation Format: Silvia A. Teixeira, Julia A. Pezuk, Maria S. Brassesco, Carlos G. Carlotti, Luiz G. Tone, Carlos A. Scrideli. Inhibition of carbonic anhydrase (9 and 12) decreases cell proliferation and gene expression in human glioblastoma cell. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C292.
Abstract C52: A novel combinatorial treatment for glioblastoma of temozolomide and JLK1486.
Authors: Weatherbee Jessica L. , Kraus Jean-Louis , Moser Richard P. , Ross Alonzo H. 
Published: August 2014

Abstract
Background: Glioblastoma multiforme (GBM) is a grade IV brain tumor characterized by a heterogeneous population of cells that are highly invasive and resistant to chemotherapeutic treatments. The current standard of care, comprised of surgical resection followed by radiation and chemotherapy, only provides GBM patients with a 12-14 month survival period. Our lab is currently investigating the potential therapeutic combination of temozolomide, the chemotherapeutic agent currently used to treat GBM patients, with a novel agent, JLK1486, to determine if this combination decreases or inhibits tumor recurrence in vitro.
Materials and Methods: GBM neurospheres and primary lines were treated with single or combination treatments of temozolomide (TMZ) and/or JLK1486. Spheres were counted on day 7 to determine initial sphere formation, re-counted on day 14 to determine recovery, and were then pH dissociated and counted on day 21 to determine secondary sphere formation.
Results: Our lab found that neither TMZ nor JLK1486 alone eliminated secondary sphere formation. When cells were treated with a single dose of both TMZ+JLK1486 on day 0 secondary sphere formation was not inhibited. However, when cells where treated with TMZ+JLK1486 on day 0 and then dosed a second time with JLK1486 on day 7, secondary sphere formation was significantly reduced in double versus single agent treated cells. At least part of the enhanced efficacy of TMZ and JLK1486 involves activation of the unfolded protein response (UPR), which in turn increases expression of CHOP and induces apoptosis.
Conclusion: Combining novel chemotherapeutic agents with the current standard of chemotherapeutic care, TMZ, may not only inhibit tumor growth but also tumor recurrence. Our lab found that when a novel chemotherapeutic agent, JLK1486, was combined with TMZ, secondary sphere formation was inhibited, suggesting that dual treatment is more efficacious than single agent in inhibiting secondary sphere formation and may reduce tumor recurrence. Combined therapy of UPR-inducing agents with chemotherapy is a promising approach to enhance efficacy by eliminating the few surviving cells that allow formation of secondary spheres and, perhaps, tumor recurrence.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C52.
Citation Format: Jessica L. Weatherbee, Jean-Louis Kraus, Richard P. Moser, Alonzo H. Ross. A novel combinatorial treatment for glioblastoma of temozolomide and JLK1486. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C52.
Abstract CN03-03: Use of the zebrafish for studying cancer genetics.
Authors: Zon Leonard I. 
Published: August 2014

Abstract
Melanoma is a devastating disease and there are few therapies that lead to substantial long-term remission for metastatic disease. We have created a zebrafish model of melanoma by overexpressing BRAF-V600E in the combination of P53 mutation. This fish develops melanoma at a characteristic rate and the tumors greatly resemble those of human melanomas. Examination of gene expression in the melanomas demonstrated neural crest transcription factor expression in the zebrafish melanomas. A neural crest marker called Crestin was substantially upregulated in the tumors compared to adjacent skin. A chemical screen was undertaken to find small molecules that prevent neural crest development during embryogenesis in the zebrafish, hoping to find a small molecule that would inhibit the gene expression signature in the tumor. A drug called leflunomide was found to inhibit transcription elongation in the crest and also in human melanomas. Combination of a BRAF inhibitor plus leflunomide led to a substantial decrease in human tumors when placed into nude mice. A Phase II clinical trial has been undertaken using the combination of BRAF inhibitor and leflunomide. Leflunomide has an important effect on transcription elongation that is dependent on a new tumor suppressor complex called the HEXIM complex. Inactivation of the HEXIM complex interferes with the effect of the drug. HEXIM has also been shown to be a tumor suppressor in our zebrafish model system. In an effort to understand the effects of leflunomide, we undertook a screen for a chemical suppressor of leflunomide. This demonstrated pathways that affected drug metabolism as well as transcription elongation. Our studies demonstrate a novel pathway for interrupting cancer development by blocking transcription elongation in combination with BRAF inhibitors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN03-03.
Citation Format: Leonard I. Zon. Use of the zebrafish for studying cancer genetics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN03-03.
Abstract CN04-01: Poking cancer cells with BH3 profiling to personalize cancer therapy.
Authors: Montero Joan , Ni Chonghaile Triona , Sarosiek Kris , Ryan Jeremy A. , Leah Hogdal , Letai Anthony G. 
Published: August 2014

Abstract
Nearly all attempts to understand and predict response of patient cancer cells to therapeutics rely on measurements of static properties at a single time point such as protein abundance, gene expression profiling, or genetic code. While these approaches have doubtless yielded useful information to guide therapy, it is often the case that observing how a system responds to systematic perturbation can be a more powerful guide to understanding and predicting behavior. Using BH3 profiling, we systematically perturb the mitochondria of cancer cells with BH3 peptides and can make predictions about response to therapy based on the response observed. So far, we have successfully applied BH3 profiling to understanding and predicting clinical response to conventional chemotherapy, targeted pathway inhibitors and direct inhibitors of anti-apoptotic proteins like BCL-2. Since BH3 profiling can provide results within a single day, it is applicable to studying primary cancer cells from patient biopsies without the need for prolonged ex vivo culture. BH3 profiling has the potential to provide a predictive biomarker for any cancer therapeutic that kills cancer cells via the mitochondrial pathway of apoptosis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN04-01.
Citation Format: Joan Montero, Triona Ni Chonghaile, Kris Sarosiek, Jeremy A. Ryan, Hogdal Leah, Anthony G. Letai. Poking cancer cells with BH3 profiling to personalize cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN04-01.
Abstract CN05-03: Targeting oncogene-induced DNA damage for cancer therapy.
Authors: Fernandez-Capetillo Oscar 
Published: August 2014

Abstract
Our laboratory has focused much of its research in trying to understand how cells respond to "replicative stress" (RS), a type of DNA damage which arises unavoidably every time that a cell replicates its DNA, and which is mainly prevented by a RS-Response (RSR) coordinated by ATR and Chk1 kinases.
Given that certain oncogenes can generate substantial amounts of RS, we hypothesized that cells carrying these oncogenes might be “addicted” to a proficient RSR. To explore these ideas, we have generated several cellular, animal and chemical tools for the study of ATR function in mammals. These include (1) a cell system in which ATR can be selectively activated at will; (2) mice with a reduced or increased RSR, and (3) chemical inhibitors of ATR. Our early works suggested that ATR inhibitors would indeed be particularly deleterious for tumors with high levels of RS, such as those induced by the Myc oncogene. Our ideas and new results in this area will be presented.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN05-03.
Citation Format: Oscar Fernandez-Capetillo. Targeting oncogene-induced DNA damage for cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN05-03.
Abstract PL03-03: Designing p300/CBP histone acetyltransferase inhibitors for cancer.
Authors: Cole Philip A. 
Published: August 2014

Abstract
The transcriptional coactivator p300/CBP catalyzes protein lysine acetylation on histones and other proteins and has been implicated in a wide array of physiologic and pathologic processes including cancer. In contrast to HDACS, methyltransferases, and bromodomains, it has historically been difficult to identify drug-like small molecules as potent histone acetyltransferase inhibitors. We will discuss our longstanding effort to design selective p300/CBP acetyltransferase inhibitors using enzymologic and structural considerations. We will provide current pharmacodynamic and pharmacokinetic properties of our most recent p300/CBP inhibitors and future directions related to anticancer therapies. We will also highlight the use of protein microarrays as a tool to understand the regulation and substrate profile of p300/CBP protein acetylation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL03-03.
Citation Format: Philip A. Cole. Designing p300/CBP histone acetyltransferase inhibitors for cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL03-03.
Abstract LB-185: Oxidative damage targets complexes containing DNA methyltransferases, SIRT1 and polycomb members to promoter CpG islands
Authors: O'Hagan Heather M. , Wang Wei , Sen Subhojit , Lee Stella S. , Clements Eriko G. , Cai Yi , Van Neste Leander , Easwaran Hariharan , Baylin Stephen B. 
Published: August 2014

Abstract
A key question in cancer epigenetics is how cancers of multiple types simultaneously acquire global losses and gains of DNA methylation. The increases often occur in promoter CpG islands and can be associated with transcriptional inactivation of key tumor suppressor genes. Here we demonstrate a molecular response to oxidative damage, a key factor in cancer risk states, which could help explain the gains and losses of DNA methylation that occur during tumor progression. Within 30 minutes of exposing cells to the reactive oxygen species, hydrogen peroxide (H2O2), the major maintenance enzyme for DNA methylation, DNMT1, becomes notably more tightly bound to chromatin. Concomitantly, DNMT1 targets SIRT1 to chromatin and both proteins become part of a large multi-protein complex(es) which also contains the de novo DNA methyltransferase, DNMT3B. This oxidative damage-induced complex also contains specific polycomb group members, which, in the context of SIRT1, define the Polycomb Repressive Complex 4 (PRC4), previously found only in embryonic and adult stem cells and cancer cells. By examining chromatin on a genome-wide scale, we demonstrate that H2O2 treatment preferentially damages GC-rich regions of DNA. This damage causes a shift in localization of the above complex(es) from non-GC-rich to GC-rich regions of the genome including promoter CpG islands of which some are DNA hypermethylated in cancer cells. Additionally, this treatment causes a decrease in nascent RNA transcript levels of these genes that have oxidative damage-induced enrichment of the silencing complex in their CpG island-containing promoters. Thus, oxidative damage induces formation and localization of a silencing complex that may in part explain cancer specific aberrant losses and gains in DNA methylation associated with gene transcriptional silencing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-185. doi:10.1158/1538-7445.AM2011-LB-185
Abstract 103: A prospective study of plasma inflammatory markers and risk of colorectal cancer in men.
Authors: Song Mingyang , Wu Kana , Ogino Shuji , Fuchs Charles S. , Giovannucci Edward L. , Chan Andrew T. 
Published: August 2014

Abstract
Chronic inflammation may mediate risk of colorectal cancer (CRC); however, the association between circulating inflammatory markers and risk of CRC has been inconsistent. We prospectively evaluated the association of plasma C-reactive protein (CRP), interleukin-6 (IL-6), and the soluble tumor necrosis factor receptor 2 (sTNFR-2) with incident CRC among 18,225 men in the Health Professionals Follow-up Study who provided blood samples in 1994. Through 2008, we documented 274 CRC cases and matched up to 2 controls by age and date of blood draw. We used conditional logistic regression to estimate relative risks (RRs) and confidence intervals (CIs). Compared to men in the lowest quartile of plasma IL-6 (Q1), men in the highest quartile (Q4) had a multivariate RR for CRC of 1.54 (95% CI, 0.99-2.40; Ptrend = .02). However, after excluding cases diagnosed within 2 years of blood draw, the association was substantially attenuated (Q4 versus Q1, RR = 1.26, 95% CI = 0.78-2.05; Ptrend = .21). In analyses restricted to cases diagnosed at least 2 years after blood draw, the association of IL-6 with CRC appeared to differ by body mass index such that the significantly positive association was only present among lean individuals (Pinteraction = .03). We did not observe any significant association between CRP or sTNFR-2 and CRC. Taken together, plasma inflammatory markers are not generally associated with risk of CRC among men. However, the possibility that plasma IL-6 is associated with increased risk of CRC among lean men requires further investigation.
Citation Format: Mingyang Song, Kana Wu, Shuji Ogino, Charles S. Fuchs, Edward L. Giovannucci, Andrew T. Chan. A prospective study of plasma inflammatory markers and risk of colorectal cancer in men. [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 103. doi:10.1158/1538-7445.AM2013-103