bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5456: The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer.
Authors: Qi Jianfei , Tripathi Manisha , Sahgal Natasha , Fazil Ladan , Ettinger Susan , Placzek William J. , Claps Giuseppina , Chung Leland W.K. , Bowtell David , Gleave Martin , Bhowmick Neil , Ronai Ze'ev 
Published: August 2014

Abstract
The androgen receptor (AR) plays a central role in the development of castration-resistant prostate cancer (CRPC), which is a major challenge for hormone therapy of advanced/metastatic prostate cancer (PCa). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination-dependent degradation, and this promotes the subsequent recruitment of p300-bound, transcriptionally active AR to a select group of AR target gene promoters/enhancers. Consequently, Siah2 promotes the expression of ∼13% of androgen-responsive genes involved in lipid metabolism, cell motility and proliferation. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under the androgen-deprivation condition in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity.
Citation Format: Jianfei Qi, Manisha Tripathi, Natasha Sahgal, Ladan Fazil, Susan Ettinger, William J. Placzek, Giuseppina Claps, Leland W.K. Chung, David Bowtell, Martin Gleave, Neil Bhowmick, Ze'ev Ronai. The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5456. doi:10.1158/1538-7445.AM2013-5456
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5468: Interaction between cetuximab and chemotherapy in colon cancer.
Authors: Santoro Valeria , Hartley John A. , Hochhauser Daniel 
Published: August 2014

Abstract
The epidermal growth factor receptor (EGFR) is overexpressed in many tumours and is a target for cancer therapy. Cetuximab is a monoclonal antibody targeting EGFR. It is used for the treatment of metastatic colorectal cancer (mCRC) as monotherapy and in combination with oxaliplatin or irinotecan-based chemotherapy. Several clinical studies have shown no benefit when cetuximab is combined with oxaliplatin as opposed to the positive effects observed with irinotecan. The aim of this study is to investigate these interactions in cellular models of colon cancer.
The antitumour effects of cetuximab in vitro in combination with oxaliplatin or irinotecan were determined in the SW 48 colon cancer cell line and the isogenic KRAS mutant G12A cell line. Combination indices (CI) describing the interaction of a fixed concentration of cetuximab and a range of concentrations of oxaliplatin or irinotecan were determined. Combination of cetuximab (100μg/ml) with oxaliplatin (1μM) indicated antagonism in both cell lines tested (CI=4.7 in the KRAS wild type cell line and CI=19.9 in the KRAS G12A cell line). In contrast, the combination of cetuximab (100μg/ml) with irinotecan (0.1μM) showed synergistic effects (CI=0.28 in the KRAS wild type cell line and CI=0.14 in the KRAS G12A cell line). Preclinical studies have suggested that the cytotoxic efficacy of oxaliplatin may depend partially on the production of Reactive Oxygen Species (ROS). The combination of cetuximab with oxaliplatin resulted in a reduction of ROS levels by 30% ± 2.9 in the KRAS WT and by 40% ± 10 in the KRAS G12A cell line compared to those produced by oxaliplatin alone. Additionally, levels of oxaliplatin-induced apoptosis measured by caspase 3/7 cleavage, were reduced by 70% ± 5.4 in the KRAS WT and by 50% ± 2.7 in the KRAS G12A cell line with the antioxidant N-acetyl-cysteine (NAC), suggesting that oxaliplatin induces apoptosis through the production of ROS. To elucidate the mechanism of the modulation of ROS by cetuximab and oxaliplatin, RT-PCR arrays analyzing 84 genes involved in oxidative stress response were performed following cetuximab, oxaliplatin and their combination treatment. Experiments to determine the contribution of these genes to the antagonism between oxaliplatin and cetuximab are under investigation.
Our results show that alteration of ROS levels by cetuximab affects efficacy of oxaliplatin and suggests a key role for ROS in the observed antagonism between the two drugs.
Citation Format: Valeria Santoro, John A. Hartley, Daniel Hochhauser. Interaction between cetuximab and chemotherapy in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5468. doi:10.1158/1538-7445.AM2013-5468
Abstract 5470: Pre-clinical characterization of ARGX-110: A neutralizing, humanized monoclonal antibody to the human CD70 antigen with enhanced ADCC properties.
Authors: Silence Karen , De Haard Hans , Dreier Torston , Ulrichts Peter , Moshir Mahan , Gabriels Sofie , Thibault Alain 
Published: August 2014

Abstract
The expression of CD70 is normally restricted to activated B- and T- cells, as well as mature dendritic cells. Overexpression has been documented in a variety of solid and hematological tumors, where it is thought to play a role in evasion of immune surveillance. ARGX-110 is a defucosylated, humanized IgG1 monoclonal antibody that selectively targets and neutralizes CD70, a ligand of CD27. A detailed biological and functional characterization of ARGX-110 was carried out to support its clinical development for the treatment of cancers dependent on signaling through the CD70/CD27 axis. In competitive equilibrium binding experiments, ARGX-110 bound to human and cynomolgus monkey CD70 with affinities of approximately 0.4 nmol/L and 0.6 nmol/L, respectively. ARGX-110 inhibited in a dose-dependent fashion CD70/CD27-induced IL-8 release in Raji cells with IC50 values of 0.1 nmol/L. CD70 is minimally internalized (&lt;40%) by most hematological cell lines, thus providing a plausible rationale to develop a therapeutic mAb designed to enhance ADCC. In cell depletion studies, ARGX-110 was associated with comparable to better cell lysis compared to Rituximab. Cell lysis by ARGX-110 was not dependent on the internalization rate of the ARGX-110/CD70 complex in hematological cell lines. Independence from CD70 copy numbers at the cell surface was also demonstrated. In a Burkitt lymphoma (CD70+ Raji cells) SCID mouse model, ARGX-110 administered intraperitoneally twice weekly at doses ranging from 0.001 to 10 mg/kg starting one day after inoculation resulted in a dose-response effect on animal survival. In cynomolgus monkeys, ARGX-110 did not demonstrate any toxicity upon repeated administration of high doses of 30 mg/kg. B, T and NK cell numbers remained unaltered. ARGX-110 is currently in phase I clinical trial for patients with CD70+ malignancies.
Citation Format: Karen Silence, Hans De Haard, Torston Dreier, Peter Ulrichts, Mahan Moshir, Sofie Gabriels, Alain Thibault. Pre-clinical characterization of ARGX-110: A neutralizing, humanized monoclonal antibody to the human CD70 antigen with enhanced ADCC properties. [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 5470. doi:10.1158/1538-7445.AM2013-5470
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5517: MD-164 strongly inhibited various tumor cells and also metastasis of pancreatic tumor cells via modulation of Arp2/3 complexes.
Authors: Kwon Byoung-Mog , Han Young Min 
Published: August 2014

Abstract
Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology in Korea Daejon 305-806, Republic of Korea
The most difficult problem in the treatment of cancer patients is a metastatic recurrence. We focused to find novel anti-metastatic chemicals without cytotoxicity. In preliminary results, more than 800 commercially available pharmaceuticals and pre-clinical drugs were screened to identify inhibitors of tumor cell migration that are intimately tied to the steps of metastasis. The ARP2/3 complex which induces actin-polymerization and Y-branching is an essential element for lamellipodia, invadopodia and filopodia at the early stages of the metastasis in cells. Two classes of small molecule inhibitors of Arp2/3 were reported. However, inhibitors of ARPC1∼5 subunit have not yet been reported. Regulating the ARPC1∼5 subunits for inhibition of actin polymerization by utilizing small molecules will benefit actin based cell migration research. Furthermore, Inhibitors of specific ARPC1∼5 subunit are highly advantageous for developing anti-metastasis drug without toxicity and side effects. As a result of the screening, MD-164 was found to effectively reduce migration and invasion in various cancer cell lines by targeting an ARP2/3 complex subunit2, a component of actin related protein complex 2/3 (ARP 2/3). When AsPc-1 cells stably expressing luciferase were injected into the tail vein of the mice and the mice were treated with MD164, MD164 inhibited lung metastases about 70%.
Citation Format: Byoung-Mog Kwon, Young Min Han. MD-164 strongly inhibited various tumor cells and also metastasis of pancreatic tumor cells via modulation of Arp2/3 complexes. [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 5517. doi:10.1158/1538-7445.AM2013-5517
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 552: The role of the mTORC1/S6K1 signaling pathway in ER-positive breast cancer.
Authors: Sedletcaia Anya , Unger Helen A. , Snyder Rose B. , Holz Marina K. 
Published: August 2014

Abstract
The mammalian target of rapamycin complex 1 (mTORC1) is a central signaling node in mediating cellular responses to mitogens, hormones and nutrients. The 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt, RSK and many others. S6K1 is the principal kinase effector downstream mTORC1. S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels, and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis, and cell migration and invasion.
Growing evidence indicates that there exists a close interaction between the mTORC1/S6K1 pathway and estrogen receptor (ER) signaling. Notably, endocrine resistance is often associated with ligand-independent activation of ERα signaling due to hyperactivation of the mTORC1 signaling pathway, and can be reversed by the mTORC1 inhibitor everolimus in vitro.
Several lines of evidence suggest an important role for S6K1 in ER-positive breast cancer. We demonstrated that S6K1 directly phosphorylates ERα on Ser167, leading to activation of its transcriptional activity. While the MAPK-regulated p90 RSK also contributes to phosphorylation of this site, its contribution is early and transient, while the phosphorylation of Ser167 by S6K1 is prolonged and sustained. Intriguingly, we also found that S6K1 expression is estrogenically regulated by a mechanism that involves the transcription factor GATA-3. Thus it appears that S6K1 expression is maintained in two modes: a basal level of expression, typical of normal cells, and an estrogen/ERα-dependent specific upregulation. Therefore, there exists a feed-forward regulatory loop whereby S6K1 activates ERα transcriptional activity, leading to increased expression of S6K1. Our current work aims to uncover the mechanistic details of the transcriptional regulation of S6K1 expression, to delineate signaling cross-talk between mTORC1, S6K1 and ERα, and to asses whether inhibition of S6K1 overexpression and activation affects the development and progression of breast cancer.
Citation Format: Anya Sedletcaia, Helen A. Unger, Rose B. Snyder, Marina K. Holz. The role of the mTORC1/S6K1 signaling pathway in ER-positive breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 552. doi:10.1158/1538-7445.AM2013-552
Abstract 5526: Mass-action law algorithm-based computer simulation for efficient and econo-green cancer drug discovery and development.
Authors: Chou Ting-Chao 
Published: August 2014

Abstract
Physico-chemical principle of the mass-action law algorithm (MALA) is the basis for systematic pharmacodynamics (PD) that leads to general median-effect equation (MEE) for single entity effect and the combination index equation (CIE) for multiple entity interactions (Chou TC, Pharmacol. Rev. 58: 621-681, 2006; Free web access: http://pharmrev.aspetjournals.org/content/58/3/621). “Median” is the common-link and universal reference point for single and multiple entities and for 1st-order and higher-order dynamics. Median is also the harmonic mean of kinetic constants where the harmony is the state of pure non-competitiveness [Chou, Nature Precedings (npre.2008.2064-2). Available free at http://precedings.nature.com/documents/2064/version/2]. Based on MEE, all dose-effect curves whether hyperbolic or sigmoidal, weak or strong, 1st-order or higher-order, in vitro or in vivo, can be linearlized by the median-effect plot with small number of data points in small size experiments (Chou, J. Theor. Biol. 59: 253-276, 1976; Pharmacol. Rev. .ibid). Based on CIE, CI&lt;1, =1, and &gt;1 quantitatively indicates synergism, additive effect, and antagonism, respectively (Chou & Talalay, Adv. Enz. Regul. 22: 27-55, 1984; Cancer Res. 70: 440-446, 2011). Thus. MEE is the common denominator for simple and complex bio-systems in vitro, in animal and in clinics. Computerized simulation of MEE or CIE can take &lt;1 second, and the graphics can be drawn automatically (CompuSyn, www.combosyn.com, Free download). Applying this theory in this author's laboratory (personnel &lt; 5 for decades) has published 253 articles that have been cited 13,749 times in over 523 different biomedical journals with h-index of 55 (Thomson Reuters Web of Science, www.researcherid.com/rid/B-4111-2009) along with 30 US patents. Thus, MALA-PD theory is the common denominator for integrating complex bio-systems and its computerized simulation have proven to lead to efficient, quantitative and econo-green bio-research and new drug discovery and development as illustrated in Chou, Integr. Biol. 3: 548-559, 2011; DOI: 10.1039/c0ib00130a and in Am. J. Cancer Res. 1(7): 925-954, 2011, Free web access: www.ajcr.us.
Citation Format: Ting-Chao Chou. Mass-action law algorithm-based computer simulation for efficient and econo-green cancer drug discovery and development. [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 5526. doi:10.1158/1538-7445.AM2013-5526
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5560: Characterization of a new non-steroidal small molecule inhibitor of CYP17 for castration-resistant prostate cancer.
Authors: Oehlen Bert , McCormack Siobhan , Ma Gaifeng , Lim Dong Sung , Panicker Bijoy , Goldberg Itzhak D. 
Published: August 2014

Abstract
Prostate cancer affects 1 in 6 men and is the second most common cause of cancer-related death. Since the majority of prostate cancers critically depend on androgens for growth, androgen deprivation therapy is a frontline treatment for advanced prostate cancer. The majority of prostate tumors initially respond to androgen deprivation therapy, but eventually the disease often progresses to castration-resistant prostate cancer. However, the current therapies that only reduce androgen produced in the testis do not affect androgen produced by adrenal glands can also produce androgens. This extra-testicular androgen production is thought to be a key factor in the development of castration resistant prostate cancer. CYP17 is a P450 enzyme that catalyzes the last step of androgen biosynthesis in both the testis and the adrenals. Inhibition of CYP17 therefore completely blocks androgen production and it is thus thought to be more effective to prevent prostate cancer progression than current therapies.
Angion Biomedica has identified a promising series of proprietary non-steroidal CYP17 inhibitors. Our lead compound is potent, orally bioavailable, and significantly reduces serum testosterone levels in mice. Treatment of rats and mice with our lead CYP17 inhibitor significantly reduces the weights of androgen dependent organs. In two mouse xenograft models of androgen-dependent tumor growth our lead CYP17 inhibitor markedly reduces primary tumor growth, serum testosterone and PSA levels. Angion is currently further evaluating the therapeutic potential of this series of compounds as a possible therapy for castration resistant prostate cancer.
Citation Format: Bert Oehlen, Siobhan McCormack, Gaifeng Ma, Dong Sung Lim, Bijoy Panicker, Itzhak D. Goldberg. Characterization of a new non-steroidal small molecule inhibitor of CYP17 for castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5560. doi:10.1158/1538-7445.AM2013-5560
Abstract 5564: Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis.
Authors: Wang Ying , Cheryan Vino T. , Jamal Shazia , Chen Di , Yang Huanjie , Polin Lisa A. , Pass Harvey I. , Dou Q Ping , Sharma Sunita , Rishi Arun K. , Wali Anil 
Published: August 2014

Abstract
Disulfiram (DSF) is a member of the dithiocarbamate family of compounds that bind with copper and function as inhibitor of aldehyde dehydrogenase. DSF is one of the drugs approved by Food and Drug Administration for treatment of alcoholism. Recent studies have indicated anti-tumor and chemosensitizing properties of DSF. However, the molecular mechanisms of DSF action remain unclear. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of DSF and the molecular mechanisms involved. DSF inhibited growth of the murine as well as patient-derived MPM cells in part by decreasing the chymotryptic activity of the proteasome that resulted in accumulation of ubiquitinated proteins. DSF suppression of MPM growth also involved elevated apoptosis as evidenced by activation of caspase-3, elevated levels of pro-apoptotic Bax protein and cleavage of poly-(ADP-ribose)-polymerase. Our studies including gene-array based analyses further revealed that DSF suppressed a number of cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10. DSF treatments also stimulated expression of sulfatase 1, growth arrest-specific (GAS) 6 protein, and CARP-1/CCAR1, a novel transducer of cell growth signaling. Administration of 50mg/kg DSF by daily i.p injections inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating cell growth arrest and apoptosis. Together our in vitro and in vivo studies suggest that DSF suppresses MPM growth by targeting multiple pathways that include blockage of metastasis signaling and stimulation of apoptosis, and thus holds promise as an anti-MPM agent.
Citation Format: Ying Wang, Vino T. Cheryan, Shazia Jamal, Di Chen, Huanjie Yang, Lisa A. Polin, Harvey I. Pass, Q Ping Dou, Sunita Sharma, Arun K. Rishi, Anil Wali. Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis. [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 5564. doi:10.1158/1538-7445.AM2013-5564
Abstract 5569: Tumor Treating Fields inhibit the growth of pancreatic and ovarian cancer in preclinical models .
Authors: Giladi Moshe , Schneiderman Rosa S. , Porat Yaara , Munster Mijal , Itzhaki Aviran , Mordechovich Daniel , Cahal Shay , Weinberg Uri , Kirson Eilon D. , Palti Yoram 
Published: August 2014

Abstract
Tumor Treating Fields (TTFields) therapy is an established anti-mitotic treatment modality. The Novo TTF-100A system, which delivers TTFields to the brain received FDA approval for the treatment of patients with Recurrent Glioblastoma (GBM) Brain Tumors. The goal of the present study is to test whether TTFields therapy is effective as a treatment in pre-clinical models of pancreatic and ovarian cancer.
TTFields of various frequencies were applied for 72h to cancerous tumor cells using two pairs of perpendicular insulated electrodes. Pancreatic adenocarcinoma and ovarian carcinoma culture growth was significantly reduced compared to controls (65%+10% and 21%+13%, respectively) with a maximal inhibitory effect seen at 150 and 200 kHz (respectively). The surviving cells exhibited increased cell volume (35%+11% and 61%+43% for pancreatic and ovarian cell lines, respectively) and a reduced viability. Fluorescence microscopy and FACS analysis revealed abnormal mitotic figure in the treated cells cultures and an increase in the 4N population, suggesting these cells failed to complete mitosis. Yet, the increase in the 4N cells fraction was too small to explain for the observed increase in cell volume in the entire remaining cell population. Combining TTFields with gemcitabine and paclitaxel commonly used for the treatment of pancreatic and ovarian cancer, enhanced treatment efficacy and led to a further increase in cell volume.
The efficacy of TTFields either alone or in combination with 5FU or gemcitabine was tested in hamsters bearing syngeneic, orthotopic pancreatic tumors. In vivo imaging as well as post mortem analysis demonstrated a significant decrease in tumor weight and volume. Compared to chemotherapy treatment alone, TTF had a sensitizing effect and increased tumor response to chemotherapy.
Based on previous reports, the observed increase in cell volume is expected to shift the peak response to TTFields to a lower frequency, allowing some of the cells to escape the effect of TTFields. While this is the first proposed mechanism of resistance to TTFields it also opens the possibility of overcoming that resistance using serial application of several frequencies.
Citation Format: Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Mijal Munster, Aviran Itzhaki, Daniel Mordechovich, Shay Cahal, Uri Weinberg, Eilon D. Kirson, Yoram Palti. Tumor Treating Fields inhibit the growth of pancreatic and ovarian cancer in preclinical models . [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 5569. doi:10.1158/1538-7445.AM2013-5569