bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4505: Development of small molecules to target ezrin as anti-metastatic agents
Authors: Bulut Gülay , Hong Sung-Hyeok , Chen Kevin , Rahim Said , Kosturko George W. , Beauchamp Elspeth M. , Glasgow Eric , Toretsky Jeffrey A. , Khanna Chand , Uren Aykut 
Published: June 2012

Abstract
The most common cause for mortality in osteosarcoma (OS) is respiratory failure due to metastasis to lungs. Thus targeting underlying molecular events that lead to metastasis can provide a significant benefit to patients with fatal metastatic disease. Accumulating evidence from experimental animal models and human cases suggests that ezrin is a key factor in the metastasis of OS cells. Ezrin is a multifunctional protein that connects the actin cytoskeleton to extracellular matrix through transmembrane proteins. We screened small molecule libraries for compounds that directly interact with ezrin protein. Two small molecules that directly bind to ezrin with low micromolar affinity were selected based on inhibiting ezrin function in multiple assays. They inhibited ezrin phosphorylation, ezrin-actin interaction, and ezrin mediated motility of OS cells in culture. These compounds were unique in their mechanism of action such that they inhibited in vitro phosphorylation of ezrin by protein kinase C (PKC) by binding to the substrate not by inhibiting the kinase activity of the enzyme. PKC was able to phosphorylate other substrates in the presence of these novel ezrin inhibitors. They also mimicked the ezrin morpholino phenotype and caused a unique developmental defect consistent with reduced cell motility in zebrafish. Following tail vein injection of osteosarcoma cells to mice, both molecules inhibited lung metastasis of ezrin-sensitive cells, but not ezrin-resistant cells. These two molecules demonstrate a novel targeted therapy that directly inhibits ezrin protein as an approach to prevent tumor metastasis in osteosarcoma and other tumors with elevated ezrin in their metastatic subclones.
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 4505. doi:10.1158/1538-7445.AM2011-4505
Abstract 451: Macrophages are critical for promotion of urethane-induced lung carcinogenesis during early stages
Authors: Zaynagetdinov Rinat , Sherrill Taylor P. , Polosukhin Vasiliy V. , Han Wei , McMahon Frank B. , Gleaves Linda A. , Ausborn Jamie A. , McLoed Allyson G. , Yull Fiona E. , Blackwell Timothy S. 
Published: June 2012

Abstract
Among the multiple factors initiating and supporting tumor growth, inflammation plays one of the most important roles. Macrophages, which are the primary immune cells in the lungs, have established roles in tumor growth and metastasis; however, information about the role of macrophages in early carcinogenesis is limited. The purpose of this study was to evaluate the role of macrophages in modulation of tumor formation during different stages of urethane-induced lung carcinogenesis. To assess the role of macrophages in our lung tumor model, we developed a method of non-invasive long-term lung macrophage depletion by repetitive intratracheal injections of liposomal clodronate. Clodronate encapsulated liposomes are well known to cause selective apoptosis of macrophages. Depletion of macrophages during the entire experiment (4 Months) or during the late promotion and progression stages (Months 2-4), when macrophages primarily exhibited a M2 phenotype, significantly reduced tumor vasculogenesis and lung tumor multiplicity. Interestingly, depletion of alveolar macrophages during lung tumor initiation and early promotion stages (Week 1-2), when macrophages were polarized toward an M1 phenotype, caused similar attenuation of tumor vasculogenesis and lung carcinogenesis as observed after depletion of cells during the entire experiment or late promotion/progression stages. Moreover, early macrophage depletion, but not late depletion, significantly reduced formation of atypical adenomatous hyperplasia (AAH) lesions in the lungs. Our results demonstrate that macrophages are critical for promotion of lung carcinogenesis during early stages and suggest that the M1/M2 paradigm may not be an important concept for describing the impact of macrophages on tumor promotion.
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 451. doi:10.1158/1538-7445.AM2011-451
Abstract 4513: Predicting response of non-small cell lung cancer to the telomerase inhibitor imetelstat
Authors: Frink Robin E. , Girard Luc , Wright Woodring E. , Shay Jerry W. , Minna John D. 
Published: June 2012

Abstract
Telomerase is active in more than 80% of non-small cell lung cancers (NSCLC) but is not active in most somatic cells, making it an attractive target for cancer therapy. Furthermore, telomerase is required for cancer stem cell maintenance so targeting telomerase could affect this chemo-resistant subpopulation. Imetelstat, a 13-mer N3’ P5′-thio-phosphoramidate, inhibits telomerase by binding to the RNA template component leading to shortened telomeres and associated cell death. Because imetelstat is currently in clinical trials for NSCLC, it is important to determine the spectrum of activity of imetelstat in a variety of NSCLCs. To accomplish this, we examined the in vitro effect of short-term imetelstat treatment in both the colony formation assay and a 5 day MTS assay using a panel of NSCLC cell lines. For the colony formation assay, cells were plated at clonal density, treated with 3 μM imetelstat 24 hours later, and allowed to grow into colonies for 2-4 weeks. The end point was determined by untreated control cells in colony formation and was dependent on inherent population doubling time. We found an array of responses ranging up to 96% inhibition of colony formation. The panel can be divided into 3 groups: responders (&gt;70% inhibition), intermediate (20%-70% inhibition), and non-responders (&lt;20% inhibition). These groups may be used to develop a biomarker signature predictive of which patients will be most sensitive to imetelstat. With the 5 day MTS assay, cells were treated with imetelstat concentrations ranging from 2.6 nM to 42.5 μM and allowed to incubate for 5 days. Cell viability was determined by a colorimetric readout using MTS. Because of expected delayed response time due to the mechanism of action of imetelstat, we were surprised to find a cell line sensitive to 1 μM imetelstat in the short-term assay. Only 50% of the cells remained after 5 days of treatment. Although this cell line is not sensitive to the imetelstat mismatch control, further studies are needed to determine if this effect is telomere specific. Our studies indicate a wide range of response of NSCLC to imetelstat emphasizing the importance of predicting which patients are most likely to respond to imetelstat therapy.
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 4513. doi:10.1158/1538-7445.AM2011-4513
Abstract 4514: NMR study of XR5944 interaction with diverse estrogen response elements (EREs)
Authors: Mathad Raveendra I. , Zhang Zhenjiang , Shu Feng-jue , Chen Xi , Carver Megan , Kallen Caleb , Sidell Neil , Yang Danzhou 
Published: June 2012

Abstract
ER has emerged as one of the most effective targets for breast cancer therapy since the discovery of the estrogen receptor (ER) as the modulator of estrogen action. However, the current ER-targeting therapies have a main limitation related to resistance. Our previous studies have shown that XR5944, a DNA bis-intercalator is capable of inhibiting the ER activity by its ability to specifically block the binding of ER to its consensus EREs. An DNA intercalator that targets ERE may be a useful therapeutic agent that can overcome the resistance to existing endocrine therapies. To understand the mechanism of the inhibition of ER-ERE interactions by XR5944, we have tested the specificity of XR5944 binding to consensus EREs (AGGTCAnnnTGACCT) with different tri-nucleotide spacer sequences as well as natural EREs using 1H NMR titration studies. Our results suggested that the ERE spacers play a significant role in determining the binding characteristics of the complex. XR5944 binds the ERE sequences in a slow-exchange binding mode on the NMR time-scale. The binding stoichiometry of XR5944 with ERE sequences was shown to be 2:1. Of those tested, the CGG/GCC and AGG/CCT spacers showed the best binding, while the CGT/ACG and TTT/AAA spacers showed the worst binding with XR5944. Results of luciferase reporter assays in MCF-7 cells indicated that XR5944 was significantly more potent in inhibiting the activity of reporters containing ERE-CGG than those containing ERE-TTT, consistent with our NMR results. Natural ERE sequences, including those located in the promoter of ER target genes TFF1, GREB1, Cathepsin D, Lactoferrin, and TGF-α, also appear to bind to XR5944 with different specificities as evident by differences in the 1H NMR spectra of their drug-DNA complexes. Thus, the affinity and specificity of the XR5944-ERE complex is influenced both by the nucleotide sequence of the half-sties and the tri-nucleotide spacer. Of the natural EREs tested, XR5944 appears to bind with the highest specificity to the ERE sequence of TFF1; hence we carried out further NMR studies of the binding of XR5944 to the TFF1 ERE sequence. Using site-specific labeling at each base, we were able to assign both the imino and H8 protons of the free TFF1 DNA and its drug complex. These assignments provide important information on the XR5944 binding sites with TFF1 ERE.
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 4514. doi:10.1158/1538-7445.AM2011-4514
Abstract 4515: A novel obatoclax derivative is a promising agent to overcome bortezomib's resistance in acute leukemia cells
Authors: Liu Chun-Yu , Shiau Chung-Wai , Kuo Hsin-Yu , Cheng Ann-Lii , Tzeng Cheng-Hwai , Chen Kuen-Feng 
Published: June 2012

Abstract
Background: Our previous work showed that bortezomib, a reverse-inhibitor of the 26S proteasome, exerts differential cytotoxic effects to acute leukemia cells through down-regulation of phosphor-Akt (AACR 2010 abstract 1575). Interestingly, some acute leukemia cells (MOLT-3 and K562) are resistant to bortezomib. One of the resistant mechanisms of bortezomib involves the abnormality in intrinsic apoptotic pathway members, the bcl-2 family. Of particular, it has been shown that bortezomib induces upregulation of Mcl-1 and that Mcl-1 accumulation may delay bortezomib-induced apoptosis. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 members, including MCL-1, synergizes with bortezomib in mantle cell lymphoma (Blood 2007) and may overcome bortezomib resistance. Here, we designed a novel Mcl-1 inhibitor deriving from obatoclax, SC-2001, to overcome the resistance. Methods: MOLT-3 and K562 cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). Results: MOLT-3 and K562 were resistant to bortezomib up to 100nM. Upregulation of Mcl-1 expression after bortezomib treatment were evident in these cells. Interestingly, the addition of either obatoclax or SC-2001, restored the sensitivity of K562 and MOLT-3 cells to bortezomib. SC-2001, comparing to obatoclax, exerted better efficacy in sensitivity restoration of bortezomib in association with Mcl-1 downregulation in MOLT-3 cells. Moreover, down-regulation of Mcl-1 by siRNA overcame the apoptotic resistance to bortezomib in K562 cells. These data indicate that novel Mcl-1 inhibitors could restore bortezomib sensitivity in resistant acute leukemia cells. Conclusions: a novel Mcl-1 inhibitor SC-2001, is a promising agent to overcome bortezomib's resistance in acute leukemia, further elucidating the drug mechanism regulating Mcl-1 inhibition is needed. Supported by VGHTPE 99DHA0100332 and 100DHA0100591
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 4515. doi:10.1158/1538-7445.AM2011-4515
Abstract 4524: ON015640, a novel anti-cancer agent with tubulin depolymerizing activity
Authors: Hoffman Benjamin S. , Cosenza Stephen C. , Palella Venkat , Reddy Ramana , Reddy EP 
Published: June 2012

Abstract
Oncology drug discovery is constantly evolving by integrating new basic findings with established developmental practice. Two drug discovery platforms currently exist. One is an extension of basic research, rational drug design. Its alternative, one based on cytotoxicity, which qualifies leads by their ability to selectively kill cancer cells. Using this cytotoxicity based approach we recently discovered a novel synthetic small molecule we have called ON015640. This compound is highly effective at killing 15 different cancer cell lines with IC50 ranges from 20-90 nanomolar. The predominant phenotype associated with this compound is that of cellular rounding and detachment from substratum, a similar phenomenon to that observed during treatment of cultured cells with mitotic inhibitors like Taxol and Nocodazole. Using FACS, molecular mitotic indexing, and fluorescent microscopy we have subsequently demonstrated that ON015640 induces mitotic arrest and aberrant spindle formation. This mitotic arrest and spindle disruption can be attributed to this molecule's ability to depolymerize tubulin both in vitro and in vivo in a similar manner to Nocodazole. At effective concentrations this compound commences a program of mitotic catastrophe subsequently initiating effector caspases 3/7 and cleavage of Poly ADP Ribose Polymerase, primary steps in the activation of the intrinsic apoptotic pathway. Unlike classical tubulin depolymerizing agents, ON015640 is not a substrate for the ATP binding cassette family of efflux pumps and is capable of killing Multi Drug Resistant cell lines. This characteristic and the compound's nanomolar activity make it an attractive candidate for further development and characterization. To date, the exact site where ON015640 binds to tubulin remains unknown. Additionally, the pharmacokinetics and efficacy of this molecule have yet to be fully characterized. Thus, current and future efforts will be focused on establishing the dynamics by which ON015640 interacts with tubulin, while also developing this molecule into a clinically relevant drug.
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 4524. doi:10.1158/1538-7445.AM2011-4524
Abstract 4539: Androgen receptor N-term death domains induce apoptosis through a bax-mediated mitochondrial pathway
Authors: Haferkamp Bonnie , Lin Yuting , Godfrey Brad , Xiang Jialing 
Published: June 2012

Abstract
While the DNA- and ligand-binding domains of the androgen receptor (AR) have been extensively studied to elucidate AR transcriptional mechanisms in androgen-independent prostate cancer, the role of the N-terminal is poorly understood. Previously, we showed that AR is required for stress-induced cell death in androgen-independent prostate cancer cells, and that cell death does not require AR transcriptional activity. Here we show that N-term AR is sufficient to induced cell death in androgen-independent prostate cancer PC3 cells without death stimulus. The minimal death domain is located in the first 85 amino acids of AR, rich in polyQ. The pro-death activities of full length AR and its N-term truncated proteins act through the Bax-mitochondrial apoptotic pathway. Electronic microscope imaging revealed mitochondrial swelling in PC3 cells transfected with death-inducing AR truncated constructs, but not with constructs that failed to induce cell death. Cell death induced by AR N-term truncated constructs can be effectively blocked by caspase 3, but not caspase 1 inhibitor. Finally, transfection of AR death-active N-term truncations caused significant cell death in Bax wild-type but not Bax-/- MEFs. Taken together, these results indicate that pro-death AR N-term fragments generated by stress-induced proteolysis cause cell death through a Bax-dependent mechanism involving the mitochondrial apoptosis pathway in androgen-independent prostate cancer cells.
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 4539. doi:10.1158/1538-7445.AM2011-4539
Abstract 4542: Dose-dependent effects of progestins on progesterone receptor activity and target gene expression: less is more
Authors: Wade Hilary , McDonnell Donald , Brown Myles 
Published: June 2012

Abstract
While the molecular mechanisms by which the progesterone receptor (PR) regulates breast tumor growth and metastasis have not been fully elucidated, recent studies highlight the fact that PR has a complex role in breast cancer progression that may be dependent on ligand dose. For example, data from the Women's Health Initiative trial suggest that low-dose progestins used in combination with estrogen are associated with an increased risk of invasive breast cancer compared to estrogen alone. On the other hand, high-dose progestin therapy has been used as an effective front-line and second-line treatment for advanced, metastatic breast cancer. To investigate this paradox, we undertook studies to identify aspects of PR biology that respond differently to treatment with low or high doses of progestins. Interestingly, we found that treatment of T47D breast cancer cells with low-dose progestins generates a significantly more robust induction of a subset of PR target genes, including the cell cycle regulators cyclin D1 and E2F1, than treatment with high-dose progestins. Furthermore, we show that varying doses of progestins have differential effects on the receptor itself, including the subcellular localization, phosphorylation and subsequent turnover of PR. At the level of transcriptional regulation, our ChIP analyses have led us to hypothesize that the strength of PR activation of target gene expression may hinge upon the ratio of phospho-PR versus unmodified PR that is recruited to enhancer elements. This dose-dependent effect may result in the formation of different PR transcriptional complexes and explain the diverse downstream biologies that are regulated by varying levels of progestins throughout the female reproductive cycle and in diseases such as breast cancer. Given the wide range of medical therapies that utilize progestins, our findings may have important clinical implications.
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 4542. doi:10.1158/1538-7445.AM2011-4542
Abstract 455: Adipocyte sTNFR2 secretion and macrophage migration in the breast tumors
Authors: Rego Stephen , Swamydas Muthulekha , Ricci Krista , Dréau Didier 
Published: June 2012

Abstract
The breast tumor microenvironment greatly influences tumor progression and modulates the migratory abilities of both cancer cells and macrophages, especially M2 macrophages, at the tumor site. The pleiotropic inflammatory cytokine TNFα through interactions with TNFR promotes macrophage migration and tumor cell apoptosis. The shedding of TNFR increases the concentration of sTNFR within the tumor microenvironment. We determined whether sTNFR modulates the trafficking of specific macrophage subtypes in the tumor microenvironment. Concentrations of TNFα, sTNFR1 and sTNFR2 secreted by 4T1 and NMuMG mammary epithelial cells, stroma mesenchymal stem cells, and adipocyte-derived cells were measured by cytokine arrays and ELISA. The migration of murine monocytes cultured in media promoting preferential expression of M0, M1, or M2 phenotypes toward tumor or stroma cell conditioned media (CM) was determined by transwell assays. The effects of conditioned media obtained following treatment with the sheddase inhibitor TAPI-0 on cell migration were also assessed. The concentrations of sTNFR2 secreted were drastically higher in the CMs from 4T1 cells compared to NMuMG cells (p&lt;0.05). In addition, adipocytes secreted markedly more sTNF2 compared to D1 mesenchymal stem cells (p&lt;0.05). sTNFR2 concentrations were significantly decreased in the presence of a sheddase inhibitor (p&lt;0.05). The transwell migration of M2 phenotype macrophages toward 4T1-CM was significantly greater than the migration of M0 or M1 phenotype macrophages (p&lt;0.05). Furthermore, only the migration of the M2 macrophage subtype following TAPI-0 treatment toward 4T1 CM was markedly higher (p&lt;0.05). These results strongly suggest a role for sTNFR secreted by tumor cells and adipocytes in the infiltration of M2 phenotype macrophages within the tumor microenvironment. Whether selective prevention of sTNFR shedding may have therapeutic benefit for breast cancer patients remains to be determined.
This work was supported by grants from the Department of Defense Era of Hope program (BC044778) and the National Science Foundation EFRI program (CBE0736007).
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 455. doi:10.1158/1538-7445.AM2011-455