bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5435: Increased tumor susceptibility to low glucose under hypoxia is increased by BRAF(V600E) mutation: correlation with persistent phosphoP90RSK activation.
Authors: Rieber Manuel , Chavez-Perez Valery , Strasberg-Rieber Mary 
Published: August 2014

Abstract
BACKGROUND.- Oncogenic BRAF(V600E) mutations, found in &gt;50 % of melanomas, promote melanoma cell proliferation by constitutively activating mitogen-activated Mek1/2 kinases and extracellular signal-regulated kinases (Erk1/2). This pathway can further activate downstream the p90- ribosomal S6 kinase (p90RSK). OBJECTIVES.- Since BRAF mutations increase melanoma progression which could lead to metabolic stress when oxygen, glucose, and other nutrients are limiting within poorly vascularized regions, we investigated whether hypoxia and metabolic stress can differentially influence the survival of human melanoma cells harbouring either wt or oncogenic BRAF. EXPERIMENTAL. human melanoma cells with unequal BRAF status were exposed to glucose and/or glutamine limitations under normoxia or hypoxia. Relative metabolic activity was fluorometrically quantitated by the cellular conversion of resazurin to resorufin. Differential cell survival was assesed by crystal violet staining. Mechanisms influencing the response to metabolic stress were studied by specific immune blotting. RESULTS. the metabolic activity and survival of melanoma cells harbouring oncogenic BRAF was preferentially decreased under hypoxia at sub-physiological glucose, compared to wt BRAF melanoma cells. Addition of the anti-oxidant N-acetylcysteine or pyruvate enhanced the metabolic activity and survival of wt BRAF cells, but these were much less effective when added to BRAF (V600E) mutant cells, implying a greater oxidative stress induced by low oxygen and glucose in them. Susceptibility to metabolic stress under hypoxia and low glucose in BRAF (V600E) mutant cells, correlated with persistent (p90RSK) activation but lower GLUT-1 and MnSOD expression. In contrast, wt BRAF melanoma cells resistant to metabolic stress reciprocally showed higher GLUT-1 and MnSOD expression, but negligible p90RSK activation. CONCLUSION.- Although mutations in BRAF can drive acquired resistance to MEK1/2 inhibitors, our results suggest that restricting glucose consumption in hypoxic melanomas harbouring mutant BRAF with persistent phosphorylation of the p90-ribosomal S6 kinase, may contribute to their preferential killing.
Citation Format: Manuel Rieber, Valery Chavez-Perez, Mary Strasberg-Rieber. Increased tumor susceptibility to low glucose under hypoxia is increased by BRAF(V600E) mutation: correlation with persistent phosphoP90RSK activation. [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 5435. doi:10.1158/1538-7445.AM2013-5435
Abstract 5471: Notch-antibody drug conjugates have a different mechanism of action than Notch signaling inhibitors and induce tumor regression.
Authors: Geles Kenneth G. , Gao Yijie , Sridharan Latha , Giannakou Andreas , Yamin Ting-Ting , Golas Jonathan , Charati Manoj , Khandke Kiran , Lucas Judy , Maderna Andreas , O'Donnell Christopher J. , Tchistiakova Lioudmila , Gerber Hans-Peter , Sapra Puja 
Published: August 2014

Abstract
There are four different Notch receptors in mammalian cells that have overlapping patterns of expression in embryonic and adult tissues, but fulfill non-redundant roles during hematopoietic stem cell specification, T cell development, intestinal crypt cell specification and vascular development. Notch receptors are over-expressed or amplified in certain human tumors and regulate cell proliferation, differentiation, and survival through an intracellular domain that functions as a transcriptional activator. Several strategies are in development to block Notch signaling for therapeutic purposes in cancer, including gamma-secretase inhibitors that block all Notch signaling and antibody-based targeting of individual receptors. However, blocking pathway activation with inhibitory antibodies has proven to be less efficacious than originally anticipated. Therefore, we have targeted Notch with antibody-drug conjugates (ADCs) that combine the specificity of high affinity anti-Notch antibodies with the cytotoxicity of microtubule inhibitors. These ADCs enhance efficacy and also allow targeting in tumors that overexpress Notch but are not driven by its signaling. Notch antibodies were conjugated though cleavable and non-cleavable linkers to novel tubulin inhibitor-based payloads. Notch-ADCs inhibited the in vitro growth of lung, breast and ovarian cancer cell lines in the low ng/ml range and in vivo regressed the growth of established human tumor xenografts. Our data demonstrate that Notch-ADCs are more potent than small molecule inhibitors and unconjugated antibodies, and induce sustained tumor regression in pre-clinical models.
Citation Format: Kenneth G. Geles, Yijie Gao, Latha Sridharan, Andreas Giannakou, Ting-Ting Yamin, Jonathan Golas, Manoj Charati, Kiran Khandke, Judy Lucas, Andreas Maderna, Christopher J. O'Donnell, Lioudmila Tchistiakova, Hans-Peter Gerber, Puja Sapra. Notch-antibody drug conjugates have a different mechanism of action than Notch signaling inhibitors and induce tumor regression. [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 5471. doi:10.1158/1538-7445.AM2013-5471
Abstract 5509: Natural occurring leelamine inhibits melanoma development by targeting multiple signaling pathways.
Authors: Gowda Raghavendra , Madhunapantula SubbaRao V. , Kuzu Omer F. , Sharma Arati , Gavin Robertson P. 
Published: August 2014

Abstract
Melanoma remains a highly drug resistant tumor type. Melanoma cells rapidly progress resistance to drugs targeting single proteins by circumventing the point of inhibition. To overcome this problem, one approach has been to develop drugs targeting multiple proteins or pathways deregulated in the growth of the disease, such as the PI3 kinase, MAP kinase, and STAT3 signaling cascades. Agents simultaneously inhibiting several key pathways aiding melanoma development would be a first in class type of new drug for treating melanoma. To identify a drug that might target the PI3K, MAPK and STAT3 cascades, a natural product library was screened identifying leelamine as a potential inhibitor. Leelamine had the greatest inhibitory efficacy selectively killed melanoma cells by decreasing levels of cellular proliferation and increasing apoptosis rates. Leelamine inhibited the growth of preexisting xenografted tumors by ∼60%, by targeting PI3K, MAPK and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The most prominent tumor inhibitory mechanisms of actions of leelamine occurred through by decreasing of Akt, Erk and Stat3 activity, which reduced cellular proliferation and consequently decreased tumor vascularization as well as increasing apoptosis. Collectively, these discoveries demonstrate the development of a naturally occurring pharmacological agent that targets multiple pathways and thereby more effectively treat melanoma.
Citation Format: Raghavendra Gowda, SubbaRao V. Madhunapantula, Omer F. Kuzu, Arati Sharma, Robertson P. Gavin. Natural occurring leelamine inhibits melanoma development by targeting multiple signaling pathways. [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 5509. doi:10.1158/1538-7445.AM2013-5509
Abstract 5512: Mechanisms of inhibition of cancer cell growth and metastasis by novel small molecule compounds.
Authors: Ashour Abdelkader E. , Cheryan Vino T. , Jamal Shazia , Alafeefy Ahmed M. , Zoheir Khairy M. , Abdallah Adel R. , Rishi Arun K. 
Published: August 2014

Abstract
The molecular complexity of cancers and therapy-associated side effects often limit effectiveness of many therapies, and warrant development of new agents for specific molecular targets while minimizing the off-target effects. Thus, our goal is to develop novel, safer and effective anti-cancer therapies on the basis of cell growth and survival inhibiting functions of an apoptosis regulatory protein, termed CARP-1. CARP-1 was identified by us as a novel target of select chemotherapy (adriamycin, etoposide, or Iressa)-dependent human breast cancer cell growth suppression. By conducting the high-throughput screening of chemical libraries, we identified a number of novel, small molecule compounds called CARP-1 Functional Mimetics (CFMs). MTT assay results showed that CFMs, as well as quinazoline analogues of CFMs, inhibited growth of a variety of cancer cells, including the drug-resistant breast cancer cell line MDA-MB 468, without affecting growth of immortalized mammary epithelial cells. Results of MTT assay indicated also that CFM-4 (1(2-chlorobenzyl)-5′-phenyl-3′H-spiro[indoline-3,2′-[1,3,4]thiadiazol]-2-one) was the most potent one. CFMs suppressed cancer cell growth in part by stimulating CARP-1 levels and promoting cell cycle arrest and apoptosis. RT-PCR assay results revealed that CFM-4 induced the extrinsic pathway of apoptosis via upregulation of TRAIL receptors, caspase-8 and caspase-3 which can then cleave multiple cellular proteins, leading to cancer cell death. Cancer-related deaths are often due to spread of cancers to other organ sites (metastasis) that involves invasion and movement of cancer cells through the nearby normal tissue and the lymph and blood vessels to reach other tissues to form secondary tumors. Here we also demonstrate that CFMs impact biological properties of cancer cells by inhibiting their movement and invasion through the membranes coated with the extra-cellular matrix. CFMs also inhibited abilities of cancer cells to grow as colonies in soft-agar. These proof-of-concept studies suggest that CFMs could induce cancer cell apoptosis and effectively inhibit migration and tumor-forming abilities of cancer cells. Thus CFMs or their analogues have potential as anti-cancer agents to target cancer cell proliferation, survival, migration, invasion and metastasis, and provide a strong basis for their development as anti-cancer agents.
Citation Format: Abdelkader E. Ashour, Vino T. Cheryan, Shazia Jamal, Ahmed M. Alafeefy, Khairy M. Zoheir, Adel R. Abdallah, Arun K. Rishi. Mechanisms of inhibition of cancer cell growth and metastasis by novel small molecule compounds. [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 5512. doi:10.1158/1538-7445.AM2013-5512
Abstract 5513: Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase (PDI) for ovarian cancer treatment.
Authors: Xu Shili , Butkevich Alexey N. , Yamada Roppei , Zhou Yu , Debnath Bikash , Duncan Roger , Zandi Ebrahim , Petasis Nicos A. , Neamati Nouri 
Published: August 2014

Abstract
Protein disulfide isomerase (PDI), an endoplasmic reticulum (ER) chaperone protein, catalyzes disulfide bond breakage, formation and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a need for potent, selective and safe small-molecule inhibitors of PDI. Here, we report a new class of novel propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and mass spectrometry, we established that PACMA 31, one of the most active analogues, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with PDI's active site cysteines. We also demonstrated that PDI activity is essential for the survival and proliferation of human ovarian cancer cells. In vivo, PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent a new approach for the development of targeted anticancer agents for ovarian cancer therapy, and can also serve as useful probes for investigating the biology of PDI-implicated pathways.
Citation Format: Shili Xu, Alexey N. Butkevich, Roppei Yamada, Yu Zhou, Bikash Debnath, Roger Duncan, Ebrahim Zandi, Nicos A. Petasis, Nouri Neamati. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase (PDI) for ovarian cancer treatment. [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 5513. doi:10.1158/1538-7445.AM2013-5513
Abstract 5514: Antitumor activity of (R,R’)-4′-methoxy-1-naphthylfenoterol in a rat C6 glioma xenograft model in the mouse.
Authors: Paul Rajib K. , Ramamoorthy Anuradha , Zhang Yongqing , Becker Kevin G. , Paris Arnaud , Cloix Jean-Francois , Bernier Michel , Wainer Irving W. 
Published: August 2014

Abstract
(R,R’)-4’-methoxy-1-naphthylfenoterol (MNF) inhibits in vitro proliferation of several types of cancer cell lines. In this study, the in vivo antitumor effects of MNF were evaluated using rat C6 glioma cells implanted subcutaneously into the lower flank of 5 week-old NMRI/Nude female Swiss mice (0.5 x 10(6) cells, 100μl). Three days after the inoculation, the mice were subjected to intraperitoneal injections of saline or MNF (10μl/g, 2mg/kg of body weight) for 5 days per week for 2 weeks. Tumor volumes were measured everyday using slide calipers. Significant reductions in mean tumor volumes were observed in mice receiving MNF when compared with the saline-treated group (p &lt; 0.001, n=17-19). At the end of the study, animals were sacrificed and tumors were collected for cDNA microarray, quantitative PCR and immunoblot analyses. Comparison of cDNA microarray analysis of tumors from mice treated with MNF vs. saline demonstrated a significant decrease in expression of genes involved in cellular proliferation, including mitotic checkpoint kinase MAD3L (BUB1B), cyclin-dependent kinase inhibitor 3 (CDKN3) and cyclin A2 (CCNA2), as well as molecular markers for glioblastoma, such as oligodendrocyte transcription factor 1 (OLIG1) and SRY-box 4 (SOX4). Target gene validation is currently in progress. Our results show that MNF reduces growth of flank xenografted C6 glioma tumors and expression of genes related to tumor proliferation and suggest that this compound may be useful in cancer treatment. This work was supported in part by the Intramural Research Program of the NIA/ NIH.
Citation Format: Rajib K. Paul, Anuradha Ramamoorthy, Yongqing Zhang, Kevin G. Becker, Arnaud Paris, Jean-Francois Cloix, Michel Bernier, Irving W. Wainer. Antitumor activity of (R,R’)-4′-methoxy-1-naphthylfenoterol in a rat C6 glioma xenograft model in the mouse. [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 5514. doi:10.1158/1538-7445.AM2013-5514
Abstract 5518: A novel 1,3-bis(3,5-dichlorophenyl) urea compound ‘COH-SR4’ for targeting melanoma.
Authors: Dalasanur Nagaprashantha Lokesh Prasad Gowda , Figarola James , Singhal Jyotsana , Horne David , Jove Richard , Rahbar Samuel , Awasthi Sanjay , Singhal Sharad S 
Published: August 2014

Abstract
The current clinical modalities in the management of malignant melanomas are met with limited response. The molecular events that regulate oncogenic transformation, invasive progression and resistance to therapy in melanomas are determined by an interplay between various complex signaling networks. In the context of evident demographic risk, limited response to current clinical interventions and molecular complexity of melanomas, novel candidate molecules capable of effectively inducing tumor inhibition along with targeting critical nodes of melanoma signaling assume translational significance. In this regard, we investigated the anti-cancer effects of a novel dichlorophenyl urea compound called SR4 in melanoma. The SR4 treatment decreased the survival and inhibited the clonogenic potential along with inducing apoptosis in vitro cultures of melanoma. SR4 treatments lead to inhibition of GST activity along with inducing G2/M phase cell cycle arrest. Oral administration of 4 mg/kg b.w. SR4 leads to effective inhibition of tumor burdens in both syngeneic and nude mouse models of melanoma. The SR4 treatment was well tolerated and no overt toxicity was observed. The histopathological examination of resected tumor sections reflected decreased blood vessels, decrease in the levels of angiogenesis marker, CD31, and proliferation marker, Ki67, along with an increase in pAMPK levels. Western blot analyses of resected tumor lysates revealed increased PARP cleavage, Bim, pAMPK along with decreased pAkt, vimentin, fibronectin, CDK4 and cyclin B1. Thus, SR4 represents a highly effective candidate for the further development of single agent and combinatorial therapies to effectively target aggressive and clinically resistant melanomas (Supported by NIH grant CA 77495).
Citation Format: Lokesh Prasad Gowda Dalasanur Nagaprashantha, James Figarola, Jyotsana Singhal, David Horne, Richard Jove, Samuel Rahbar, Sanjay Awasthi, Sharad S Singhal. A novel 1,3-bis(3,5-dichlorophenyl) urea compound ‘COH-SR4’ for targeting melanoma. [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 5518. doi:10.1158/1538-7445.AM2013-5518
Abstract 5532: A pro-fluorescent membrane integrity dye for the real-time assessment of cytotoxicity.
Authors: Somberg Richard L. , Niles Andrew , Worzella Tracy , Lazar Dan 
Published: August 2014

Abstract
Cell-based assay models are now universally employed as a routine means of establishing and ranking on- and off-target toxicities. It is well appreciated, however, that individual cytotoxic phenotypes are shaped not only by compound dosage, but by the length of compound-cell exposure. In addition to compound-specific attributes, inherent cellular factors such as biotransformation capacity, cell cycle susceptibility, and receptor expression often dictate the kinetics of cytotoxicity. Unfortunately, the majority of conventional cytotoxicity assays are performed at a terminal endpoint (48-72h) which at worst can underestimate cytotoxicity due to biomarker degradation, or at best, fail to reveal important features of the cytotoxic event which may be important for establishing mechanism-of-action. We have developed a pro-fluorescent, cell-impermeant probe which can be applied to cells at the time of dosing to report changes in membrane integrity as they occur in real-time. The dye enters cells with impaired membrane integrity, greatly enhancing fluorescence which is proportional to non-viable cell number. The dye can be used in traditional plate based formats using standard fluorometry or with image based readers (Essen Bioscience Incucyte™) to establish the dose-dependent kinetics of cytotoxicity. Here we describe the dye's utility using mechanistically distinct cytotoxins with both cancer cell lines (on-target) and terminally differentiated cells (off-target) and correlate this dead cell fluorescence activity to other cytotoxicity biomarkers by same-well multiplexed methods.
Citation Format: Richard L. Somberg, Andrew Niles, Tracy Worzella, Dan Lazar. A pro-fluorescent membrane integrity dye for the real-time assessment of cytotoxicity. [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 5532. doi:10.1158/1538-7445.AM2013-5532
Abstract 5535: Development of peptidomimetic inhibitors of the ERG transcription factor in prostate cancer.
Authors: Wang Xiaoju 
Published: August 2014

Abstract
Transcription factors play a key role in the development of a number of cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the ETS transcription factor ERG is recurrently rearranged and likely plays a critical role in prostate oncogenesis. Here we identified a consensus peptide from a phage library which interacts specifically with the DNA binding domain of ERG. The interactive interface was mapped to 9-residues in the 3rd α-helix of the ETS domain, which is critical for ERG activity as a transcription factor. The peptides were found to efficiently disrupt ERG-mediated protein-protein interactions, transcription, DNA damage, and cell invasion. Furthermore, a retroinverso peptidomimetic suppressed tumor growth, intravasation, and metastasis in vivo. Taken together, our results suggest that transcription factors have specific residues that are important for protein-protein interactions, that may be amenable to therapeutic targeting.
Citation Format: Xiaoju Wang. Development of peptidomimetic inhibitors of the ERG transcription factor in 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 5535. doi:10.1158/1538-7445.AM2013-5535
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5593: A cancer-associated hyperphosphorylation site on topoisomerase I serine 506 as a biomarker for camptothecin sensitivity.
Authors: Bandyopadhyay Keya , Li Pingchuan , Gjerset Ruth A. 
Published: August 2014

Abstract
Topoisomerase I (topo I) plays a central role in cancer as the target of a potent class of chemotherapeutic drugs derived from the plant alkaloid camptothecin that includes irinotecan and topotecan. We have identified a novel cancer-specific phosphorylation site at serine 506 in topo I (PS506), targeted by protein kinase CK2, that identifies cancer cells with elevated CK2, hyperphosphorylated topo I, increased topo I activity, and increased sensitivity to camptothecin. CK2 treatment of recombinant topo I in vitro also induces topo I hyperphosphorylation and expression of the PS506 epitope, and results in increased binding of topo I to supercoiled plasmid DNA. The hyperphosphorylated, PS506-form of topo I is more effective than the basal phosphorylated enzyme at relaxing plasmid supercoils but has a similar catalytic rate as the basal phosphorylated enzyme once bound to DNA. The PS506 epitope is not detected in normal cells or cancer cell lines with lower levels of CK2 activity. By experimentally manipulating CK2 activity in cancer cell lines, we have demonstrated a cause and effect relationship between CK2 activity, PS506 expression, camptothecin-induced cellular DNA damage, and cellular camptothecin sensitivity. The PS506 epitope is therefore an indicator of dysregulated, hyperphosphorylated topo I in cancer cells, and holds promise as a novel diagnostic biomarker that predicts tumor responsiveness to widely used topo I-targeted therapies.
Citation Format: Keya Bandyopadhyay, Pingchuan Li, Ruth A. Gjerset. A cancer-associated hyperphosphorylation site on topoisomerase I serine 506 as a biomarker for camptothecin sensitivity. [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 5593. doi:10.1158/1538-7445.AM2013-5593