bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3251: Characterization of a novel Rac inhibitor as an anti cancer metastasis compound
Authors: Ortiz Brendaliz Montalvo , Ofarrill Eliud Hernandez , Hernandez Jonibeth , Vlaar Cornelis , Flanagan Surangani Dharmawardhane 
Published: June 2012

Abstract
The objective of this project is to design novel therapeutics targeting cancer metastasis, the most deadly aspect of epithelial cancers. Our previous studies have shown that Rac, a key signaling intermediate that regulates actin cytoskeletal changes during cell migration/invasion and cancer metastasis, is associated with high cancer metastatic efficiency. Since Rac proteins are activated by GDP/GTP exchange, inhibition of the interaction of Rac with its guanine nucleotide exchange factors (GEF) is expected to inhibit Rac activity. Since the known Rac inhibitor NSC-23766 is not effective at therapeutically useful concentrations, we synthesized novel NSC-23766 derivatives. Results show that the new inhibitor EHop-016 is 100-fold more efficient than the parent compound at inhibiting Rac activity of metastatic cancer cells without affecting the activity of the related GTPase, Rho. EHop-016 inhibited Rac activity of metastatic cancer cells with an IC50 of 0.78 microM. Cell viability assays, performed to test for the toxicity of this compound, demonstrated that at concentrations below 5 microM, EHop-016 did not affect mammary epithelial cell (MCF-10A) viability and decreased proliferation of metastatic cancer cells (MDA-MB-435) by only 20%. We conclude that EHop-16 is a potent Rac inhibitor with promise of further development as a small molecule inhibitor of cancer cell invasion, and thus, metastasis.
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 3251. doi:10.1158/1538-7445.AM2011-3251
Abstract 3253: Novel oxindole inhibitors of Aurora A kinase: Structure based hit-to-lead approach
Authors: Pireddu Roberta , Lawrence Harshani R. , Martin Mathew P. , Betzi Stephane , Yip Richard , Yang Hua , Sun Nan N. , Cheng Jin Q. , Schonbrunn Ernst , Sebti Said M. , Lawrence Nicholas J. 
Published: June 2012

Abstract
The M-phase of cell division is controlled by phosphorylation events performed by several mitotic serine/threonine kinases. For example, the three human isoforms of Aurora kinase (A, B, and C) have been amply investigated as they are essential for the execution of numerous mitotic events and required for genome integrity and stability. Studies have shown that Aurora A and B are frequently over-expressed in various cancer cells. Aurora A also acts as an oncogene inducing malignant transformation when over-expressed. Since the discovery of the Aurora kinases and their association with cancer, there has been great interest in developing small molecule inhibitors of Aurora kinases as potential anticancer drugs.In-house screening campaign directed toward the discovery of novel Aurora A inhibitors, led to the identification of a new and potent class of oxindole derivatives as inhibitors of Aurora-A kinase. The initial hit HL1-058-1 was identified as an inhibitor of histone H3-Ser10 phosphorylation (IC50 1-5 μM).
By using a Z’-lyte kinase assay kit, the inhibitory effect of HL1-058-1 was shown to be the direct consequence of the Aurora kinase inhibition (IC50 of 2.7 ± 0.3 µM). Based on the preliminary data, HL1-058-1 was selected for further study. Synthesis of a focused library of analogs based on this hit revealed RPM305 and RPM304 as potent inhibitors of Aurora A (IC50 0.020 ± 0.005 μM, and 0.038 ± 0.018 μM, respectively). Interestingly, compound RPM304 showed 26 fold selectivity over Aurora B (IC50 0.99 ± 0.08 μM).
A coupled enzyme assay was also used to carry out further structure activity relationship studies of the most potent analogs.
One of the lead compounds was co-crystallized with the kinase domain of Aurora A. The design and synthesis of further focused libraries of oxindoles, based on this X-ray structure will be described. Details of the cell activity of this class of compound to inhibit Aurora A activity and tumor cell growth will be described.
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 3253. doi:10.1158/1538-7445.AM2011-3253
Abstract 3255: Tetrahydropyridine derivatives: Novel and potent histone demethylase LSD1 inhibitors
Authors: Callery Patrick S. , Wichitnithad Wisut , Borysiewicz Elizabeth , Konat Gregory W. , Konat Gregory W. 
Published: June 2012

Abstract
Flavin-dependent histone demethylases play an important role in epigenetic gene regulation. The most studied enzyme, LSD1 (KDM1), catalyzes the oxidative demethylation of methylated Lys4 of histone H3. Known LSD1 inhibitors also inhibit other flavin-dependent enzymes, in particular monoamine oxidase (MAO). Therefore, selective inhibition of LSD1 is a significant drug discovery target. We designed, synthesized and evaluated in vitro a series of eleven N-substituted tetrahydropyridines as inhibitors of flavin-dependent enzymes. Complete chemical structures of the compounds used will be disclosed at the time of presentation. The inhibition of LSD1 was measured in rat glioma C6 cells. Briefly, cells grown in serum-free medium were treated with the inhibitors for 24 h, and the level of Lys4 dimethylated form of histone H3 was measured by immunoblot. MAO A activity was determined using human recombinant enzyme with kynuramine as substrate. The most selective among the inhibitors showed low nanomolar potency toward LSD1 and weak inhibition of MAO A. The observed high potency and substrate selectivity justifies further evaluation of the drug discovery potential of the tetrahydropyridine scaffold.
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 3255. doi:10.1158/1538-7445.AM2011-3255
Abstract 3260: Identification and synthesis of benzimidazole carboxamides as potent inhibitors of focal adhesion kinase (FAK)
Authors: Verma Sharad K. , Leber Jack D. , LaFrance Louis V. , Li Mei , Duquenne Celine , Cui Guanglei , Miller William H. 
Published: June 2012

Abstract
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals from integrins and growth factor receptors. FAK has been reported to play a role in the regulation of cell survival, growth, spreading, migration and invasion. Overexpression of FAK mRNA and/or protein has been documented in many human tumors, including cancers of the breast, colon, thyroid, and prostate. FAK is regulated and activated by phosphorylation on multiple tyrosine residues. More significantly, there is evidence that phosphorylated FAK is increased in malignant compared to normal tissues. Accordingly, compounds that inhibit FAK activity are expected to be useful for the treatment of cancer. Cross-screening of the GSK compound collection led to the identification of benzimidazole carboxamides having weak FAK inhibitory activity. As benzimidazole carboxamides are known kinase templates, a structure based hit-to-lead optimization campaign was executed. Team efforts culminated in the rapid identification of a series of substituted benzimidazole carboxamides having highly potent and selective inhibitory activity towards FAK (i.e. FAK IC50 &lt; 10 nM). The structure-based optimization of this series including the synthesis, binding mode, and profile of lead compounds will be described.
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 3260. doi:10.1158/1538-7445.AM2011-3260
Abstract 3283: VB-111 a novel anti-angiogenic vector and a promising treatment for metastatic cancer in combination with other anticancer drugs
Authors: Breitbart Eyal , Cohen Yael C. , Bangio Livnat 
Published: June 2012

Abstract
Background: VB-111 is a vascular disruptive and anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5, E1 deleted), which contains a novel Vascular Targeting System™, VTS™, and a fas and human tumor necrosis factor receptor chimeric transgene. This modified promoter specifically expresses the fas chimera transgene in tumor vessel endothelium, leading to targeted apoptosis. Preclinical in vitro and in vivo studies as well as a phase I clinical trial, have shown that VB-111 was safe and well tolerated, and had significant antitumor activity. We report here the results of a comprehensive set of in vivo studies of VB-111 in combination with chemotherapeutic and anti-angiogenic drugs.
Methods: The safety and efficacy of VB-111 were evaluated employing the Lewis Lung metastasis model as a monotherapy, in combination with bevacizumab and in combination with Paclitaxel.
Results: VB-111 was found to induce a dose dependent reduction of up to 90% in tumor burden of lung metastases in Lewis Lung metastasis model. Evaluation of the combined therapy with VB-111 and Avastin in Lewis Lung metastasis model showed no additive effect of Avastin 4 or 8 mg/kg as compared to VB-111 as a monotherapy. Additive effect was seen when mice were treated with a lower dose of VB-111 (1×10E9 VP/mouse) in combination with Paclitaxel (40mg/kg) and with higher dose of VB-111 (1×10E11 VP/mouse) with Paclitaxel (20mg/kg). No toxicity was observed as a result of the combined therapy, except for the lungs the organ weights among the different treatment groups showed minimal variation. In all the mice tested, the harvested organs were found to have normal growth pathology with no lesions or evidence of metastasis.
Monotherapy with VB-111 did not result in any toxicity and combination therapy did not introduce additional toxicities.
Conclusions: As previously shown, VB-111 was found to be safe and specific. VB-111 may provide additive effect to chemotherapy in a combination regimen. This will be further explored in clinical trials.
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 3283. doi:10.1158/1538-7445.AM2011-3283
Abstract 3310: Regulation of reprogramming factors by c-Met signaling in glioblastoma stem cells
Authors: Li Yunqing , Li Angela , Ying Mingyao , John Laterra 
Published: June 2012

Abstract
Reprogramming transcription factors such as Sox2, c-Myc, Klf4, Oct4 and Nanog have an essential role in sustaining the growth and self-renewal of embryonic stem cells. Forced expression of these reprogramming factors can reprogram differentiated somatic cells into pluripotent stem cells. Reprogramming factor overexpression has also been found in human cancer stem-like cells including glioblastoma stem cells (GBM SCs). This suggests that reprogramming factors support the self-renewing and tumor-initiating phenotype of cancer stem cells. Hence, the molecular signaling pathways that regulate reprogramming factor and their support of the cancer stem-like phenotype in GBM and other solid tumors are of considerable interest. We recently found that the tyrosine kinase c-Met oncogene up-regulates a network of reprogramming factors consisting of Oct4. Sox2, Klf4, c-Myc and Nanog in GBM-derived neurospheres that are enriched in GBM SCs. Reprogramming factor induction by c-Met was observed under serum-free culture conditions that support neurosphere-formation and in cells that were pre-differentiated in serum-containing medium. Using flow cytometry and quantitative reverse transcription-PCR, we also found that GBM neurosphere cell subpopulations expressing c-Met at high levels also express high levels of Nanog and Sox2 in comparison to low c-Met expressing cells. Using specific pharmacological inhibitors of PI(3)kinase (LY294002, wortmannin), MAPkinase (PD98059, U0126), and Stat3 (Stattic, Janus Kinase JSI-124), we found that c-Met signaling regulates reprogramming factors mainly via two parallel pathways: the Jak-Stat3 and PI(3)K-Akt pathways. Inhibiting Oct4 induction abrogated the capacity of c-Met to induce Sox2, c-Myc, and Nanog but not KLF4 expression. Inhibiting Nanog induction significantly inhibited (84% inhibition) the capacity of c-Met signaling to stimulate GBM SC self renewal as measured by neurosphere formation and Edu incorporation, 84% and 61% inhibition, respectively. Together, these findings indicate that c-Met signaling upregulates an Oct4- and Nanog-dependent reprogramming factor network that supports GBM SCs.
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 3310. doi:10.1158/1538-7445.AM2011-3310
Abstract 3321: The benefits from combined temozolomide and sunitinib in medulloblastoma cells: The antitumor effect, inhibition of invasiveness, and blocking of cancer stem cells
Authors: Kim Dong-Ok , Ra Young Shin 
Published: June 2012

Abstract
Objectives: Medulloblastoma is the most common malignant and metastatic pediatric brain tumor in children. Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. Temozolomide (TMZ) also became the standard of care for GBM patients by removing alkyl groups from the O6-position of guanine. But, there is little evidence about migration and invasion study on medulloblastoma cells treated with sunitinib or TMZ. In this study, we identified the effects of sunitinib or TMZ only, and the combination of them on migration and invasiveness in medulloblastoma cell line (DAOY). Also the characteristics of cancer stem cells were investigated. Methods and Results: The cell proliferation rate showed TMZ (1000µM) 70%, sunitinib (62.5µM) 60%, and the combination of TMZ and sunitinib (1000/62.5µM) 35% at 72hr after treatment with the drugs in DAOY cells. Treatment with sunitinib in addition to TMZ in the cells demonstrated more G2/M arrest than cells treated respective drugs at 24hr exposure of the drugs from cell cycle analysis. Through Rhodamine phalloidin staining, we also observed change of cell size and F-actin alterations in all cells treated TMZ, sunitinib only or the combination of the reagents, in contrast to cells treated DMSO as a control. And, in invasion assay using Matrigel chamber, the cells treated with combination of drugs were inhibited invasiveness the most when compared with control, sunitinib, and TMZ only at 72hr after exposure to the drugs. Moreover, when the cells were treated with sunitinib and TMZ simultaneously, migration ability from wound-healing assay represented higher than in cells treated TMZ or sunitinib only during exposure of 24hr. We investigated properties of cancer stem cells as well as characteristics of migration and invasion in cells treated the drugs analyzing the expression of protein during exposure of 24, 48, 72hr by western blotting. As a result, we identified the decreased levels of the protein such as p-PDGFR-β, p-VEGFR1, integrin-β1, MMP-9, CD44, Rac1 as migration and invasion markers, nestin, CD133, Oct3/4, Sox2 as cancer stem cell markers and O6-methylguanine methyltransferase(MGMT). Conclusions: Taken together, the combination therapy functions as very effective therapeutic tool in terms of, not only inhibititor of proliferation, migration and invasiveness, but also cancer stem cells in medulloblastoma cell line.
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 3321. doi:10.1158/1538-7445.AM2011-3321
Abstract 3359: Maspin induces MET in prostate cancer cells cultured in 3D-collagen I
Authors: Dean Ivory , Bernardo Margarida , Li Xiaohua , Dzinic Sijana , Yin Shuping , Moin Kamir , Sakr Wael , Sheng Shijie 
Published: June 2012

Abstract
The aggressiveness of carcinoma is typically associated with a significant epithelial-to-mesenchymal phenotypical shift (EMT). While several pathways have been identified as the driving force for EMT, mechanisms that epithelial cells depend on to prevent or reverse EMT are largely unknown. To this end, the tumor suppressive maspin inhibits tumor cell motility, invasion, pericellular plasminogen activation and extracellular matrix (ECM) degradation, and blocks the prostate tumor-induced bone remodeling. Furthermore, a general correlation between maspin expression and better differentiated epithelial phenotypes has been noted, with established cell lines, in an in vivo model for prostate tumor bone metastasis and in human prostate tissue specimens. The objective of the current study is to test whether maspin is sufficient to drive the program of mesenchymal-to-epithelial transition (MET). We showed that stably transfected DU145 that express maspin (M7) formed spheroid structures of polarized cells with a hollow lumen in 3D collagen I culture. The M7 acini in 3D collagen were encircled with reorganized fibrillar collagen, while the Neo control cells degraded collagen fibrils. The spheroid formation was abolished when M7 cells were transfected with maspin shRNA. Under the same condition, no redifferentiation of DU145 cells, with or without maspin, occurred in 3D Matrigel. To examine what other cellular and molecular changes are associated with the maspin-led tumor cell redifferentiation, we performed immunofluorescent staining and found that maspin correlated with highly organized β1-integrin localized on the periphery of the M7 spheroids. We confirmed the secretion of maspin protein by prostate epithelial cells. To test whether the effect of maspin on prostate epithelial cell differentiation depends on uPA or uPAR, we performed the 3D collagen spheroid formation assay in the presence of specific neutralizing antibodies. We found that only the neutralizing antibodies of either uPA or uPAR led to a slight increase of the size of the spheroids. While uPA and uPAR may be targeted as a part of the biological activities of maspin, our results suggest that the effect of maspin more than just blocks the uPA/uPAR cascade. Indeed, mRNA microarray, with cDNA derived from Neo and M7 cells grown in 2D cultures, 3D culture in collagen I and bone tumors in the Scid-Hu model, identified 32 commonly up-regulated genes and commonly down-regulated genes upon maspin expression. These epigenetic changes, along with other evidence, support the hypothesis that maspin induces MET in prostate tumor 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 3359. doi:10.1158/1538-7445.AM2011-3359
Abstract 3361: Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells
Authors: Ahmad Aamir , Aboukameel Amro , Kong Dejuan , Wang Zhiwei , Raz Avraham , Sarkar Fazlul H. 
Published: June 2012

Abstract
Phosphoglucose isomerase/autocrine motility factor (PGI/AMF), a housekeeping gene product that plays a key role in both glycolysis and gluconeogenesis pathways, is associated with invasion and metastasis of cancer cells. PGI/AMF is involved in the induction of Epithelial-to-Mesenchymal transition (EMT) phenotype in breast cancer cells, which leads to increased aggressiveness; however, the molecular mechanism by which PGI/AMF regulates EMT is not known. Here, we show, for the first time, that the over-expression of PGI/AMF leads to an increase in the DNA-binding activity of NF-κB, which in turn causes increased expression of ZEB1/ZEB2. Since microRNA-200s (miR-200s; miR-200a, miR-200b and miR-200c) are known to negatively regulate the expression of ZEB1/ZEB2, we assessed their expression and found that the expression of miR-200s was lost in PGI/AMF over-expressing MCF-10A cells as well as in highly invasive MDA-MB-231 cells, which was consistent with increased expression of ZEB1/ZEB2. Moreover, silencing of PGI/AMF expression in MDA-MB-231 cells led to re-expression of miR-200s, which was associated with the reversal of EMT phenotype i.e. Mesenchymal-to-Epithelial Transition (MET), and these findings were consistent with alterations in the relative expression of epithelial (E-cadherin) and mesenchymal (vimentin, ZEB1, ZEB2) markers, and decreased aggressiveness, as judged by clonogenic, motility and invasion assays. Silencing of PGI/AMF was also found to result in significantly reduced pulmonary metastases in vivo. Collectively, these results suggest, for the first time, the role of miR-200s in PGI/AMF induced EMT-MET, and thus clinical approaches for up-regulation of miR-200s could become a novel therapeutic strategy for the treatment of highly invasive breast cancer.
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 3361. doi:10.1158/1538-7445.AM2011-3361
Abstract 337: HPV16 infection plays a significant role in laryngeal carcinogenesis among Puerto Ricans
Authors: Vélez-Reyes Germán L. , Ruiz-Fullana Francisco J. , García Aurian , Trinidad-Pinedo Juan , Baez Adriana 
Published: June 2012

Abstract
Aims: Incidence of head and neck cancer (HNSCC) has increased in the past decades in younger adults. Oncogenic proteins E6 and E7 in HPV 16 are known to block the p53 and pRB pathways leading to abnormal cell growth and development of cancer. We have shown that human papillomavirus type 16 (HPV-16) plays a significant role in the etiology of head and neck cancer in the Puerto Rican population. Furthermore, there is an increasing trend in the incidence of oropharyngeal cancers, particularly among men under 50 years old, for which HPV infection is the likely cause. This study aims to evaluate the association between clinicopathologic and demographic characteristics of HPV16- positive HNSCC Puerto Rican patients.
Methodology: Clinical and pathological data of all newly diagnosed cancer patients was collected, after signing the informed consent. The distribution by anatomical site was as follows: 86 larynx, 16 oropharynx, 12 hypopharynx, and 70 in the oral cavity. Detection and quantification of HPV16 E6 oncoproteins in tumor tissue was made by real time PCR technology. Associations between HPV status, risk factors and tumor characteristics were analyzed.
Results: HPV16 was found in 52% of tumors tested. When the HNSCCs were analyzed by anatomical site for HPV-status, 52% of the larynx, 53% of oral cavity, 62% of oropharynx, and 42% of the hypopharynx were HPV-positive. The highest prevalence was observed in patients under the age of 60 years. No significant association was found between HPV status and histological grade, alcohol usage, and smoking status.
Conclusions: Our results suggest that the high HPV DNA present in laryngeal HNSCCs indicates that HPV16 has significant role in the development of SCC of the larynx in Puerto Ricans. These results may be further validated in a larger sample of patients.
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 337. doi:10.1158/1538-7445.AM2011-337