bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3467: A novel interplay between Rap1, Epac and PKA regulates induction of angiogenesis
Authors: Menon Jyotsana , Doebele Robert C. , Rosner Marsha R. 
Published: June 2012

Abstract
Advanced stage prostate cancer is associated with poor prognosis since therapeutic options are limited when the disease has progressed into a hormone refractory state. One therapeutic strategy is angiogenesis inhibition, which interferes with the blood supply of the tumor instead of targeting tumor cells directly. Here we focus on the role of three factors as regulators of angiogenesis: Rap1, a small GTPase homologous to Ras; Epac, a cAMP-activated guanine nucleotide factor for Rap1; and Protein kinase A (PKA), a cAMP-activated kinase. In previous studies, we showed that activation of Epac/Rap1 in human microvascular endothelial cells (HMVECs) inhibited VEGF-mediated chemotaxis and angiogenesis in a SCID mouse model of human angiogenesis. To test the efficacy of Epac/Rap1 activation in a prostate tumor xenograft model, we analyzed the effects of constitutive Rap1 or 8 CPT-2Me-cAMP (8CPT), a strong Epac agonist and weak PKA agonist, in PC-3 cells. PC3 cells rank high in expression levels of Rap1. Surprisingly, although 8CPT did not alter tumor growth in PC-3 cells, the drug significantly reduced tumor size in PC-3 cells expressing constitutively active Rap1. Tumor analysis showed an increase in VEGF and CD31 immunostaining in Rap1-expressing tumors, and a significant decrease in their levels upon treatment of the mice with 8CPT. To understand the mechanism of tumor inhibition, we cultured PC-3 cells under hypoxic conditions that mimic the tumor microenvironment. As observed in vivo, constitutive Rap-1 expression induced VEGF and Glut-1 mRNA levels as well as HIF-1α protein, and 8CPT reversed this effect. However, in contrast to HMVECs, 8CPT acts in PC-3 cells via PKA. A PKA activator mimicked 8CPT by inhibiting VEGF secretion in PC3-Rap1 cells under hypoxic conditions. Furthermore, the PKA inhibitor, H-89, reversed the inhibition of VEGF secretion in PC3-Rap1 cells in culture and inhibited growth in mouse xenografts. Thus, expression of Rap1 in PC-3 human prostate tumor cells promotes hypoxic induction of angiogenesis and increases the susceptibility of the cells to PKA inhibition. Taken together, our results suggest that a novel interplay between Rap1, Epac and PKA regulates tumor-microenvironment induction of angiogenesis.
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 3467. doi:10.1158/1538-7445.AM2011-3467
Abstract 3468: MMP-9 inhibition abolishes hypoxia-induced angiogenesis in medulloblastoma
Authors: Chetty Chandramu , Bhoopathi Praveen , Rao Jasti S. , Lakka Sajani S. 
Published: June 2012

Abstract
Hypoxia-inducible factor-1 (HIF-1) transcription factor is a critical mediator of the hypoxic response and upregulates expression of various proteins that promote angiogenesis and many other survival pathways in cancer. Overexpression of HIF-1α and matrix metalloproteinase-9 (MMP-9) is common in human cancers, including medulloblastoma, and is correlated with a malignant phenotype. Therefore, we investigated the effects of hypoxia-induced MMP-9 on angiogenesis in medulloblastoma cells. Western blotting and immunohistochemical analysis showed that hypoxia enhanced stabilization of HIF-1α and expression of VEGF and MMP-9 in medulloblastoma cells in vivo and in vitro. Further, endothelial tube formation assay in vitro and dorsal air sac assay in vivo showed that hypoxia enhanced angiogenesis in medulloblastoma cells. Transcriptional inactivation of MMP-9 using siRNA (pMMP-9-Si) inhibited hypoxia-induced stabilization of HIF-1α, and induced expression of VEGF and prolyl hydroxylase. Moreover, supplementation of human recombinant MMP-9 in MMP-9-Si-transfected cells restored VEGF expression and angiogenesis. In summary, the results of the present study indicate that MMP-9 upregulation could be an important mediator of tumor hypoxia-induced angiogenesis. Therefore, inhibition of MMP-9 could be an effective therapeutic strategy for the treatment of hypoxic medulloblastoma 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 3468. doi:10.1158/1538-7445.AM2011-3468
Abstract 3471: Antibody-directed neutralization of fibrinolytic receptor annexin II inhibits human breast cancer growth in a xenograft model
Authors: Sharma Meena , Blackman Marc , Sharma Mahesh C. 
Published: June 2012

Abstract
The fibrinolytic pathway has long been known to be associated with breast cancer. Plasmin is the major end product of fibrinolytic pathway and is critical for normal physiological functions. The mechanism(s) by which plasmin is generated in breast cancer is not yet fully understood. Previously we identified ANX II, a fibrinolytic receptor, in human breast cancer samples and observed a strong positive correlation with advanced stage of cancer. We further demonstrated that the tissue plasminogen activator (tPA) binds to ANX II in invasive breast cancer MDA-MB231 cells which at least in part responsible for plasmin generation. We hypothesized that ANX II-dependent plasmin generation in breast cancer is necessary to activate the switch for neoangiogenesis thereby promoting aggressive cancer phenotype. Our immunohistochemical studies of human breast cancer tissues demonstrate strong positive correlation between annexin II expression and neoangiogenesis. These data not only indicate a link between ANX II and neoangiogenesis but also suggest that ANX II may be a potential target to slow or inhibit breast cancer growth by inhibiting neoangiogenesis. In this report we show that administration of anti-ANX II antibody potently inhibits the growth of human breast cancer in a xenograft model. Inhibition of tumor growth was due to inhibition of neoangiogenic activity within the tumor. In vitro studies demonstrated that anti-ANX II antibody inhibited angiogenesis on three dimensional matrigel cultures. The inhibition of in vitro angiogenesis was due to endothelial cell (EC) apoptosis. Taken together, these data suggest that selective disruption of fibrinolytic activity of ANX II may be a novel strategy for inhibition of neoangiogenesis in human 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 3471. doi:10.1158/1538-7445.AM2011-3471
Abstract 3478: Latent KSHV infection increases the vascular permeability of endothelial cells
Authors: Damania Blossom , Guilluy Christophe , Zhang Zhigang , Burridge Keith 
Published: June 2012

Abstract
Infection with Kaposi's sarcoma-associated herpesvirus (KSHV) is closely linked to the development of Kaposi's sarcoma (KS). The KS lesion is driven by KSHV-infected endothelial cells and is highly dependent on autocrine and paracrine factors for survival and growth. We report that latent KSHV infection increases the vascular permeability of endothelial cells. Latent KSHV-infected endothelial cells display increased Src kinase activity, increased Rac1 activation and activation of its downstream modulator, p21 activated kinase (PAK1). The KSHV-infected endothelial cells exhibited increases in tyrosine phosphorylation of VE-cadherin and β-catenin, while total levels of these proteins remained unchanged, suggesting that latent infection disrupted endothelial cell junctions. Consistent with these findings, we found that latent KSHV-infected endothelial cells were more permeable than uninfected endothelial cells. Knockdown of Rac1, as well as inhibition of ROS, resulted in decreased permeability of the KSHV-infected endothelial cells. In sum, KSHV latent infection increases the vascular permeability of infected endothelial cells thereby contributing to the pathogenesis of Kaposi's sarcoma.
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 3478. doi:10.1158/1538-7445.AM2011-3478
Abstract 3494: Combining ATRA and GSK3 inhibition in AML
Authors: Gupta Kalpana , Sun Lillian , Agarwal Divya , Ramdeo Ritu , Wald David 
Published: June 2012

Abstract
Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of all-trans retinoic acid (ATRA) for a rare subtype of AML (APL, 5-10% of AML). The use of the differentiation agent, ATRA, in combination with low dose chemotherapy leads to the long term survival and presumed cure of 75-85% of patients. Unfortunately ATRA is not clinically useful for other subtypes of AML. Though the non-APL leukemic cells also express retinoic acid receptors (RAR), they require significantly higher concentrations of ATRA for effective differentiation. The requirement for high doses of ATRA for differentiation is at least partially due to the fact that ATRA initiates a negative feedback loop resulting in the degradation of RAR. This feedback loop limits the magnitude and duration of its effects. Despite the high clinical significance of inhibiting the degradation of RAR to enhance the efficacy of ATRA, little is known about the pathways leading to RAR degradation. Our data suggests that the kinase, GSK3, plays a role in RAR degradation. Utilizing genetic and biochemical approaches with AML cell lines and mouse xenograft studies, we have identified that inhibition of GSK3 in combination with ATRA is a promising strategy to induce AML differentiation and growth inhibition. For example, the combination of ATRA and GSK3 inhibitors including Lithium and SB415286 leads to a significant enhancement in anti-tumor activity in a mouse AML xenograft model system. Mechanistically, our data suggests that GSK3 enhances ATRA activity through modulating the expression of RAR. Utilizing HL-60 cells, we have found that not only can endogenous GSK3 and RAR physically interact, but GSK3 can directly phosphorylate RAR and modulate its stability. After the addition of GSK3 inhibitors, the interaction with RAR is disrupted and the GSK3-mediated phosphorylation of RAR is blocked. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen.
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 3494. doi:10.1158/1538-7445.AM2011-3494
Abstract 3495: Targeted therapies in melanoma – in vitro effects of single and combined drug treatment
Authors: Azimi Alireza , Egyházi Suzanne , Johansson Carolina , Hansson Johan 
Published: June 2012

Abstract
Malignant melanoma is one of the most rapidly increasing malignancies in Caucasian populations. So far, curative treatment is achieved only by surgical resection at an early stage, while the prognosis in cases with disseminated melanoma is poor, and we lack predictive tools to identify the few patients who respond to existing chemotherapy. Promising clinical trials of targeted therapies are ongoing, however, it is already clear that drug resistance will be a clinical reality also for these new therapies. Thus, novel predictive markers are urgently needed to identify responders to different types of therapy in melanoma.
The aim of the study is to unravel molecular mechanisms and pathways underlying resistance to new therapies in melanoma.
We are studying the effects of a set of MAPK and PI3K pathways inhibitors in melanoma cell lines that are wildtype or have different mutations/deletions in genes affecting these pathways (BRAF, NRAS, PTEN etc.). Cells are exposed to single drugs as well as combinations of inhibitors and/or chemotherapeutic agents.
Our results have shown that there is a wide range of sensitivity to the BRAF inhibitor PLX4720 among BRAF mutated cell lines, with IC50 values varying from 0.3 µM to 30 µM. We are investigating the underlying mechanisms causing this variation in sensitivity to the drug. Using gene expression profiling of a clinical material, we have identified several candidate genes that may predict response to DNA alkylating agents dacarbazine and temozolomide. The expression of some of these genes can be affected by PLX4720, and their potential relevance for response to different treatments is currently tested in vitro.
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 3495. doi:10.1158/1538-7445.AM2011-3495
Abstract 3508: High antitumor activity of cetuximab combined with taxotere-cisplatin-flourouracil (TPF) association on an orthotopic head and neck cancer model
Authors: Bozec Alexandre , Sudaka Anne , Etienne-Grimaldi Marie-Christine , Fischel Jean-Louis , Milano Gérard Alain 
Published: June 2012

Abstract
Background : Cetuximab (cetux), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard of care in advanced head and neck (HN) cancer when combined with irradiation or cisplatin. The TPF association including taxotere (T), cisplatin (P) and fluorouracil (F) has become a chemotherapy of reference in the management of HN tumors. The aim of the study was to evaluate the antitumor activity of the association of cetux with TPF. In addition the potential benefit to add bevacizumab (beva), an anti-VEGF monoclonal antibody, was also examined.
Methods : investigations were performed on CAL33 human head and neck cancer cell line (high content of EGFR) injected as an orthotopic xenograft into the mouth floor of nude mice. The anti-tumor efficacy of cetux 2,5 mg/kg, beva 20 mg/kg and of TPF at the MTD (T : 20 mg/kg, P : 6 mg/kg, and F : 17mg/kg) administered alone or in combination at day 3 and 10 after tumor cell injection was assessed at day 12 (animal sacrifice for ethical reasons, 10 animals per treatment group). Tumor volume, tumor histology, tumor cell proliferation (Ki67 by immunohistochemistry) and apoptosis (Bcl2 by immunohistochemistry) were examined. Statistical analyses were performed according to non-parametric methods.
Results : As compared to controls, TPF-cetux and TPF-cetux-beva had a significant impact on tumor volume and histological response. The highest efficacy was observed with the combination TPF-cetux. The effects of the association TPF-cetux-beva were not significantly different than those observed with TPF-cetux. Data were corroborated by a diminution in Ki67 labelling and Bcl2 expression.
Conclusion : the association of cetux with TPF could be an interesting clinical option to evaluate in advanced HN cancer 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 3508. doi:10.1158/1538-7445.AM2011-3508
Abstract 3510: Fluvastatin enhances sorafenib cytotoxicity in melanoma cells via modulation of AKT and JNK signaling pathways
Authors: Doudican Nicole A. , Zhang Shali , Quay Ellinor , Orlow Seth J. 
Published: June 2012

Abstract
Background: Most metastatic melanomas are refractory to current available therapy, underscoring the need to identify new effective treatments. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, showed promise in earlier stages of clinical development, but ultimately failed to demonstrate efficacy as a single agent in the treatment of melanoma. In order to enhance the efficacy of sorafenib in the treatment of melanoma, we tested over 2,000 naturally occurring compounds and marketed drugs in the presence of a sorafenib in two chemoresistant human melanoma cell lines (M14 and SKM-173) resistant to sorafenib-induced apoptosis. Of the 9 compounds identified as sorafenib sensitizers, we prioritized the cholesterol lowering agent fluvastatin based on its favorable pharmacokinetics and safety profile.
Methodology: Growth inhibition was examined by MTT assay in a panel of 6 human melanoma cell lines. Drug interaction was analyzed by Calcusyn software which determines the effects of two drugs (i.e., synergy, antagonism, or additivity) through calculations of the combination index (CI). The effect of combination therapy on cellular signaling and induction of apoptotic pathways was evaluated by immunoblotting techniques.
Results: Our results demonstrate that fluvastatin at 1µM, a level which is safely achieved through oral administration, dramatically enhances the growth inhibitory activity of clinically achievable concentrations of sorafenib in M14 and SKM-173 melanoma cells with a 3.2 and 3.6-fold reduction in the sorafenib GI50, respectively, with similar effects observed in other melanoma cell lines. Combination indices analysis revealed a synergistic relationship between the two agents. Fluvastatin enhances sorafenib-mediated apoptosis as revealed through enhanced cleavage of PARP. In combination with sorafenib, fluvastatin treatment results in reduced levels of activated AKT along with enhanced levels of activated JNK. Sensitization to sorafenib is unique to fluvastatin as other statins (ie. pravastatin and simvastatin) do not enhance sorafenib-mediated growth inhibition.
Conclusions: These promising results warrant further investigation into the clinical applicability of fluvastatin as an agent for enhancing the efficacy of sorafenib in the treatment of melanoma. Fluvastatin sensitization to sorafenib will be further addressed through follow-up studies in mouse melanoma xenograft models.
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 3510. doi:10.1158/1538-7445.AM2011-3510
Abstract 3531: Functional characterization of genes that sensitize pancreatic cancer cells to gemcitabine
Authors: Bhattacharjee Vikram 
Published: June 2012

Abstract
Pancreatic cancer has been one of the most aggressive cancers to date. At the point of diagnosis, most patients’ life expectancies are measured in months. While several chemotherapeutic agents have been used to treat pancreatic cancer, none have been very successful in prolonging a patient's lifespan in a major way. Pancreatic adenocarcinoma, the major form of pancreatic cancer, has several risk factors including chronic pancreatitis, advanced age, smoking, obesity, diabetes, and genetic predispositions. Chronic pancreatitis has been thought to promote tumorigenesis ultimately resulting in pancreatic adenocarcinoma. Presently, several classes of drugs (anti-proliferative agents, platanating agents, fluoropyrimidines, and taxanes) are used in the clinic to treat pancreatic cancer, but patient response is very poor when compared to other cancers. Therefore, there is an urgent need to identify novel molecular targets that sensitize pancreatic cancer cells to chemotherapeutic agents.
Gemcitabine (an inhibitor of DNA replication) is of particular interest to us because it remains the drug of choice in the treatment of pancreatic cancer. We have completed a genome wide RNA interference (RNAi) screen and have identified numerous targets that greatly sensitize pancreatic cancer cells to gemcitabine. In the screen, every gene in the human genome was ablated individually via RNAi, so we can identify gene candidates that negatively affect cell survival following drug treatment. We have finalized our validated gene target list. We have utilized automated microscopy tools in addition to molecular biological approaches that are established in our lab in order to chronicle in real time how these pancreatic cancer cells are being sensitized to gemcitabine either via aberrant mitotic processes, direct induction of apoptosis, or other forms of cell death. Indeed, we have found two distinct stages of the cell cycle where death is prevalent. We have the capacity to observe the cells at every stage of the cell cycle before, during, and after the addition of drug. We have established pancreatic cancer cells lines that stably express fluorescent marker proteins that enable us to observe and get a handle on how these cancer cells are surviving drug treatment and how coupling siRNA treatment with chemotherapy sensitizes these cells. We have focused on two major pathways that are aiding cell survival in order to characterize major players that help pancreatic cancer cells survive drug treatment.
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 3531. doi:10.1158/1538-7445.AM2011-3531
Abstract 3540: Characterization of a novel class of P70S6K in preclinical models
Authors: Araldi Gian Luca , Ronsheim Matthew , Diep Nhut , Guan Ruth , Kalyan Yuriy , Liolis Ira , Ronsheim Melanie , Tang Fuxing 
Published: June 2012

Abstract
P70S6K is a serine/threonine protein kinase responsible for the phosphorylation/ regulation of several important targets like S6, BAD, and IRS1/2. It acts downstream of the mammalian target of Rapamycin (mTOR) and regulates cell growth, proliferation, survival and migration via control of protein translation and a number of important downstream effectors. The over-expression of P70S6K confers clinical aggressiveness in solid tumors, and several findings using indirect inhibition (mTOR inhibitors) or biological tools (RNAi) suggest a critical role for p70S6K signaling in the regulation of invasion and cell motility, making selective inhibitors of this kinase potential anti-metastatic agents. A novel class of phthalazine derivatives were developed that are potent and selective inhibitors of P70S6K, with IC50s for P70S6K in the low nM to sub μμ ρανγε. We have used these inhibitors to further demonstrate and confirm the usefulness of this target for the treatment of metastatic cancers. The effect of the P70S6K inhibitors in regulating cell invasion and motility were determined in several breast (MDA-MB-231, MDA-MB-468), prostate (DU-145, PC-3, and RWPE-2), and melanoma (A-375) cancer cell lines using the modified Boyden chamber assay. All the compounds tested showed dose-dependent inhibitory activity against tumor cell motility and invasion. The activity of these compounds is broad against all the cancer cell lines tested. The activity of our p70S6K inhibitors is comparable to Rapamycin and MEK inhibitors (PD325901), supporting the hypothesis that p70S6K may be a key component for both pathways. Besides the potent in vitro activity, our Lead compound was also effective in the systematic B16-F10 murine melanoma tumor model.
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 3540. doi:10.1158/1538-7445.AM2011-3540