bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5200: Role of MLK3 in breast cancer cell migration and metastasis
Authors: Sondarva Gautam , Mehrotra Suneet , Mishra Rajakishore , Rangasamy Velusamy , Fareed Jawed , Rana Basabi , Rana Ajay 
Published: February 2011

Abstract
Effectively treating breast cancer metastasis is one of the biggest challenges in breast cancer therapy. The overall poor prognosis associated with cancer cell migration to distal organs underscores the critical need to understand the biology of the disease in order to develop more effective therapies. Members of protein kinase family have often been targeted for therapeutic purposes in different types of cancer, including breast cancer, and several protein kinase inhibitors are currently in clinical trials for specific types of cancer.
The members of Mixed Lineage Kinases (MLKs) are novel family of MAP3Ks and their physiological function is not known, however, we and others have shown that several of MLK family members activate Jun- N-terminal Kinases (JNKs) and MLK activation regulates survival in neuronal cells. Recently, we have seen that MLK3 is highly expressed in invasive breast cancer cell lines and in primary breast tumors, compared to the normal mammary tissue from same patient. Since MLK3 was initially identified from platelet cell line, CMK11-5, and association of venous thrombosis and occult cancer was recognized almost 140 years ago, we hypothesized that MLK3 or other MLKs are important in proteinase receptor-mediated signaling. Furthermore, the downstream effectors of proteinase receptors (PARs) that mediate the breast cancer cell growth, migration and metastasis to distal organs are currently unknown.
We examined the role of MLK3 in thrombin mediated signaling in a highly invasive breast cancer cell line, MDA-MB-231. Thrombin treatment of these cells activated MLK3 kinase in a time dependent manner. MLK3 was activated within 2 minutes of thrombin treatment and the activity peaked at 5 minutes, and was associated with consequent activation of its downstream target JNK. Furthermore, pretreatment of MDA-MB-231 with an MLK inhibitor, CEP-11004 completely blocked thrombin-induced JNK activation. Importantly, we also discovered that thrombin induces MLK-dependent migration in MDA-MB-231 cell line was blocked by MLKs inhibitor, CEP-11004.
These results collectively suggest that MLK3 is an important target of proteinase receptors-mediated migration/invasion/metastatic pathways, and help us to identify MLK family members’ inhibitors as viable drugs to treat metastatic breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5200.
Abstract 5210: PRL-1 promotes cell metastatic processes and regulates filamentous actin dynamics
Authors: Nakashima Masanao , Lazo John S. 
Published: February 2011

Abstract
The phosphatases of regenerating liver (PRL) are a family of the protein tyrosine phosphatases that have been hypothesized to be involved in metastatic cancer. While the PRLs appear to regulate cancer cell migration, invasion and proliferation, we do not fully understand mechanistically how they control these processes. In the current study, we present new findings demonstrating that PRL-1 regulates filamentous actin dynamics, which could promote cell metastatic processes. Human A549 non-small cell lung cancer cells stably expressing wildtype PRL-1 exhibited a 60% increase in cell migration at 72 hours and a three-fold increase in cell invasion at 24 hours. Cells expressing catalytic mutants of PRL-1 (C104S and D72A) did not demonstrate increased cell migration and invasion, indicating that these phenotypic changes required the PRL-1 phosphatase activity. PRL-1 siRNA decreased PRL-1 protein levels by 50% and decreased cell migration by 25%. Cellular invasiveness is controlled by the cadherin-catenin complex and dynamic filamentous actin. We found wildtype PRL-1 interrupted E-cadherin and regulated Rho family kinase function, which have important roles in actin filament assembly and stabilization of focal adhesion. We also observed that expression of wildtype PRL-1 caused diffusely disassembled F-actin with reduced F-actin levels as compared to that seen in cells expressing the vector control or the catalytic mutant. We conclude the PRL-1 enhanced lung cancer cell migration and invasion. These results suggest PRL-1 could be a productive therapeutic target for cancer metastasis and support further efforts to identify its substrates.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5210.
Abstract 5212: Akt signaling enhances carcinoid cell secretion, migration, and invasion
Authors: Silva Scott R. , Li Jing , Bowen Kanika A. , Townsend Courtney M. , Evers B. M. 
Published: February 2011

Abstract
Carcinoid tumors are slow growing neuroendocrine tumors characterized by the secretion of peptides and biogenic amines such as serotonin (5-HT) and TGF-β. Although relatively indolent, carcinoid tumors of the GI tract can metastasize to the liver and release secretory products into the systemic circulation resulting in the carcinoid syndrome. PI3K/Akt signaling is increased in carcinoid tumors and is hypothesized to promote carcinoid progression. The purpose of our current study was to delineate the role of Akt signaling in carcinoid cell secretion, migration, and invasion using the BON cell line, derived from a human pancreatic carcinoid tumor. Methods. i.) BON cells were transfected with either non-targeting control shRNA (BON shControl) or shRNA to PTEN (BON shPTEN), the natural inhibitor of Akt activation. Conditioned media was collected from BON shControl and shPTEN cells and assessed for 5-HT and TGF-β by ELISA. Western blots were performed to assess changes in the expression of 5-HT and TGF-β. ii.) Scratch and Boyden chamber assays were performed to compare the migration and invasion, respectively, of BON shControl and shPTEN cells. The protein levels of the epithelial-to-mesenchymal transition (EMT) markers E-cadherin, a cell adhesion protein, and snail were assessed in both cell groups with western blot. Cells were injected into the pancreas of athymic nude mice and liver metastases were assessed via immunofluorescence. Results. i.) Knockdown of PTEN increased the secretion of 5-HT and TGF-β from BON cells. Compared to control, lysates from BON shPTEN cells displayed increased expression of tryptophan hydroxylase, the rate limiting enzyme of 5-HT biosynthesis, and TGF-β. ii.) Compared to BON shControl cells, BON shPTEN cells exhibited a 3.2- and a 1.6-fold increase in migration at 24 h and 48 h, respectively. At 24 h BON shPTEN cells displayed an 8-fold increase in invasion, while at 48 h a 2.6-fold increase in invasion was noted compared to BON shControl cells. Knockdown of PTEN in BON cells significantly decreased E-cadherin expression, whereas snail expression was increased. BON shPTEN and BON shControl cells formed liver metastases in 60% and 10% of mice, respectively. Conclusions. The Akt pathway enhances carcinoid cell secretion and metastatic potential by increasing expression and synthesis of secretory products and by altering expression of EMT markers, respectively. In addition to promoting metastasis, Akt signaling may also contribute to carcinoid syndrome. These results suggest that targeting Akt signaling may provide a dual strategy to decrease peptide secretion and inhibit carcinoid cell invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5212.
Abstract 5220: Early prediction of tumor response to APO866 treatment with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography in human ovary cancer xenografts in mice
Authors: Jensen Mette Munk , Erichsen Kamille Dumong , Björkling Fredrik , Madsen Jacob , Højgaard Liselotte , Sehested Maxwell , Kjær Andreas 
Published: February 2011

Abstract
Introduction: APO866 is a new anti-tumor compound found to inhibit nicotinamide phosphoribosyltransferase (NAMPT), an enzyme involved in the biosynthesis of NAD. The compound has anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3′-deoxy-3′-[18F]fluorothymidine (FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to evaluate if FLT positron emission tomography (PET) may be used to monitor early anti-proliferative effects of APO866.
Methods: In vivo uptake of FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment (15 mg/kg ip twice daily for 7 days) was initiated. Baseline FLT scans were made before either APO866 (n=10 tumors) or vehicle (n=6 tumors) was injected and repeated after 24 hours (2 treatments), 48 hours (4 treatments) and 7 days (14 treatments). Tumor volume was followed with computed tomography (CT) during the experiment. FLT uptake was quantified using small animal PET/CT. One hour after iv injection of 10 MBq FLT, static PET scans were performed for 10 minutes and region of interests (ROIs) covering whole tumors were defined on PET/CT images for calculation of standard uptake values (SUV). Comparison within treatment groups was performed using paired t-tests and between control and APO866 groups with unpaired t-tests. All p-values were corrected for multiple comparisons using the Bonferroni algorithm. P&lt;0.05 was considered significant.
Results: Tumors treated with APO866 had volumes that were 122% (24h), 129 % (48h) and 88% (day 7) relative to baseline volumes day 0. In the control group tumor volumes were 123% (24h), 150% (48h) and 318% (day 7) relative to baseline volumes day 0. Tumor volume between groups were significantly different at day 7 (P=0.006). APO866 treatment caused significant decrease in uptake of FLT at 24 hours (−23%; P&lt;0.001), 48 hours (−29%; P&lt;0.001) and day 7 (−25%; P=0.0013) after treatment start compared to baseline uptake. In the control group uptake of FLT did not change.
Conclusions: APO866 treatment caused a significant decrease in FLT uptake 24 and 48 hours after injection of first dose. The early reductions in tumor cell proliferation preceded decrease in tumor volume on day 7. Our data indicate that FLT PET is promising for early non-invasive assessment of APO866 anti-tumor effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5220.
Abstract 5223: Towards MYC targeted cancer therapy: Noninvasive molecular imaging of c-Myc signaling
Authors: Fan-Minogue Hua , Cao Zhongwei , Ramasamy Paulmurugan , Carmel Chan , Massound Tarik , Dean Felsher , Gambhir Sanjiv 
Published: February 2011

Abstract
MYC protein regulates a variety of human genes and is deregulated in most of human cancers. The deregulation of MYC is at multiple levels, from gene transcription to mRNA translation and protein activity. Activation of Myc protein is phosphorylation-mediated and has been found to be essential for development of many cancers. Here, we developed a bioluminescent sensor, using protein assisted split luciferase complementation system, to noninvasively detect the phosphorylation-mediated activation of the cytoplasmic Myc (c-Myc). In this sensor system, the c-Myc phosphorylation motif and the phosphorylation recognition domain of GSK3beta were fused with the two split luciferase fragments respectively. Phosphorylation induced c-Myc interaction with GSK3beta resulted in complementation of the two split luciferases and reconstitution of luciferase activity. Signal of the optimal sensor was specific for the c-Myc phosphorylation. It detected as low as 2-fold higher levels of c-Myc phosphorylation in cancer cells versus normal cells. It also detected the temporal regulation pattern of c-Myc phosphorylation upon serum stimulation in normal cells. MAP kinase inhibitor, PD98059 and U0126, and Atorvastatin (AT), induced dose dependent signal reduction in tumor cells, which was correlated with the decrease of endogenous c-Myc phosphorylation. In mouse tumor xenograft models, the sensor detected the inhibitory effects of AT well before there was a detectable difference in tumor size (P&lt;0.05). For the first time, we developed a sensor that can noninvasively monitor phosphorylation mediated c-Myc activation. It may also facilitate drug development by allowing rapid readout of inhibition effect in high throughput drug screen for MYC-targeted cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5223.
Abstract 5236: Intermittent anti-angiogenic therapy with sunitinib in a murine xenograft model monitored by dynamic contrast enhanced ultra high frequency sonography
Authors: Hunnam Titaina C. Potdevin , Tuthill Theresa A. , Dorow Donna S. , Cullinane Carleen , McCarthy Timothy J. , Hicks Rodney J. 
Published: February 2011

Abstract
Sunitinib is an orally bio-available small-molecule inhibitor that targets multiple pro-angiogenic receptor tyrosine kinases including VEGFR, PDGFR, c-KIT, FLT3, CSF-1R and RET. Sunitinib treatment induces growth arrest or regression in a range of preclinical tumour models via its anti-tumour and anti-angiogenic effects. An intermittent 4 weeks on, 2 weeks off sunitinib dosing schedule is routinely used in the clinic to reduce pharmacologic toxicity of the compound. However, the effects of treatment withdrawal on tumour vasculature are currently poorly defined. The aim of this study was to use dynamic contrast enhanced ultra high frequency sonography (DCE-UHS) to investigate the effects of intermittent therapy on vascular function in a preclinical xenograft tumour model. Nude mice bearing A431 human squamous cell tumours (mean volume 296 +/− 19 mm3) were randomized to receive either vehicle or 80 mg/kg sunitinib p.o. daily following a treatment regimen of 6 days on, 7 days off, 7 days on (n = 4/group). During the 20 day regimen period, mean tumour volumes in the sunitinib treated group regressed by 42% at day 6 but increased by 38% during the off treatment period days 6 - 13. Upon resuming sunitinib therapy, tumour volumes decreased once again by 13% (days 13 - 20). Mean tumour volumes in the vehicle treated group reached 561+/−27 mm3 at day 6 becoming too large for DCE-UHS measurements and were thus removed from the remainder of the experiment. DCE-UHS was performed at baseline and during the treatment regimen at days 4, 6, 11, 13, 17 and 20. Measures of tumour perfusion including relative fractional blood volume (RFBV; percentage of tumour volume with blood flow) and mean refill rate (MRR, mean rate at which blood re-perfuses a defined tumour area) are calculated from the DCE-UHS data. During the treatment periods, mean RFBV in the treated animals decreased by 52% (p = 0.011; days 0-6) and 55% (p = 0.021; days 13-20) and MRR by 77% and 72% (p values not significant). However, during the intervening off treatment period tumor perfusion increased by 66% RFBV and 58% MRR. While these data clearly demonstrate the inhibitory effects of sunitinib treatment on tumour perfusion they also highlight the rapid reversibility of the anti-vascular effects of the drug. Further, the study demonstrates the utility of DCE-UHS to investigate effects of intermittent sunitinib therapy on vascular parameters.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5236.
Abstract 5251: Endosialin: A novel cell surface therapeutic target for early-stage and late-stage neuroblastoma
Authors: Rouleau Cecile , Smale Robert , Kurtzberg Leslie , Weber William , Jones Craig , Roth Stephanie , Bormann Christy , Dunham Sarah , Krumbholz Roy , Curiel Maritza , Wallar Gina , Fu Yao-Shi , Horten Bruce , Gianolio Diego , Schmid Steven , Miller Glenn , Teicher Beverly A. 
Published: February 2011

Abstract
Hypothesis: Endosialin emerged recently as a potential marker and therapeutic target for adult and pediatric sarcoma. Given evidence of a possible common progenitor cell for mesenchymal and neural cell lineages, we wondered whether expression of endosialin may be shared by sarcomas and neuroblastomas, which are cancers of mesenchymal origin and neural crest origin, respectively.
Methods: Endosialin protein expression was studied in live human neuroblastoma cell lines by flow cytometry using a fully human monoclonal antibody against human endosialin. Endosialin-positive human neuroblastoma cells were subsequently implanted at different anatomic sites in nu/nu mice and allowed to grow. Tumors were collected, formalin fixed and subjected to immunohistochemistry using a fully human monoclonal antibody against human endosialin. Using the same IHC assay, endosialin protein expression was also studied in formalin-fixed paraffin-embedded human clinical specimens of neuroblastoma.
Results: We tested 10 human neuroblastoma cell lines for endosialin protein expression by flow cytometry and found that 9/10 expressed endosialin. Several of the positive cell lines were derived from bone marrow metastases, suggesting that endosialin expression is maintained in advanced disease. We modeled endosialin-positive neuroblastoma in vivo by implanting SK-N-AS cells in mice subcutaneously and in the subrenal capsule, kidney being a site where neuroblastoma sometimes originates. Immunohistochemical analysis revealed that SK-N-AS cells, which are positive for endosialin in vitro and derived from the bone marrow metastasis of an adrenal primary tumor, formed endosialin-positive subcutaneous tumors and endosialin-positive renal tumors, demonstrating that endosialin expression is supported by different microenvironments in various anatomic locations.
Immunohistochemistry of human clinical specimens of neuroblastoma showed expression of endosialin. All specimens of neuroblastoma were bone marrow metastases, demonstrating that endosialin is expressed in advanced disseminated neuroblastoma.
Conclusions: Our work demonstrates that endosialin expression is shared by sarcomas and neuroblastomas. The expression of endosialin in neuroblastoma potentially opens up a new therapeutic horizon for neuroblastoma patients, including those suffering from advanced disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5251.
Abstract 5257: Preclinical evaluation of lestaurtinib (CEP-701) with the retinoids for neuroblastoma
Authors: Norris Robin E. , Minturn Jane E. , Brodeur Garrett M. , Maris John M. , Adamson Peter C. 
Published: February 2011

Abstract
Purpose
Lestaurtinib (CEP-701), a selective and potent inhibitor of the Trk family of receptor tyrosine kinases, has undergone initial clinical evaluation in children with relapsed neuroblastoma. We studied the interaction of CEP-701 with 13-cis retinoic acid (13cRA) and fenretinide (4HPR), two retiniods that have been studied in children with high-risk neuroblastoma.
Methods
In a panel of 5 neuroblastoma cell lines (CHP-134, IMR-5, E6-NBLS, SH-SY5Y, and the SH-SY5Y-BR6 line that has been engineered to express high levels of functional TrkB receptors), in vitro cytotoxicity was assessed following a 72-hour drug exposure using the sulforhodamine B assay. When appropriate, the combination index (CI) of Chou-Talalay was used to characterize the interaction of 13cRA (non-constant ratio) or 4HPR (constant ratio) with CEP-701.
Results
The median (range) IC50 of single agent CEP-701 across all cell lines was 0.09 (0.08-0.17) μM. The combination of 13cRA and CEP-701 resulted in additive to synergistic interactions in 4 of the 5 cell lines studied. Addition of 1 and 5 µM of 13cRA decreased the median (range) CEP-701 IC50 1.5-fold (1.1 to 2.8-fold) and 1.7-fold (1.5 to 1.8-fold), respectively. With 10 µM 13cRA, less than 50% of cells survived when combined with various concentrations of CEP-701. The combination of 4HPR and CEP-701 trended toward being antagonistic, with a median (range) CI at the ED50 of 1.3 (1.1-1.5).
Conclusions
The combination of 13cRA and CEP-701 was additive or synergistic in a spectrum of neuroblastoma cell lines, suggesting that these agents can be used together to eliminate minimal residual disease following intensive chemoradiotherapy for high-risk neuroblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5257.