bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3110: Targeting the Wnt/PCP signaling through ROCK: A new neuroblastoma drug target
Authors: Dyberg Cecilia , Forsberg David , Papachristou Panos , Lannerholm-Palm Jessika , Haug Bjorn Helge , Sveinbjörnsson Baldur , Lagercrantz Hugo , Kogner Per , Johnsen John inge , Wickstrom Malin 
Published: May 2015

Abstract
Background: The non-canonical Wnt/planar cell polarity (PCP) pathway regulates cytoskeletal organization, migration and neuritogenesis. Signaling is characterized by activation of the GTPases Rho and Rac, and the downstream Rho-associated protein kinases (ROCKs). Neuroblastoma is a malignant embryonal tumor of the sympathetic nervous systems, often with poor prognosis. The need for novel therapeutic approaches is great. Genetic analyses have revealed mutations and aberrations in the regulators Rho/Rac in neuroblastoma. The aim of this study was to characterize the Wnt/PCP signaling and the effects of ROCK inhibition in neuroblastoma.
Methods: Cytotoxic activity of ROCK inhibitors was studied in cell viability assays. Morphology and invasion were studied with microscopy. The molecular mechanisms were characterized using cell- and molecular biology techniques. In vivo studies in mice were carried out to validate the therapeutic effects and toxicity.
Results: Several mediators in the pathway were differentially expressed in cell lines and patient samples. Using compounds blocking ROCK1 and ROCK2 activity revealed that the ROCK2 inhibitor HA-1077 effectively repressed proliferation and reduced cell viability in neuroblastoma. Additionally, HA-1077 inhibited migration and induced differentiation through initiating neural outgrowth. Furthermore, HA-1077 reduced the growth of established neuroblastoma xenografts in nude mice.
Conclusions: These results suggest that non-canonical Wnt signaling in general and ROCK in particular is a promising new therapeutic target for high-risk neuroblastoma.
Citation Format: Cecilia Dyberg, David Forsberg, Panos Papachristou, Jessika Lannerholm-Palm, Bjorn Helge Haug, Baldur Sveinbjörnsson, Hugo Lagercrantz, Per Kogner, John inge Johnsen, Malin Wickstrom. Targeting the Wnt/PCP signaling through ROCK: A new neuroblastoma drug target. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3110. doi:10.1158/1538-7445.AM2014-3110
Abstract 3118: Chemokine-targeted colorectal cancer: improved models of human primary tumor formation, liver metastasis and chemoresistance
Authors: Chen Huanhuan Joyce , Sun Jian , Hou Harry , Edelmann Winfried , Shen Xiling , Lipkin Steven M. 
Published: May 2015

Abstract
Current human colorectal cancer (CRC) orthotopic xenograft models require surgery and do not readily progress to form tumors in liver, the most common site for metastasis. We developed cell and patient-derived xenograft models that use chemokine-targeting to recapitulate the vast majority of recurrent human somatic CRC mutations as primary gastrointestinal (GI) tumors in mice without requiring surgery. Importantly, we incorporate early-stage mouse blastocyst microinjection techniques to extend this approach and demonstrate that it can also model primary human CRCs in immunoproficient mouse hosts. Next, we show that primary GI tumors can inducibly metastasize to liver. Finally, we use this system to demonstrate that human CRC liver metastases in vivo are more chemoresistant than paired sub-cutaneous xenografts. Overall, we anticipate that this resource can help improve our mechanistic understanding of human primary CRC growth, progression to liver metastasis and potentially provide a more physiological model than sub-cutaneous xenograft for pre-clinical drug discovery.
Citation Format: Huanhuan Joyce Chen, Jian Sun, Harry Hou, Winfried Edelmann, Xiling Shen, Steven M. Lipkin. Chemokine-targeted colorectal cancer: improved models of human primary tumor formation, liver metastasis and chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3118. doi:10.1158/1538-7445.AM2014-3118
Abstract 3135: Pre-treatment p-EGFR levels in tumors from a genetically engineered mouse model of BRAFV600E colorectal cancer predict response to combined BRAF/EGFR inhibition
Authors: Coffee Erin M. , Corcoran Ryan B. , Engelman Jeffrey A. 
Published: May 2015

Abstract
BRAFV600E colorectal cancer (CRC) patients do not exhibit responses to single-agent BRAF inhibition due to activation of EGFR. While combined BRAF and EGFR inhibition has shown some success in early clinical trials, there are still a subset of patients who do not respond to this combination. The purpose of this study is to identify which BRAFV600E tumors would be expected to respond to combined BRAF/EGFR inhibition based on the pre-treatment levels of pEGFR.
A genetically engineered mouse model (GEMM) for Apc-/- BrafV600E/+ p53-/- CRC was used for the study. Tumors were induced in the colons using adenovirus expressing Cre recombinase. Tumors were visualized by optical colonoscopy and pre-treatment tissue biopsy samples were obtained. BRAF mutant mice were randomized to a combination treatment with a BRAF inhibitor (Dabrafenib), combined with either an EGFR inhibitor (Erlotinib) or a MEK inhibitor (Trametinib). Tumor growth or regression was followed for 21 days by colonoscopy.
A retrospective analysis indicated that those tumors with high pre-treatment phosphorylated EGFR (p-EGFR) levels had significant responses to combined BRAF/EGFR therapy, while those tumors with little to no response to combined BRAF/EGFR therapy had low levels of p-EGFR prior to treatment. Furthermore, the majority of tumors that had a significant response to the combined BRAF/MEK therapy had the lowest levels of pre-treatment p-EGFR.
These pre-clinical data suggest that BRAFV600E CRC patients could benefit from being stratified by p-EGFR levels prior to treatment. Those patients with high p-EGFR levels would be expected to respond best to combined BRAF/EGFR treatment, while those patients with low p-EGFR levels might benefit from a different combination therapy, such as combined BRAF/MEK inhibition.
Citation Format: Erin M. Coffee, Ryan B. Corcoran, Jeffrey A. Engelman. Pre-treatment p-EGFR levels in tumors from a genetically engineered mouse model of BRAFV600E colorectal cancer predict response to combined BRAF/EGFR inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3135. doi:10.1158/1538-7445.AM2014-3135
Abstract 3144: PDZ-RhoGEF/β-arrestin-1 interaction mediates endothelin A receptor-induced RhoA activation and cell motility in ovarian tumor cells
Authors: Tocci Piera , Cianfrocca Roberta , Semprucci Elisa , Castro Valeriana Di , Bagnato Anna , Rosanò Laura 
Published: May 2015

Abstract
β-arrestins (β-arrs), consisting of β-arr1 and β-arr2, are involved in G-protein-coupled receptor signaling, and guide the receptor signals in chemotaxis and cytoskeletal reorganization. Among them, receptor A for endothelin-1 (ET-1), namely ETAR, is overexpressed in epithelial ovarian cancer (EOC) and promote metastatic spread. We have recently reported that β-arr1 regulates ETAR-mediated β-catenin signaling to promote EOC cell invasion. Here we evaluated the effects of ET-1 on polarized cell migration correlating with the regulation of Rho-GTPase activity and its subsequent organization of the actin structures supporting migration and the involvement of β-arr1 in these effects. We show that, in EOC cells cultured on collagen type I, ET-1 promotes actin-based dynamic protrusion resembling to pseudopodia, containing β-arr-1. Furthermore, in a β-arr1/ETAR-dependent manner, ET-1 activates RhoA GTPase and downstream the dephosphorylation/activation of cofilin, as shown by pull down assay and immunoblotting analysis. The inhibitory effect of the Rho pathway inhibitor I, Y-27632, demontrates that RhoA GTPase is involved in ET-1-induced cell migration. By screening members of a Rho-guanine nucleotide exchange factor (Rho-GEF) family involved in RhoA activation, we found that PDZ-RhoGEF mRNA levels are highly expressed in EOC cells. Moreover, PDZ-RhoGEF is responsible for ET-1-induced RhoA activation through interaction with β-arr1, that in turn, promotes PDZ-RhoGEF tyrosine phosphorylation and activation. Depletion of PDZ-RhoGEF expression significantly impaired ET-1-stimulated migration of EOC cells, demonstrating that PDZ-RhoGEF/β-arrestin-1 interaction mediates ETAR-driven ovarian tumor cell motility through regulation of RhoA. Analysis of EOC human tissues revealed that PDZ-RhoGEF is overexpressed in human EOC tissues. Collectively, our data establish a novel role for β-arr1 and PDZ-RhoGEF as regulator of ET-1-induced EOC cell migration, unraveling new components required for tumor progression. Supported by AIRC.
Citation Format: Piera Tocci, Roberta Cianfrocca, Elisa Semprucci, Valeriana Di Castro, Anna Bagnato, Laura Rosanò. PDZ-RhoGEF/β-arrestin-1 interaction mediates endothelin A receptor-induced RhoA activation and cell motility in ovarian tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3144. doi:10.1158/1538-7445.AM2014-3144
Abstract 3165: Docosahexaenoic acid attenuates survival and progression in subtype-specific breast cancer by modifying Myc activity
Authors: Mouradian Michael , Bains Palvinder K. , Chattin Amy M. , Pardini Ronald S. 
Published: May 2015

Abstract
Overexpression of Myc in breast cancer is associated with poor prognosis and has a unique profile distribution among subtypes. Myc overexpression has been shown to be greatest in basal-like tumors, ∼50%, and least in luminal Her2-overexpressing tumors, ∼9%. Previous studies from our laboratory have identified a relationship between docosahexaenoic acid (DHA, C22:6 n-3) treatment and Myc activity and the effect seems to be specific to the breast cancer subtype and Myc overexpression profile, but is still unclear. In the current study, we investigated the effect of DHA on tumor growth, survival, and invasion in a high Myc expressing cell line, basal-like MDA-MB-231, and a low Myc expressing cell line, luminal Her2-overexpressing BT-474, in vitro. Basal expression analysis confirmed Myc overexpression levels in each cell line. While DHA treatment in the basal-like MDA-MB-231 cells significantly decreased Myc transcriptional activity and p-T58/S62-c-Myc phosphorylation status, the opposite response was observed with DHA treatment in the BT-474 luminal Her2-overexpressing cells, significantly enhancing Myc transcriptional activity and phosphorylation status. Although different responses in Myc activity existed between the two subtype-specific breast cancers, cell viability and apoptosis assays produced similar findings, revealing decreased cellular viability and increased early and late-apoptotic cellular status in response to DHA treatment. Additionally, dramatic decreases in wound healing and invasion index were observed in both cell lines with DHA supplementation compared to control treatments. Myc siRNA treatment rescued BT-474 cells from DHA treatment, confirming that DHA-induced alterations in apoptosis and invasion were initiated by Myc modification. Moreover, Myc knockdown in the MDA-MB-231 cell line displayed results similar to DHA treatment, consistent with our hypothesis that Myc activity is responsible for cellular survival and progression in subtype specific breast cancer. These results show that DHA is applying some of its anti-cancer effects by modifying Myc activity, inducing apoptosis and decreasing invasion in breast cancer, revealing new dietary targets that may enhance current therapeutics.
Citation Format: Michael Mouradian, Palvinder K. Bains, Amy M. Chattin, Ronald S. Pardini. Docosahexaenoic acid attenuates survival and progression in subtype-specific breast cancer by modifying Myc activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3165. doi:10.1158/1538-7445.AM2014-3165
Abstract 3170: Alternative NF-κB pathway activation enhanced by deficient TRAF3 in human papillomavirus (HPV)-associated head and neck cancer
Authors: Zhang Jialing , Cheng Hui , Yang Xinping , Maiorov Emine Guven , Keskin Ozlem , Gursoy Attila , Nussinov Ruth , Chen Zhong , Waes Carter Van 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) arises from the oral cavity, pharynx and larynx, and is the 6th most common cancer worldwide. The incidence of oropharyngeal SCC (OSCC) due to HPV is rising despite a decline in tobacco related HNSCC. However, the molecular mechanisms promoting HPV+ OSCC has not been clearly established. Recently, The Cancer Genome Atlas (TCGA) HNSCC project revealed a higher frequency of homozygous and heterozygous deletions in chromosome 14q32.32 associated with lower expression of the TNF receptor-associated factor 3 (TRAF3) gene, unique to HPV+ tumors. Deleterious nonsense and frame shift mutations of TRAF3 are also exclusively observed in HPV+ HNSCC. Structural interactions of TRAF3 with other signaling molecules were modeled three dimensionally using the PRISM algorithm (PRotein Interactions by Structural Matching). The interactions revealed that these TRAF3 mutations abolished key inhibitory interactions at the interface between receptors and NF-κB inducing kinase (NIK) in the alternative NF-κB pathway. Consistent with TCGA findings, we found varying TRAF3 expression in HPV+ HNSCC cell lines. Overexpression of TRAF3 in HPV+ cell lines suppressed the alternative NF-κB pathway and p52/p100 nuclear localization, and key target genes, while increasing expression of IFN genes implicated in anti-viral immunity. Further, overexpression of TRAF3 inhibited cell growth, colony formation, and migration, as well as sensitized cells to TNF-α and cisplatin induced cell death. Our data reveal that decreased TRAF3 promotes the malignant phenotype via alternative NF-κB signaling, and attenuates antiviral IFN expression, important in pathogenesis of HPV+ HNSCC.
Supported by NIDCD intramural project ZIA-DC-000016, 73, 74
Citation Format: Jialing Zhang, Hui Cheng, Xinping Yang, Emine Guven Maiorov, Ozlem Keskin, Attila Gursoy, Ruth Nussinov, Zhong Chen, Carter Van Waes. Alternative NF-κB pathway activation enhanced by deficient TRAF3 in human papillomavirus (HPV)-associated head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3170. doi:10.1158/1538-7445.AM2014-3170
Abstract 3210: Supercritical extract of Azadirachta indica in chemoprevention of colon cancer
Authors: Khoogar Roxanne , Mukhophadyay Keya , Morris Jay , Soman Girish , Wargovich Michael 
Published: May 2015

Abstract
The leaves bark, and seed of Azadirachta Indica (Neem tree) have long been used in Ayurvedic medicine for health benefits. We have investigated a Supercritical CO2 Neem Extract (SCNE) in human colon cancer cell lines for chemopreventive potential.
A SCNE of leaf was procured from Nisarga Ltd, Sartara, India and subjected to HPLC and LC-MS to develop of signature of triterpenoids with potential cancer preventive activity. One compound, nimbolide, suggested to account for anti-proliferative activity against cancer cells was found to be present in the extract. The effects of the SCNE were determined on HT29 and HCT116 human colon cancer cell lines. The proliferative activity of HT29 and HCT116 cells were studied after 48 and 72 hours treatment with SCNE and Nimbolide at various concentrations. We also evaluated the effects of SCNE and nimbolide on cell cycle parameters, and examined relevant proteins associated with cancer cell proliferation. Cell cycle analysis was performed by flow cytometry and confirmed a pre-apoptotic peak in SCNE treated HCT116 cells. The modulation of apoptotic markers (intrinsic pathway: Bax, Bcl-2, and caspase-3, 9), proliferation pathway (cyclin D1) were studied at the protein and mRNA level. Treatment with SCNE and Nimbolide in a range from 8- 18 µg/ml resulted in dose -dependent growth inhibition in 48 and 72 hours. At these concentrations SCNE caused changes in cyclin D1. The induction of apoptosis by SCNE in HT29 and HCT116 was shown by caspase activation, cleavage of PARP, increased levels of pro-apoptotic protein Bax, and reduced levels of the anti-apoptotic protein Bcl-2. The effect of SCNE on colon cancer cell migration will be reported by scratch wound healing assay.
Overall, our data suggested that SCNE can suppress the growth of human colorectal cancer through induction of apoptosis. Current experiments are now focused on NF-kB and associated proteins as targets of SCNE inhibition.
Supported by grant P30CAO54174.
Citation Format: Roxanne Khoogar, Keya Mukhophadyay, Jay Morris, Girish Soman, Michael Wargovich. Supercritical extract of Azadirachta indica in chemoprevention of colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3210. doi:10.1158/1538-7445.AM2014-3210
Abstract 3212: Ganoderma lucidum (Reishi) chemosensitizes EGFR-overexpressing inflammatory breast cancer cells to erlotinib
Authors: Suárez-Arroyo Ivette , Moraskie Michael , Cubano Luis A. , Martínez-Montemayor Michelle M. 
Published: May 2015

Abstract
Inflammatory Breast Cancer (IBC) is an aggressive cancer with a unique ability of forming tumor spheroids, which invade the dermal lymphatics causing the inflammatory phenotype. IBC cell lines and human tissues, overexpress Epidermal Growth Factor Receptor (EGFR), which has been associated with increasing IBC tumor growth rate, invasion and metastasis. Among the current therapeutic strategies for EGFR inhibition are the small molecule Tyrosine Kinase Inhibitors (TKIs). The high incidence of resistance to such therapies has greatly diminished their overall effectiveness, thus it seems feasible to identify agents that may be combined with these TKIs to provide a sustained response for IBC patients. For this reason, the purpose of this study is to investigate Reishi's therapeutic potential in IBC, focusing on the regulation of the EGFR signaling cascade and its contribution to the IBC cellular response when treated with the EGFR TKI, erlotinib. Our hypothesis is that Reishi sensitizes IBC cells to erlotinib therapy. EGFR-overexpressing SUM-149 IBC cells were treated with several concentrations of erlotinib, 0.025mg/mL Reishi, or both treatments simultaneously for 72h. Our results showed a synergistic effect when erlotinib and Reishi are used simultaneously after 72 hours of treatment. In order to study the molecular mechanism for the improved effects of the combination treatment we successfully developed an IBC erlotinib resistant cell line from the parental SUM-149 cells. Our data revealed that Reishi increases erlotinib sensitivity by inactivating AKT and extracellular signal-regulated kinase (ERK) signaling pathways. Taken together, our results provide evidence that Reishi chemosensitizes IBC cells to erlotinib therapy, highlighting its anti-IBC-therapeutic potential. This project was sponsored by NIH/NCI #1F31 CA174307 to ISA, Title V PPOHA US Department of Education #P031M105050 to UCC, NIH/RCMI #G12 MD007583 to UCC, NIH/INBRE #5P20 GM103475 to UPR/UCC and a research donation from the Commonwealth of Puerto Rico to UCC's University Center of Integral and Complementary Medicine (CUMIC)/MMM.
Citation Format: Ivette Suárez-Arroyo, Michael Moraskie, Luis A. Cubano, Michelle M. Martínez-Montemayor. Ganoderma lucidum (Reishi) chemosensitizes EGFR-overexpressing inflammatory breast cancer cells to erlotinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3212. doi:10.1158/1538-7445.AM2014-3212
Abstract 3219: Synergistic effect between Ganoderma lucidum (Reishi) and lapatinib in HER2+ inflammatory breast cancer cells
Authors: Feliz-Mosquea Yismeilin , Suárez-Arroyo Ivette , Cubano Luis A. , Martínez-Montemayor Michelle M. 
Published: May 2015

Abstract
Inflammatory Breast Cancer (IBC) is the most lethal and rare form of breast cancer. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Although IBC, like non-IBC breast cancers, is a heterogeneous disease and can occur as any of the five molecular breast cancer subtypes, they are most commonly either triple negative; or ER-, PR- and HER2+ overexpressed. There is no specific IBC treatment; thus, it seems feasible to find a therapeutic for this deadly disease. Our published data demonstrates that Ganoderma lucidum (Reishi) inhibits the viability of the triple negative IBC SUM149 cell line, but not of MCF10A noncancerous mammary epithelial cells. Consequently, in this study, we aimed to investigate Reishi effects in the viability of the ER-, PR-, HER2+ IBC cells lines SUM190 and KPL4. Also we studied the effects of Reishi on IBC cells when treated in complement with the HER2 Tyrosine Kinase Inhibitor, lapatinib (Tykerb®). Our hypothesis is that Reishi chemosensitizes IBC cells to lapatinib therapy. Herein, SUM190 and KPL-4 cells were treated with increasing concentrations of lapatinib and/or Reishi for 24 or 72h. Our results demonstrate that SUM190 and KPL-4 cells are sensitive to Reishi treatment. The combination of lapatinib plus Reishi reduced cell viability of SUM190 cells to 70% when treated with a concentration of 0.5mg/mL Reishi for 24h. Also, our data shows a reduction in cell viability of 94% in KPL-4 cells treated with lapatinib plus Reishi for 72h. We are currently directing our efforts to continue studying the contribution of Reishi in IBC cells when treated with lapatinib after 24 or 72h. Our results provide evidence that Reishi inhibits cancer cell viability and chemosensitizes IBC cells to lapatinib therapy, highlighting its anti-IBC-therapeutic potential. We thank Dr. Kurebayashi (Kawasaki Medical School, Japan) for providing KPL-4 cells. This project was sponsored by NIH/NCI #1F31CA174307 to ISA, Title V PPOHA US Department of Education #P031M105050 to UCC, NIH/RCMI #G12MD007583 to UCC, NIH/INBRE #5P20GM103475 to UPR/UCC and a research donation from the Commonwealth of Puerto Rico to UCC's University Center of Integral and Complementary Medicine (CUMIC)/MMM.
Citation Format: Yismeilin Feliz-Mosquea, Ivette Suárez-Arroyo, Luis A. Cubano, Michelle M. Martínez-Montemayor. Synergistic effect between Ganoderma lucidum (Reishi) and lapatinib in HER2+ inflammatory breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3219. doi:10.1158/1538-7445.AM2014-3219