bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4443: The tumor suppressive small GTPase DiRas1 binds the RhoGEF SmgGDS and antagonizes RhoA activation
Authors: Hauser Andrew D. , Barr Kristen M. , Frei Anne C. , Gonyo Patrick , Lorimer Ellen L. , Williams Carol L. , Bergom Carmen 
Published: May 2015

Abstract
A number of malignancies are promoted by the activation of Rho GTPases. Regulators of RhoA activity, including the RhoGEF, SmgGDS, can also promote cancer development. Both RhoA and SmgGDS have been shown to enhance NF-ĸB activation in a number of tumors. Utilizing mass spectrometry, we identified the tumor suppressive small GTPase DiRas1 as a novel binding partner for SmgGDS. DiRas1 is a tumor suppressor in malignant gliomas and esophageal squamous cell carcinomas. Examining DiRas gene expression using the ONCOMINE mRNA microarray database (www.oncomine.org) revealed that DIRAS1 and DIRAS2 are markedly decreased in central nervous system tumors, including anaplastic astrocytomas and GBMs, when compared to normal tissue. The role of DiRas1 in other cancers is largely undetermined, and the ways in which DiRas1 may antagonize pro-oncogenic small GTPase signaling is largely unknown. To define how DiRas1 expression may affect SmgGDS functions, we tested the association of DiRas family proteins with SmgGDS. SmgGDS robustly bound wildtype DiRas1, and its closely-related family member DiRas2, but only weakly bound DiRas3 in vitro and in cell lines. In addition, DiRas1, DiRas2, or DiRas3 protein expression decreased proliferation of HEK293T cells. DiRas1 expression could promote less activated RhoA, as a low level of DiRas1 expression caused markedly decreased RhoA-SmgGDS binding in a number of cell lines. DiRas1 expression also abrogated SmgGDS- and RhoA-mediated NF-ĸB activation in a concentration-dependent manner. SmgGDS may exhibit GEF activity toward DiRas1, as a dominant negative DiRas1 (S21N) binds to SmgGDS more than the wildtype protein. However, DiRas1 is predominantly GTP-bound in cells, likely due to a high rate of guanine nucleotide dissociation and low intrinsic GTPase activity. Thus, DiRas1 expression may in part promote tumor suppression by non-productively binding SmgGDS, resulting in less RhoA activity. Taken together, these results suggest that the tumor suppressive small GTPase DiRas1 can antagonize RhoA signaling by competing for binding of the RhoGEF SmgGDS. Further characterizing these actions may lead to novel therapeutic targeting of RhoA activation in cancer malignancies.
Citation Format: Andrew D. Hauser, Kristen M. Barr, Anne C. Frei, Patrick Gonyo, Ellen L. Lorimer, Carol L. Williams, Carmen Bergom. The tumor suppressive small GTPase DiRas1 binds the RhoGEF SmgGDS and antagonizes RhoA activation. [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 4443. doi:10.1158/1538-7445.AM2014-4443
Abstract 4444: The role of small GTPase Rab7 in the secretion of extracellular microvesicles by head and neck squamous cells carcinoma
Authors: Giudice Fernanda S. , Rodrigues Bruna R. , Dias Marcos V. S. , Baptistella Antuani R. , Lacerda Tonielli Cristina S. , Kowalski Luiz P. , Martins Vilma R. 
Published: May 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is an epithelial malignant tumor that shows its highest incidence in the upper aerodigestive tract and is considered one of the six most common malignancies worldwide. Among the processes involved in the poor prognosis of HNSCC, local invasion and subsequent metastasis are the most important events. Recent evidences have shown that metastasis can be the result of extracellular microvesicles (MVEs) being released from the tumor cells to the blood or lymphatic system. The molecular mechanisms involved in MVEs biogenesis and secretion are, however, poorly understood. Herein, we have performed a screen targeting for the components of MVEs biogenesis in three HNSCC cell lines (SCC-9, Cal27 and FaDu) through western blotting. MVEs were quantified using Nanoparticle Tracking Analysis (NTA - NanoSight®) and the lysosomal compartment was followed in the cell lines through immunofluorescence. Comparing the three cell lines, FaDu cells presented higher expression of proteins responsible for MVEs formation (p&lt;0.05), such as Flotilin-1, Tsg101, VPS36 and also Rab7, a small GTPase that directs vesicles to lysosomes. However, FaDu cells secreted less MVEs than SCC-9 and Cal27. Immunofluorescence experiments showed the presence of numerous perinuclear clusters positive to LAMP-1 (lysosome marker) in FaDu cells, while SCC-9 and Cal27 showed LAMP1-positive organelles dispersed throughout their cytoplasms. Taken together, the results highlight a role for Rab7 protein in the negative regulation of MVEs secretion by HNSCC cell lines, which may provide important information related to tumor progression, treatment response, and especially the development of metastasis.
Supported by São Paulo Research Foundation (FAPESP)
Citation Format: Fernanda S. Giudice, Bruna R. Rodrigues, Marcos V. S. Dias, Antuani R. Baptistella, Tonielli Cristina S. Lacerda, Luiz P. Kowalski, Vilma R. Martins. The role of small GTPase Rab7 in the secretion of extracellular microvesicles by head and neck squamous cells carcinoma. [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 4444. doi:10.1158/1538-7445.AM2014-4444
Abstract 4456: Aurora-A is a downstream target of RAS and forms a positive feedback regulation loop with NF-κB in non-small cell lung cancer
Authors: Kim Donghwa , Kanai Masayuki , Zheng Xiangqian , Zheng Dali , Coppola Domenico , Cheng Jin Q. 
Published: May 2015

Abstract
Previous studies have shown that inhibition of Aurora-A reduces mutant RAS oncogenic activity and that both Aurora-A and RAS activate NF-κB pathway through phosphorylation of IkBa and upregulation of GSKa, respectively. Here we show that Aurora-A expression and kinase activity are regulated by activating mutation of KRAS. Blockage of NF-κB by IκB-S32/36A abrogated KRAS-induced Aurora-A expression and kinase activity. Furthermore, we demonstrated that NF-κB directly bound to Aurora-A promoter and induces Aurora-A transcription. In addition, depletion of Aurora-A by siRNA and pharmacological inhibitor MLN8237 suppresses RAS-induced NF-κB activity and selectively induces cell death in KRAS mutant NSCLC cells. We also show that Aurora-A is induced by nicotine and is frequently overexpressed in NSCLCs. Overexpression of Aurora-A is associated with tobacco smoke and poor prognosis in lung adenocarcinoma but not squamous lung cancer. These data suggest that Aurora-A is regulated by RAS through NF-κB and that the feedback regulation loop between Aurora-A and NF-κB could play a pivotal role in NSCLC.
Citation Format: Donghwa Kim, Masayuki Kanai, Xiangqian Zheng, Dali Zheng, Domenico Coppola, Jin Q. Cheng. Aurora-A is a downstream target of RAS and forms a positive feedback regulation loop with NF-κB in non-small cell lung 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 4456. doi:10.1158/1538-7445.AM2014-4456
Abstract 4457: Regulation of GRM1 by estrogen receptor in breast cancer
Authors: Dolfi Sonia C. , Mehta Madhura S. , Kornblum David , Boughton Andrew , Rahim Hussein , Medina Daniel , Hirshfield Kim M. 
Published: May 2015

Abstract
Metabotropic glutamate receptor 1 (GRM1), first recognized as an important factor in the central nervous system, has more recently been implicated in melanomagenesis and breast cancer pathogenesis. Oncogenic mediators of GRM1-associated effects include both MAPK and AKT signaling cascades. Modulation of GRM1 activity in melanoma and estrogen receptor negative (ER-) breast cancer cells inhibits anchorage independent growth, migration, proliferation, and/or downstream activation of Akt and ERK. Data from our laboratory show that a significantly higher fraction of breast tumors express GRM1 compared to normal breast tissue, and GRM1 expression is more highly correlated with ER positivity. Moreover, higher GRM1 expression in human ER+ breast cancers treated with the anti-estrogen tamoxifen associates with a shorter distant metastasis free survival as compared to low expressors further supporting a critical role in ER+ breast cancer.
We hypothesize that ER has both genomic and non-genomic effects on GRM1. We evaluated the effect of hormonal treatment on GRM1 protein expression in ER+ MCF7 and ER- MDA-MB-231 breast cancer cells. Estradiol increases GRM1 expression, and this effect is abrogated by the anti-estrogen tamoxifen in MCF7 but not in MDA-MB-231 cells. These genomic effects may be exerted through three putative ER binding sites within the GRM1 promoter. We have confirmed that ER binds to one of these sites by chromatin immunoprecipitation, further supported by ChiPSeq data. GRM1 promoter activity is increased by estradiol treatment using a luciferase reporter assay validating transcriptional activation by ER. To support a non-genomic role for ER with GRM1, we have shown that ER physically interacts with GRM1 in breast cancer cells by in vitro proximity ligation assay and by co-immunoprecipitation in immortalized mouse mammary epithelial cells (iMMECs) stably expressing GRM1. Stable introduction of GRM1 into iMMECs, which lack endogenous GRM1, reduces sensitivity to tamoxifen as compared to control iMMECs. In MCF7 cells, the combination of tamoxifen with GRM1 modulators riluzole or BAY 36-7620 produces synergistic effects.
As estradiol activates MAPK signaling in breast cancer cells, we hypothesize that this may be mediated by both the physical interaction of GRM1 and ER and the indirect effects on GRM1 transcription. Results of these studies suggest that GRM1 may be a valuable therapeutic target in ER+ breast tumors.
Citation Format: Sonia C. Dolfi, Madhura S. Mehta, David Kornblum, Andrew Boughton, Hussein Rahim, Daniel Medina, Kim M. Hirshfield. Regulation of GRM1 by estrogen receptor in breast 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 4457. doi:10.1158/1538-7445.AM2014-4457
Abstract 4473: Development of ceramide liposomes for tumor interstitial and vascular drug targeting
Authors: Cheng Shaohua , Crall William , Nguyen Bryan , Dang Charles , Alkholief Musaed , Campbell Robert B. 
Published: May 2015

Abstract
Background: Interstitial and vascular targeting with cytotoxic agents has proven to be an effective approach for cancer therapy (1). Ceramide, a sphingolipid, plays an important role in apoptosis, regulation of differentiation, growth suppression, and in cell senescence (2). Liposomes containing ceramide exert an anti-proliferative effect against the growth of tumor cells in vitro (3). In this study, we attempted to apply a rational approach to the development of ceramide liposomes for tumor targeting.
Methods: We first determined the relative amounts of ceramide produced by cells normally found in the tumor interstitial matrix (ZR-75-1- human breast cancer cells), and by those lining tumor endothelia (HMEC-1 -human microvascular endothelial cells). For this experiment we measured sphingomyelinase activity. We next determined the cytotoxic effects of various liposome systems containing 0 to 20% ceramide (C6:1) content. The optimal ceramide content was determined from this study, and 2-methoxyestradiol (2-ME) was loaded in the optimal ceramide liposome preparation type. We next evaluated cytotoxic effects of the drug-loaded liposomes compared to ceramide liposomes alone.
Results: ZR-75-1 cells showed a higher level of sphingomyelinase activity (4.4 fold) as compared to that of HMEC-1. The 20% ceramide formulation demonstrated the most significant anti-proliferative effect, regardless of the cell line. The cytotoxic drug effects were favorably influenced by the ceramide content. Finally, preliminary studies suggest that the overall effectiveness of ceramide liposomes against the growth of proliferating tumor cells correlated with the sphingomyelinase activity expressed by the target cells.
Conclusion: Future studies will determine whether sphingomyelinase activity can be used to determine the population of cells (i.e., interstitial vs vascular) most likely to benefit from ceramide (cytotoxic) drug-loaded liposomes as a therapeutic approach.
Citation Format: Shaohua Cheng, William Crall, Bryan Nguyen, Charles Dang, Musaed Alkholief, Robert B. Campbell. Development of ceramide liposomes for tumor interstitial and vascular drug targeting. [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 4473. doi:10.1158/1538-7445.AM2014-4473
Abstract 4478: Biopharmaceutic studies of novel nucleoside transporter inhibitor prodrugs that can protect against nucleoside drug-induced mitochondrial toxicity
Authors: Sun Shan , Playa Hilaire C. , Deokar Hemantkumar S. , Lin Wenwei , Buolamwini John K. 
Published: May 2015

Abstract
Nucleoside analog antimetabolites are used as chemotherapy agents to treat cancer by interfering with DNA biosynthesis and therefore cell division and the growth of tumors. However, nucleoside drugs, such as the nucleoside reverse transcriptase inhibitor antiviral agents and gemcitabine, a drug approved for use against various solid tumors, have been found to cause severe mitochondrial toxicities that can limit their use. Nucleoside analogs cause toxicity by inhibiting mitochondrial DNA (mtDNA) synthesis. Nucleoside drugs can be transported from cytoplasm into mitochondrial by mitochondrial membrane nucleoside transporters (NTs) where they form the active triphosphate analogs and incorporate into mtDNA and inhibit mtDNA polymerase, Pol γ. Currently, there is no proven general treatment or prevention strategy for nucleoside drug-induced mitochondrial toxicity. Thus, the development of innovative approaches to preempt or treat mitochondrial toxicity will be an important advance in the field of nucleoside drug therapy.
In our research to overcome the mitochondrial toxicity, we developed a set of novel nucleoside transporter inhibitor (NTI) prodrugs that lack of NT inhibition but can release active drugs intracellularly to inhibit mitochondrial nucleoside uptake. In vitro biopharmaceutics studies of cell entry, in-cell hydrolysis profiles, and metabolic stability in human liver S9 faction and human plasma were carried out on a set of novel prodrugs that have shown protection against nucleoside drug-induced mitochondrial toxicity. Financial support by NIH grant RO1GM10405 is acknowledged.
Citation Format: Shan Sun, Hilaire C. Playa, Hemantkumar S. Deokar, Wenwei Lin, John K. Buolamwini. Biopharmaceutic studies of novel nucleoside transporter inhibitor prodrugs that can protect against nucleoside drug-induced mitochondrial toxicity. [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 4478. doi:10.1158/1538-7445.AM2014-4478
Abstract 4486: Stromal depletion by a docetaxel nanoparticle for enhanced therapy of breast and pancreatic cancer
Authors: Ernsting Mark , Murakami Mami , Undzys Elijus , Li Shyh-Dar 
Published: May 2015

Abstract
Tumor stroma consists of genetically normal cells that express abnormal phenotype in the tumor microenviroment, and are drivers of tumor cell proliferation and migration processes. Stromal cells can represent a significant fraction of tumor mass, and represent a barrier to drug delivery, given that stromal fibroblasts exert contractile forces which reduce vascular perfusion and increase interstitial fluid pressure. In the field, the stroma is widely recognized as a target for therapy, both to normalize the reactive microenvironment, and to reduce drug delivery barriers, but with limited clinical success.
We have developed a nanoparticle delivery system for docetaxel (Cellax), a conjugate of carboxymethylcellulose and PEG, which condenses into well defined 120 nm particles suitable for intravenous administration. In addition to enhanced pharmacokinetics, 5-10X improved tumor uptake, and enhanced anti-tumor efficacy compared to approved taxanes such as native DTX (Taxotere) and nab-PTX (an albumin-paclitaxel nano-formulation, Abraxane), we have observed an anti-stromal effect in breast and pancreatic models. In a 4T1 orthotopic breast cancer model in mice, 85% of Cellax particles were taken up by cancer-associated fibroblasts (CAF), a major component of stroma. Further, in 4T1 and MDA-MB-231 breast models, Cellax treatments reduced CAF by 82 and 70% respectively, while native DTX and Nab-paclitaxel exerted no anti-stromal activity. Concomitant effects were ∼70-fold increased perfusion, ∼3-fold decreased interstitial fluid pressure (IFP), and a 7-24 fold reduction in lung metastases. In a primary human pancreatic xenograft model (OCIP19), we measured a 50% reduction in αSMA+ cells (activated pancreatic stellate cells) and macrophage within 1 day of Cellax treatment, while nab-PTX only decreased the macrophage population 3-7 days post therapy. In addition, vascular perfusion in the Cellax treated pancreatic tumor was increased 12X relative to nab-PTX and control treatment groups, with significantly reduced metastases. Preliminary mechanistic studies indicate that albumin absorbs to Cellax particles, promoting interaction with SPARC-expressing stromal cells, leading to stroma-specific activity.
Citation Format: Mark Ernsting, Mami Murakami, Elijus Undzys, Shyh-Dar Li. Stromal depletion by a docetaxel nanoparticle for enhanced therapy of breast and pancreatic 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 4486. doi:10.1158/1538-7445.AM2014-4486
Abstract 4488: Multi-functional, miR-205 complexed, gemcitabine conjugated nanomedicines for effective treatment of chemo-resistant pancreatic adenocarcinoma
Authors: Chitkara Deepak , Mittal Anupama , Behrman Stephen W. , Mahato Ram I. 
Published: May 2015

Abstract
Aberrant expression of small, non-coding RNAs called miRNAs in tumor tissues result in anomalous levels of genes and proteins which trigger metastasis and chemoresistance, and aggravate stemness among the cancer cells. We investigated one such miRNA, miR-205 identified through various softwares (TARGETSCAN, miRDB and DIANACOT) and validated experimentally as a potential target for treatment of advanced stage pancreatic cancer. Most of the current attempts to deliver such potent biologically complex molecules fail clinically owing to the challenges of structural and functional stability involved in their formulation and in vivo delivery. In this study, we constructed a multifunctional, self-assembling, copolymer with carboxyl pendant groups (mPEG-PCC) which exhibited efficient conjugation with gemcitabine (12.1% w/w) and simultaneously formed stable complexes with miR-205 at N/P 16/1. Both the therapeutic molecules which are otherwise known for plasma degradation demonstrated long-term stability in plasma when delivered through our system. Nanomedicines prepared using this polymer by film hydration method showed a size of ∼72.9 nm and sustained gemcitabine release of ∼40% in 10 days which was not affected by the co-presence of miRNA in the formulation. In gemcitabine resistant MIA PaCa-2R pancreatic cancer cells, the formulations showed a transfection efficiency of more than 90% (by flow cytometry), reversal of chemo-resistance (cell viability assay) and decrease in invasive and migratory ability of the cancer cells (Matrigel® invasion assays). In vivo evaluation in xenograft model developed using MIA PaCa-2R cells indicated significantly diminished tumor growth in miR-205/gemcitabine nanomedicines treated group.
Note: This abstract was not presented at the meeting.
Citation Format: Deepak Chitkara, Anupama Mittal, Stephen W. Behrman, Ram I. Mahato. Multi-functional, miR-205 complexed, gemcitabine conjugated nanomedicines for effective treatment of chemo-resistant pancreatic adenocarcinoma. [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 4488. doi:10.1158/1538-7445.AM2014-4488
Abstract 4503: A small molecule glycomimetic antagonist of E-selectin (GMI-1271) prevents pancreatic tumor metastasis and offers a novel treatment for improved efficacy of chemotherapy
Authors: Steele Maria M. , Radhakrishnan Prakash , Magnani John L. , Hollingsworth Michael A. 
Published: May 2015

Abstract
The processes of intra- and extravasation of tumor cells into and out of the blood and lymphatic systems are crucial steps during metastasis to distant organ sites. These processes are tightly regulated by the initial binding of sialyl Lewis A and sialyl Lewis X (sialyl Le A/X) carbohydrate moeities found on tumor cells to the adhesion protein E-selectin expressed on the activated endothelium. GMI-1271 is a small molecule glycomimetic rationally designed based on the bioactive conformation of sialyl Lea/x and is a potent and specific antagonist of E-selectin. In vitro treatment of human lymphatic endothelial cells with GMI-1271 resulted in a decrease in the number of sialyl Lewis A-expressing pancreatic cancer cells (S2.013 and BxPC-3) binding to the endothelium in a dose-dependent manner. GMI-1271 treatment also inhibited the transendothelial migration of S2.013 and BxPC-3 cells through a lymphatic cell monolayer.
We evaluated the in vivo efficacy of GMI-1271 following orthotopic implantation of pancreatic tumor cell line S2.013, which expresses high levels of sialyl Lewis A (CA19-9), into nude mice. Following 2 weeks of tumor growth, mice were treated by intraperitoneal injections for 4 weeks with either PBS once daily, once daily with 40mg/kg GMI-1271 (low dose), twice daily with 40mg/kg GMI-1271 (high dose), twice a week with 60mg/kg gemcitabine injections, combination low dose GMI-1271 and gemcitabine injections, or combination high dose GMI-1271 and gemcitabine injections. Co-treatment of either low or high dose GMI-1271 with gemcitabine resulted in a significant decrease in the number of metastasis to the lymph nodes (p=0.02 low dose; p=0.04 high dose). In addition, compared with gemcitabine alone, low dose GMI-1271 plus gemcitabine was found to be effective at reducing the number of metastatic lesions (per histological section) in the liver (p=0.001), lung (p=0.026) and diaphragm (p=0.01). Based on the significant effects of combination therapy on tumor metastasis, the small molecule glycomimetic antagonist to E-selectin, GMI-1271, offers great promise in preventing pancreatic tumor cell entry into the blood and lymphatic systems and offers a novel treatment for the improved efficacy of standard chemotherapy.
Citation Format: Maria M. Steele, Prakash Radhakrishnan, John L. Magnani, Michael A. Hollingsworth. A small molecule glycomimetic antagonist of E-selectin (GMI-1271) prevents pancreatic tumor metastasis and offers a novel treatment for improved efficacy of chemotherapy. [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 4503. doi:10.1158/1538-7445.AM2014-4503