bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5761: An alternative isoform of the metastasis susceptibility gene Brd4 promotes EMT and metastatic progression
Authors: Alsarraj Jude , Walker Renard C. , Crawford Nigel P.S. , Webster Joshua D. , Simpson R. Mark , Ozato Keiko , Hunter Kent W. 
Published: February 2011

Abstract
Recent work from our laboratory has identified the bromodomain 4 (Brd4) as a suppressor of tumor progression and metastasis. Brd4 however has an alternatively spliced isoform that truncates the protein and substitutes a different 3′-UTR. Unlike the longer isoform, expression of the short isoform (ΔC) does not impair primary tumor growth of a highly metastatic mammary tumor cell line orthotopically implanted into the mammary fat pad, although pulmonary metastasis is significantly reduced compared to control tumors. Unexpectedly, a dramatic enhancement of metastatic colonization is observed following injection of the cells directly into the circulation of mice. In vivo invasion of the cell line was not impaired by expression of the short isoform suggesting that the inability of the orthotopic tumors to metastasize was not due to the inability of the tumor cells to escape from the primary tumor. Consistent with the tail vein experiments, in vitro analyses demonstrate that ΔC-expressing cells exhibit a more malignant phenotype with an increased ability to grow in a three dimensional culture compared to control cells. Furthermore, ΔC-expressing cells are able to form tumorspheres in serum-free and non adherent conditions, suggesting a reversion to a more stem-like state. Microarray gene expression analysis demonstrates that ectopic expression of ΔC modulates the expression of a subset of EMT markers and stem cell markers. Microarray analysis further shows that ectopic expression of ΔC induces a gene expression signature that predicts poor survival in multiple human breast cancer datasets. This expression signature nearly perfectly matches a molecular classifier of high-grade tumors. Taken together, these data suggest that the short isoform may be a metastasis-promoting molecule and that metastasis susceptibility mediated by Brd4 may be the result of a complex equilibrium between the metastasis-suppressing long isoform and the metastasis-promoting shorter isoform.
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 5761.
Abstract 5764: Opposing roles of the COX-2 pathway receptors EP1 and EP4 in metastasis and contribution to disparities
Authors: Fulton Amy M. , Ma Xinrong , Kundu Namita , Ioffe Olga , Goloubeva Olga , Konger Raymond , Baquet Claudia , Reader Jocelyn 
Published: February 2011

Abstract
Cyclooxygenase-2 is highly expressed in breast and other malignancies and contributes to a poor prognosis. Our goal is to identify novel approaches to target the COX-2 pathway in order to reduce metastatic potential and improve survival. The primary COX-2 product, prostaglandin E2, exerts cellular effects by binding to four distinct G-protein-coupled receptors designated EP1, EP2, EP3 and EP4. Using pharmacologic and genetic approaches and a preclinical model of metastatic, triple-negative (ER, PR, Her-2 negative) breast cancer, we have examined the role of EP4 and EP1 in malignant behavior. Inhibition of EP4 receptor signaling with selective EP4 antagonists limits breast cancer metastasis to the same degree as achieved with a COX-2 inhibitor. Likewise, gene silencing of EP4 with specific shRNA also limits metastatic capacity by a mechanism involving Natural Killer cells. Conversely, blocking EP1 with either pharmacologic antagonists or genetic ablation promotes tumor metastasis. The expansion of mammary-gland implanted tumors was not affected by changes in EP1 expression levels, indicating that EP1 functions selectively to suppress metastasis. In primary breast tumors or cell lines, EP1 protein is detected both on the plasma membrane and in the nucleus. Immunohistochemical examination of a tissue array containing primary breast tumors reveals that the absence of nuclear EP1 in malignant cells is associated with significantly worse long term survival. Levels of cytoplasmic EP1 were not correlated with differences in outcome. Interestingly, breast tumors from African-American women express significantly less EP1 mRNA than tumors from Caucasian women, suggesting that low EP1 could contribute to worse outcome in AA women. These data support the hypothesis that EP1 acts as a metastasis suppressor but EP4 promotes metastasis and that shifting the balance towards activation of EP1 could be a novel approach to reduce breast cancer metastasis and reduce disparities in outcome.
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 5764.
Abstract 5766: The Hsp90 inhibitor PU-H71 is a potent suppressor of metastasis in triple-negative breast cancer models
Authors: Lopes Eloisi Caldas , Bos Paula , Peinado Hector , Cerchietti Leandro , Lavotshkin Simon , Melnick Ari , Lyden David , Chiosis Gabriela 
Published: February 2011

Abstract
Background: Triple-negative breast cancer (TNBC) characterized by estrogen and progesterone receptor and HER-2-negativity is a particularly aggressive tumor with currently no effective targeted therapies. Our previous findings demonstrated that Hsp90 inhibition by the purine-scaffold inhibitor PU-H71 is a promising therapeutic approach in this tumor type. In TNBC cells, a multitude of malignancy driving proteins, including EGFR, HER3, Akt, PDK1, Bcl-xL and Raf-1, were in a complex with Hsp90 and were preferentially targeted for degradation by PU-H71 (Abstract 5637, AACR-Annual Meeting 2008/2009). In TNBC xenografts, PU-H71 exhibited potent and durable anti-tumor activity inducing complete responses without toxicity to the host. PU-H71 also inhibited the invasiveness of TNBC cells through a mechanism involving downregulation and inhibition of several pro-metastatic proteins such as NF-kB, p-Akt, ERK2, TYK2 and PKC, suggesting a potential effect of PU-H71 on TNBC metastasis.
Study design: In order to determine whether in vivo PU-H71 also inhibits TNBC metastasis, we analyzed the effect of the Hsp90 inhibitor on lung colonization and metastastic body formation in immunocompromised mice. A lung tropic MDA-MB231 derivative expressing luciferase was used to establish the experimental models of metastasis. Animals were treated with 75mg/kg PU-H71 three times/week and lung metastases were monitored periodically by bioluminiscence imaging (IVIS system).
Results: At completion of treatment both bioluminescent imaging and histological analyses demonstrated significant reduction of the metastastatic burden in mice treated with PU-H71 compared to the vehicle treated group. Importantly, flow cytometry analysis demonstrated that circulating hematopoietic precursors related to metastatic spread were reduced after treatment with PU-H71 and several hematopoietic cell types recruited to metastatic sites such as CD11b+/Gr1+ were reduced after the treatment. In addition, analysis of metastatic lungs demonstrated that CD24low/CD44+ cells were attracted to metastatic lung in MDA-MB231 bearing mice and strongly reduced after PU-H71 treatment.
Conclusion: These data demonstrate that in addition to inhibition of primary tumors, PU-H71 leads to potent impairment of lung metastasis in an in vivo model of TNBC, supporting the use of PU-H71 for clinical trials involving patients with advanced and metastatic disease.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5766.
Abstract 5768: Predictive diagnostics from circulating tumor cells
Authors: Atwal Siminder K. , Savage Heidi , Spoerke Jill , Mohan Sankar , Pandita Ajay , Chen Daniel , Lackner Mark , Punnoose Elizabeth 
Published: February 2011

Abstract
Introduction: Tumor tissue collection is essential for biomarker assessment but can be difficult in tumor types such as non small-cell lung cancer (NSCLC) where often no surgery is performed and diagnosis is done with biopsies yielding only very limited tissue quantities. Also, in cases where primary tissue is available, the samples may not be representative of patient's current disease, i.e. in the case of hormone refractory prostate cancer (HRPC).
Rationale: Evaluation of cancer biomarkers (both predictive and pharmacodynamic) from blood and other biological material could significantly enable our ability to generate biomarkers by providing an accessible and relevant source of samples that can be analyzed. Successful assessment of biomarkers that do not require access to tumor “tissue” could improve the inclusion of biomarker evaluations in clinical development and across our oncology practice.
Results: We report on our efforts to evaluate Circulating Tumor Cells (CTC) for utility in tumor biomarker assessment. These efforts included evaluating multiple technologies for isolation and molecular analysis of CTCs from blood. By spiking tumor cells into blood as a model system for CTCs we have developed assays for biomarker evaluation in CTCs including: Fluorescence in situ hybridization (FISH), Immunofluoresecnce (IF), qRT-PCR and mutation detection. Validation of these assays in patient blood is ongoing and early data suggests that biomarker assessment is indeed possible from CTCs. Using blood samples from metastatic, HER2+ breast cancer patients; we were able to evaluate the HER2 status from CTCs using immunofluorescence and/or FISH.
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 5768.
Abstract 5775: A novel role for ID1 in prostate cancer chemotherapy
Authors: Geng Hao , Beer Tomasz , Nelson Pete , Qian David 
Published: February 2011

Abstract
To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in individual human prostate cancer specimens before and after chemotherapy collected from previously untreated patients with high-risk, localized disease. Among the molecular signatures associated with treatment, transcripts encoding Inhibitor of DNA Binding 1 (ID1) were significantly upregulated. Among patients who developed biochemical relapse 5 years after chemo-surgery, patients with the ID1 upregulation following chemotherapy had significantly longer relapse-free survival time than patients without ID1 increases. In the prostate cancer LNCaP cell line that is characterized by low ID1 expression, docetaxel dose-dependently induced ID1 expression. This docetaxel-induced ID1 transcription was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Compared to the empty-vector control, stable ID1 overexpression in LNCaP increased cell proliferation, promoted cell cycle progression through the G1 phase, and enhanced docetaxel-induced cytotoxicity. These phenotypic changes were accompanied by an increase in BCL2 phosphorylation at serine 70, caspase-3 activation and PARP cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell line reduced cell proliferation and decreased docetaxel-induced cytotoxicity. The ID1-mediated chemosensitivity enhancement was in part due to the ID1-suppression of p21. Overexpression of p21 in LNCaP-ID1 overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These data demonstrate that ID1 has a novel therapeutic role in prostate cancer treatment and ID1 upregulation after chemotherapy exposure may be a useful marker of chemotherapy efficacy.
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 5775.
Abstract 5782: Androgen receptor antagonists: Lead optimization and preclinical pharmacology
Authors: Gavai Ashvin , Norris Derek , Balog Aaron , Austin Joel , Shan Weifang , Zhao Yufen , Han Wen-Ching , Sharma Lisa , Nation Andrew , Wu Dauh-Rurng , Mathur Arvind , Zhang Litai , Cvijic Mary Ellen , Yarde Melissa , Apanovitch Donald , Twamley Celeste , Tang Yuwei , Johnson Benjamin , Elzinga Paul , Cornelius Georgia , Obermeier Mary , Foster William , Marathe Punit , Dell-John Janet , Dito Gennaro , Masters Gregg , Rizzo Cheryl , Schweizer Liang , Jure-Kunkel Maria , Attar Ricardo , Gottardis Marco , Vite Gregory 
Published: February 2011

Abstract
The development and progression of prostate cancer is known to be dependent on androgens and their signaling mediated by the androgen receptor (AR). The primary therapeutic intervention involves using agents that lower serum testosterone (e.g., LHRH agonists), often in concert with an AR antagonist, such as bicalutamide. Despite a favorable initial anti-tumor response, most patients progress to the advanced hormone-refractory disease. The development of resistance to anti-androgen therapy has been shown to be associated with an increase in the levels of both AR mRNA and protein. This observation supports the concept that an AR antagonist with a significant improvement in potency as compared to bicalutamide and a broader spectrum of in vivo anti-tumor activity, including the bicalutamide-refractory human prostate tumor xenografts, may provide a significant clinical advantage in the treatment of advanced prostate cancer. This presentation will describe structure-activity relationships in a novel tetracyclic series of androgen receptor antagonists leading up to the identification of BMS-779333. It is a potent AR full antagonist, which exhibited broad spectrum efficacy in four human prostate tumor xenograft models. BMS-779333 did not exhibit agonist activity for AR mutant isoforms. Tumors that failed bicalutamide treatment were shown to retain their sensitivity to respond to BMS-779333. Transcriptomic changes in LuCaP-35 tumors treated with BMS-779333 were closer to castration than with other drug treatments. Based on its overall profile, BMS-779333 was selected for further preclinical evaluation.
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 5782.
Abstract 580: Bone marrow cells trafficking after Salmonella typhimurium A1-R tumor targeting
Authors: Zhao Ming , Liu Fang , Zhang Lei , Hoffman Robert M. 
Published: February 2011

Abstract
Our laboratory has developed the tumor-targeting S. typhimurium double auxotrophic mutant termed A1-R. The A1-R mutant requires leucine and arginine, which disable it from growing in tumor tissue but the bacteria maintain high tumor virulence. In the present study, we used fluorescent imaging to observe bone marrow cells (BMC) trafficking in Lewis lung cancer-bearing nude mice after A1-R treatment. BMC were obtained from transgenic nude mice ubiquitously expressing green fluorescent protein (GFP). The GFP bone marrow cells were injected into the tail vein of red fluorescent protein (RFP)-expressing Lewis lung carcinoma-bearing nude mice. GFP-BMC trafficking to the tumor, lung, liver, and spleen were imaged at various time points after treatment with S. typhimurium A1-R. Untreated tumor-bearing mice injected with GFP-BMC were imaged as controls. Fluorescence imaging showed that there were more GFP-BMCs trafficking to tumor, lung, liver, and spleen in A1-R treated mice compared to untreated mice at 5 hours after A1-R infection. At day-2 after infection, there were significantly more GFP-BMCs in the tumor, and at day 4 after A1-R infection, BMCs appeared to die within the A1-R-treated tumors. GFP dendritic cells were observed in the liver of A1-R infected mouse at day 2 and day 4 after A1-R infection. These results suggest that immune cells in nude mice may be involved in the bacteria-induced antitumor response. The immune cells may also play a role in clearing the bacteria from normal organs in the host. In future experiments, we will identify the types of immune cells which play various roles in A1-R tumor targeting.
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 580.
Abstract 582: Targeting the blood-brain barrier with a non-canonical iron-mimicry mechanism: A translational approach for the detection and treatment of human brain tumors
Authors: Staquicini Fernanda I. , Ozawa Michael G. , Moya Catherine A. , Driessen Wouter H.P. , Barbu Elena Magda , Soghomonyan Suren , Flores Leo G. , Alauddin Mian M. , Gelovani Juri G. , Liang Xiaowen , Hook Magnus , Basilion James P. , Bogler Oliver , Sidman Richard L. , Cavenee Webster K. , Pasqualini Renata , Arap Wadih 
Published: February 2011

Abstract
Treatment of central nervous system (CNS) diseases is limited by the blood-brain barrier (BBB), a selective vascular interface restricting passage of most molecules from blood into brain. Here we used the in vivo phage display technology to isolate peptide-targeted phage particles that can cross the BBB under normal and pathological conditions. We show that a non-canonical association of (i) transferrin, (ii) an iron-mimic ligand motif, and (iii) transferrin receptor mediates binding and transport of phage particles into the normal mouse brain through an allosteric mechanism. We also show that, in an orthotopic human glioma model, a combination of transferrin receptor overexpression plus extended vascular permeability and ligand retention results in remarkable brain tumor targeting. Such unique attributes enable molecular imaging and targeted therapy of intracranial tumors in a clinic-ready setting. Finally, we expand our data by analyzing a large panel of primary CNS tumors through comprehensive tissue microarrays. Together, our approach and results provide a translational avenue for the detection and treatment of brain tumors.
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 582.
Abstract 587: Development of brain tumor-specific targeted system by using retroviral-mediated gene therapy with SSX4 promoter
Authors: Shimizu Keiji , Ishida Eri , Kitahara Masahiro , Tamura Masakazu , Yawata Toshio 
Published: February 2011

Abstract
Despite many efforts to develop effective therapy, the outcome of malignant glioma remains poor. Previously, we reported the eradication of mouse glioma by retroviral-mediated gene therapy. In this study, a tumor-specific targeting system was studied to develop the effective and safe gene therapy. We first searched for genes expressing at high frequency in brain tumors but not in normal human astrocyte (NHA) among cancer testis antigen (CTA) genes by in silico and RT-PCR screening. MAGEA3 and SSX4 were identified as tumor-specific genes. The promoter activity was measured in glioma, telomerase-immortalized fibroblast and NHA cells. The SSX4 promoter but not MAGEA3 showed the tumor-specific activity. In order to define a useful tumor-specific promoter for targeting in context of retroviral-mediated gene therapy, the SSX4 promoter were used to restrict the expression of suicide gene HSVtk in retroviral vector. The glioma cell lines transduced with the retroviral vector were killed efficiently by addition of ganciclovir (GCV), but telomerase-immortalized fibroblast BJ-5ta cells were not. Mouse glioma RSV-M cells transduced with the retroviral vector were transplanted into S.C. of syngeneic mouse. The administration of GCV suppressed the tumor growth completely. These results suggest that trans-acting factors may play a role for tumor-specific activity of SSX4 promoter while the expression of most CTA genes is regulated by epigenetic factors and the retrovirus vector expressing HSVtk under control of SSX4 promoter is a promising therapeutic reagent for malignant brain tumors.
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 587.
Abstract 588: Effect of antibiotic treatment on Salmonella typhimurium A1-R tumor targeting of prostate cancer
Authors: Zhao Ming , Geller Jack , Liu Fang , Zhang Lei , Zhang Yong , Hoffman Robert M. 
Published: February 2011

Abstract
We have previously demonstrated that a genetically-altered Salmonella typhimurium, auxotrophic for arginine and leucine, could effectively treat metastatic PC-3 tumors in nude mice and profoundly increase survival. The auxotrophic mutations, induced by nitrosoguamidine, allow the bacteria to grow in tumors but not in normal tissue. Since human prostate cancer eventually becomes non-androgen-dependent similar to PC-3 tumors, bacterial treatment offers a novel treatment for this disease. In the current study, we observed the effect of antibiotic treatment on A1-R bacteria therapy of PC-3 tumors in nude mice. Thirty mice were implanted subcutaneously with PC-3 tumors expressing GFP. Approximately two weeks following implantation, the tumors were externally imageable. Ten of the 30 mice served as untreated control, and 10 mice were given A1 weekly intravenously as treated controls. Ten mice were given A1 intravenously weekly, combined with Gentamicin administered by intra-peritoneal injection at 100 µg daily for 10 day cycles with a two-day break between cycles. The treatment was repeated until the study end. Tumor growth was externally imaged by GFP expression of the tumors. All mice in the untreated group were sacrificed by 6 weeks after tumor implantation due to tumor size of 1.5-2.0 cm diameter. All mice in the A1-R-antibiotic combination group were sacrificed at 8 weeks due to tumor size. At the same time, all mice in the A1-R-only treatment group were alive and well. Currently, 3 treated mice were close to tumor eradication at 16 weeks following implantation and are still being injected weekly with A1-R. These results suggest that the tumor-targeting activity of A1-R bacteria was antibiotic dependent. This study gives proof of principle that A1-R can be regulated by antibiotics, an important safety feature for clinical application.
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 588.