bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-244: MiR-34a/c-dependent PDGFR-α/β reduction inhibits tumorigenesis and sensitizes TRAIL-induced apoptosis in lung cancer.
Authors: Jeon Young-Jun , Nuovo Gerard J. , Midddleton Justin , Joshi Pooja , Nazaryan Natalya , Di Leva Gianpiero , Romano Giulia , Crawford Melissa , Nana-Sinkam Patrick , Garofalo Michela , Croce Carlo M. 
Published: August 2014

Abstract
Lung cancer is the most common cause of cancer death worldwide. Despite years of research, the prognosis for patients with lung cancer remains dismal. The most frequent type, non-small cell lung cancer (NSCLC) (85%), shows an overall five year survival of 15%. Isoforms of platelet-derived growth factor receptor (PDGFR) and its ligand, PDGF, constitute a family of receptors and ligands involved in proliferative and prosurvival signaling within cells. MicroRNAs (miRNAs), a class of ~ 22 nt endogenous RNAs, are important regulators of gene expression and have been implicated in the regulation of critical processes that are deregulated in cancer cells, as proliferation differentiation and apoptosis. Alterations in miRNA expression in cancer have been documented in numerous studies and suggest that miRNAs critically contribute to the cancer cell phenotype. In mammalians, the miR-34 family comprises three processed miRNAs that are encoded by two different genes: miR-34a is encoded by its own transcript, whereas miR-34b and miR-34c share a common primary transcript. In this study we found that miR-34a/c and not miR-34b, suppress the metastatic capacity of NSCLC by targeting platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β). We also observed an inverse relation between PDGFR-α/β mRNAs and miR-34a/c expression in lung tumor compared to normal lung samples. Finally, miR34-a/c-dependent PDGFR-α/β suppression or knocking-down of PDGFR-α/β by siRNAs sensitized NSCLC cells to TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. Taken together our findings could be helpful for future anti-tumor therapy of lung cancer.
Citation Format: Young-Jun Jeon, Gerard J. Nuovo, Justin Midddleton, Pooja Joshi, Natalya Nazaryan, Gianpiero Di Leva, Giulia Romano, Melissa Crawford, Patrick Nana-Sinkam, Michela Garofalo, Carlo M. Croce. MiR-34a/c-dependent PDGFR-α/β reduction inhibits tumorigenesis and sensitizes TRAIL-induced apoptosis in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-244. doi:10.1158/1538-7445.AM2013-LB-244
Abstract LB-260: CCR5 antagonists block basal breast cancer and prostate cancer metastasis in vivo.
Authors: Pestell Richard G. 
Published: August 2014

Abstract
The identification of new therapeutic targets and treatments to reduce tumor metastasis homing requires alternative interrogation approaches. Interrogation of microarray analysis of 2,254 human breast cancers demonstrated increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes of breast cancer. Genome wide interrogation of pathways activated in patient normal breast vs. tumor identified upregulation of a CCR5 signaling module. Human breast cancer cell lines expressed CCR5 by flow cytometry, and displayed a functional response to CCL5 by calcium mobilization assays and invasion assays. Using isogenic oncogene transformed breast and prostate cancer cell lines, we show oncogene transformation induces CCR5 expression and that the subpopulation of cells that express functional CCR5 display increased invasiveness. CCR5 promoted metastasis homing in vivo. The CCR5 antagonists Maraviroc and Vicriviroc, developed to block CCR5 HIV co-receptor function, reduced in vitro invasion of basal breast cancer and prostate cancer cell lines without affecting cell proliferation or viability. In a series of preclinical mouse models, Maraviroc decreased breast pulmonary metastasis. The isogenic prostate cancer cell lines metastasized to bones in immune-competent mice representing an ideal model for testing anti-metastasis therapies. Maraviroc and Vicriviroc reduced prostate cancer metastasis to brain, bones and lungs. Our findings provide evidence for a key role of CCL5/CCR5 in the metastasis of basal breast cancer and prostate cancer cell lines, and suggest that CCR5 antagonists may be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype and prostate cancer.
Citation Format: Richard G. Pestell. CCR5 antagonists block basal breast cancer and prostate cancer metastasis in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-260. doi:10.1158/1538-7445.AM2013-LB-260
Abstract LB-330: Therapeutic activity of a combination of immunostimulatory monoclonal antibodies (anti-B7-H1, CD137 and OX40) on a c-myc-driven spontaneous transgenic model of hepatocellular carcinoma.
Authors: Morales-Kastresana Aizea , Sanmamed Miguel F. , Rodriguez Inmaculada , Palazon Asis , Martinez-Forero Ivan , Labiano Sara , Hervas-Stubbs Sandra , Sangro Bruno , Ochoa Carmen , Azpilikueta Arantza , Bolaños Elixabet , Gütgemann Ines , Melero Ignacio 
Published: August 2014

Abstract
Several immunostimulatory monoclonal antibodies (ISmAbs) that derepress and unleash antitumor immune responses are showing efficacy in cancer clinical trials. MAbs anti-B7-H1 (PD-L1) block a critical inhibitory pathway for T cells, while antibodies anti-CD137 and OX40 provide intense T cell costimulation. Documenting efficacy of immunotherapies on spontaneous tumors arising in oncogene transgenic mice is considered more predictive than experiments on transplanted tumors. A combination of these ISmAbs has been tested on a transgenic mouse model of spontaneous primary liver cancer in which c-myc drives transformation and the tumor cells express ovalbumin as a surrogate transgenic antigen. The induced tumor lymphocyte infiltrates and immune mechanisms of action were studied. The triple combination of mAbs clearly extended survival of mice bearing hepatocellular carcinomas (HCC) and synergized with adoptive T cell therapy with activated TCR-transgenic T cells that recognize OVA. Mice undergoing therapy showed a clear increase in the tumor tissue infiltration by activated and blastic CD8 T lymphocytes expressing the ISmAb-targeted receptors. The triple combination of ISmAbs did not result in enhanced OVA-specific CTL activity but other antigens in cell lines derived from such HCC were recognized by the elicited tumor infiltrating T lymphocytes. Indeed adoptive transfer of OT-1 cells to tumor bearing mice resulted in their tolerization, unless the triple mAb therapy was instigated. Our results emphasize the role of combinational immunotherapy approaches including ISmAbs to impact on agressive and highly T cell-tolerizing hepatocellular carcinomas.
Citation Format: Aizea Morales-Kastresana, Miguel F. Sanmamed, Inmaculada Rodriguez, Asis Palazon, Ivan Martinez-Forero, Sara Labiano, Sandra Hervas-Stubbs, Bruno Sangro, Carmen Ochoa, Arantza Azpilikueta, Elixabet Bolaños, Ines Gütgemann, Ignacio Melero. Therapeutic activity of a combination of immunostimulatory monoclonal antibodies (anti-B7-H1, CD137 and OX40) on a c-myc-driven spontaneous transgenic model of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-330. doi:10.1158/1538-7445.AM2013-LB-330
Abstract LB-339: Increase in tumor-associated macrophages (TAMs) after antiangiogenic therapy is associated with poor survival in recurrent glioblastoma (GBM) patients.
Authors: Lu-Emerson Christine , Snuderl Matija , Kirkpatrick Nathaniel D. , Goveia Jermaine , Taylor Jennie , Davidson Christian , Huang Yuhui , Riedemann Lars , Ivy S. Percy , Duda G. Dan , Ancukiewicz3 Marek , Plotkin Scott R. , Chi Andrew , Gerstner Elizabeth R. , Eichler April F. , Dietrich Jorg , Stemmer-Rachamimov Anat O. , Batchelor Tracy T. , Jain Rakesh K. 
Published: August 2014

Abstract
Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas (GBMs), but tumors invariably recur. Because tumor-associated macrophages (TAMs) have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of TAMs in recurrent glioblastoma (rGBM) patients. We compared autopsy brain specimens from 20 rGBM patients who received antiangiogenic treatment and chemoradiation (AAT+) to 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry (IHC) for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in TAMs in the AAT+ patients. IHC analysis demonstrated an increase in CD68+ TAMs in the tumor bulk (p&lt;0.01) and infiltrative areas (p=0.02) in AAT+ patients. We also observed an increase in CD11b+ cells in the tumor bulk (p&lt;0.01) and an increase in CD163+ TAMs in infiltrative tumor (p=0.02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumor (p=0.05 and p=0.05, respectively) correlated with poor overall survival in patients who first received antiangiogenic therapy at recurrence. In summary, rGBMs showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival in rGBM patients. These data suggest that TAMs may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in rGBM.
Citation Format: Christine Lu-Emerson, Matija Snuderl, Nathaniel D. Kirkpatrick, Jermaine Goveia, Jennie Taylor, Christian Davidson, Yuhui Huang, Lars Riedemann, S. Percy Ivy, G. Dan Duda, Marek Ancukiewicz3, Scott R. Plotkin, Andrew Chi, Elizabeth R. Gerstner, April F. Eichler, Jorg Dietrich, Anat O. Stemmer-Rachamimov, Tracy T. Batchelor, Rakesh K. Jain. Increase in tumor-associated macrophages (TAMs) after antiangiogenic therapy is associated with poor survival in recurrent glioblastoma (GBM) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-339. doi:10.1158/1538-7445.AM2013-LB-339
Abstract LB-345: Hypoxia-induced reprogramming cause normal glia to mimic tumor-associated glial cells.
Authors: Leiss Lina , Manini Ivana , Calderon Marta , Enger Per Øyvind 
Published: August 2014

Abstract
Cancer-associated fibroblasts (CAFs) have been shown to foster tumor growth in several solid cancers. In the brain, the stroma is mainly composed of glial cells such as astrocytes and oligodendrocytes whose role in brain tumor-stroma interactions are poorly characterized. We have previously identified a unique gene expression profile of tumor-associated glial cells (TAGs) by fluorescence activated cell sorting (FACS) of glial cells from GFP/Nod Scid mice engrafted with human glioblastoma biopsies. Little is known about the mechanisms mediating these expression changes, but both direct tumor cell-glial cell contact and environmental stress such as hypoxia are external cues that may induce these changes. Thus, we investigated how hypoxia impacted on the phenotype of glial cells from normal mouse brains. Briefly, mouse brains were enzymatically digested to obtain single cell suspensions, and then glial cells were isolated by FACS with simultaneous removal of immune cells (CD11b+) and endothelial cells (CD31+). These cells were then seeded at a density of 50,000 cells/well in a 48-well plate and incubated under either normoxic (21% oxygen) or hypoxic (0.5% oxygen) conditions for seven days. Notably, glial cells upregulated Sox2, HIF-2a, Nestin and Vimentin in hypoxia compared to normoxic conditions. In addition glial cells also upregulated angiogenic factors such as VEGF, Angiopoietin 2 and FGF2. Furthermore, cell cycle analysis revealed a significantly higher fraction of cycling cells in hypoxia than in normoxia. To investigate how glial cells and tumor cells interact, we made co-cultures of glial cells isolated from DsRed+ mice and GFP-transfected human glioma cells. Fluorescence imaging of the co-cultures show that these two cell types establish cell contacts in vitro, and that the glial cells alter their morphology in co-cultures compared to monocultures of glial cells alone. These changes strongly resembled the changes observed in tumor-associated glial cells, suggesting that hypoxia is a major contributor to the phenotype of tumor-associated glial cells. Furthermore direct physical contact between tumor cells and glial cells may lead to phenotypical changes in the glial cells. Ongoing work aims at further characterizing the TAG population to reveal its cell composition and address the role of various subpopulations of glial host cells.
Citation Format: Lina Leiss, Ivana Manini, Marta Calderon, Per Øyvind Enger. Hypoxia-induced reprogramming cause normal glia to mimic tumor-associated glial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-345. doi:10.1158/1538-7445.AM2013-LB-345
Abstract LB-39: Sphingosine kinase activity is not required for tumor cell viability.
Authors: Wesche Holger , Brown Matthew L. , Carlson Timothy J. , Coxon Angela , Frank Brendon , Gustin Darin J. , Jeffries Shawn , Li Shyun , Li Yihong , Morgenstern Kurt , Morgenstern Kurt , Plant Matthew , Rex Karen , Schmidt Joanna , Shen Shanling , Walker Nigel , Wickramasinghe Dineli , Xu Guifen 
Published: August 2014

Abstract
Sphingosine kinase activity is not required for tumor cell viability
Holger Wesche, Matthew L. Brown, Timothy J. Carlson, Angela Coxon, Brendon Frank, Darin J. Gustin, Shawn Jeffries, Shyun Li, Yihong Li, Kurt Morgenstern, Matthew Plant, Karen Rex, Joanna Schmidt, Shanling Shen, Nigel Walker, Dineli Wickramasinghe, Mariwil Wong, Guifen Xu
Contribution from the Departments of Oncology Research, Medicinal Chemistry, Molecular Structure and Characterization and Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, 1120 Veterans Blvd., South San Francisco, Ca, 94080.
Sphingosine kinases (SPHKs) are enzymes that phosphorylate the lipid sphingosine, leading to the formation of sphingosine-1-phosphate (S1P). In addition to the well established role of extracellular S1P as a mitogen and potent chemoattractant, SPHK activity has been postulated to be an important intracellular regulator of apoptosis. According to the proposed rheostat theory, SPHK activity shifts the intracellular balance from the pro-apoptotic sphingolipids ceramide and sphingosine to the mitogenic S1P, thereby determining the susceptibility of a cell to apoptotic stress. Despite numerous publications with supporting evidence, a clear experimental confirmation of the impact of this mechanism on tumor cell viability in vitro and in vivo has been hampered by the lack of suitable tool reagents. Utilizing a structure based design approach, we developed potent and specific SPHK1/2 inhibitors. These compounds completely inhibited intracellular S1P production in human cells and attenuated vascular permeability in mice, but did not lead to reduced tumor cell growth in vitro or in vivo. These results show that the SPHK rheostat does not play a major role in tumor cell viability, and that SPHK inhibition may not offer an advantage over S1P neutralization in the treatment of cancer.
Citation Format: Holger Wesche, Matthew L. Brown, Timothy J. Carlson, Angela Coxon, Brendon Frank, Darin J. Gustin, Shawn Jeffries, Shyun Li, Yihong Li, Kurt Morgenstern, Kurt Morgenstern, Matthew Plant, Karen Rex, Joanna Schmidt, Shanling Shen, Nigel Walker, Dineli Wickramasinghe, Guifen Xu. Sphingosine kinase activity is not required for tumor cell viability. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-39. doi:10.1158/1538-7445.AM2013-LB-39
Abstract LB-45: Multiple melanoma suppressors are downregulated by loss of human chromosome 10.
Authors: Kwong Lawrence N. , Chin Lynda 
Published: August 2014

Abstract
Increasingly high-resolution genomic studies have made it clear that recurrent focal deletions and amplifications in cancer can selectively target specific oncogenes and tumor suppressors. In melanoma, MITF, MDM2, BRAF, CDKN2A, and PTEN are some of the more well-validated oncogenes and tumor suppressors that are targeted by such focal copy number-changing aberrations. However, there are also many recurrent large losses and gains that affect up to whole chromosome arms. One hypothesis is that, in targeting single genes such as PTEN, large chromosomal losses may inadvertently hit other loci. However, gathering evidence is pointing towards a possible functional role for these other collateral loci in affecting tumor progression. Here, we ask whether recurrent losses in melanoma may broadly target multiple tumor suppressors acting at different steps in tumor progression. We demonstrate via in vivo and in vitro shRNA screens that multiple genes on human chromosome 10, other than PTEN, affect both tumor growth and invasion.
Citation Format: Lawrence N. Kwong, Lynda Chin. Multiple melanoma suppressors are downregulated by loss of human chromosome 10. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-45. doi:10.1158/1538-7445.AM2013-LB-45
Abstract LB-61: Vemurafenib promotes RAS wild-type tumor formation in a mouse model of HPV-driven cutaneous squamous cell carcinoma.
Authors: Holderfield Matthew , Lorenzana Edward , Weisburd Ben , Lomovasky Lisa , Ghoddusi Majid , Daniel Dylan , Pryer Nancy , McCormick Frank , Stuart Darrin 
Published: August 2014

Abstract
A subset of melanoma patients (18-30%) treated with Vemurafenib (and other RAF inhibitors) develop spontaneous cutaneous squamous-cell carcinoma (cSCC) and/or keratoacanthoma (KA). Preclinical studies demonstrate that RAF inhibitors paradoxically activate the MAPK pathway and stimulate growth of RAS mutated cells. Based on these observations it has been proposed that drug induced MAPK activation in pre-cancerous tissues may account for the high incidence of cSCC and KA in treated patients. Because human cSCC is frequently positive for human papillomavirus (HPV) DNA, we hypothesized that RAF inhibitors promote tumorigenesis in HPV infected epidermis. To investigate this possibility, we used a transgenic murine model (K14-HPV16) of cSCC, driven by basal keratinocyte-specific expression (K14 promoter) of HPV type 16 early genes including E6 and E7, which inactivates p53 and pRB tumor suppressors. Exposure to Vemurafenib elevated MAPK markers in epidermis and increased cSCC incidence from 22% to 70%. Exome sequencing revealed that 100% of cSCCs from untreated mice harbored activating RAS mutations, yet 55% of cSCCs from Vemurafenib treated mice were RAS wild-type. Concomitant treatment with a MEK inhibitor reduced cSCC frequency, and MEK inhibitor alone was sufficient to completely regress established cSCCs. Together, these results suggest that cSCC is dependent upon MAPK activation induced either by a RAS oncogene or alternatively by exposure to RAF inhibitors in HPV infected keratinocytes.
Citation Format: Matthew Holderfield, Edward Lorenzana, Ben Weisburd, Lisa Lomovasky, Majid Ghoddusi, Dylan Daniel, Nancy Pryer, Frank McCormick, Darrin Stuart. Vemurafenib promotes RAS wild-type tumor formation in a mouse model of HPV-driven cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-61. doi:10.1158/1538-7445.AM2013-LB-61
Abstract LB-69: Novel WBC gene expression assay for prostate cancer detection.
Authors: Kassis Amin I. , Wu Qi , Joy Maliackal Poulo , Balagurumoorthy Pichumani , Loda Massimo , Evan Carolyn , Petrozziello Gillian , Kantoff Philip W. , Adelstein S. James 
Published: August 2014

Abstract
In recent studies, we showed that several oncogenes and cancer-associated genes and proteins are differentially expressed in phagocytic WBCs of tumor-bearing mice (colon, lung, melanoma, and prostate), compared to non-phagocytic WBCs from the same mice as well as to phagocytic WBCs obtained from non-tumor-bearing mice. Prompted by the translational potential of these findings, we carried out whole genome microarray analysis of total RNA samples isolated from peripheral blood phagocytic (macrophages and neutrophils) and nonphagocytic (T cells) WBCs of prostate cancer patients (n = 58) and blood donors (n = 36). Comparison of the genomic expression profiles of macrophages vs. T cells or neutrophils vs. T cells of these patients to those identified in blood donors revealed the presence of gene signatures that are unique to the patient population. These differentially expressed genes were used to generate receiver operating characteristic curves. The area under the curve was 1.000 for macrophages and 0.980 for neutrophils, indicating the high accuracy of the assay. While the PSA cutoff of 4 ng/mL failed to identify 14 of the 58 patients, the assay reported herein correctly identified 57 out of the 58 patients and all 36 controls (sensitivity = 0.983; specificity = 1.000) when macrophages were used; with neutrophils, there were 7 false negatives (sensitivity = 0.879; Specificity = 1.000). These promising results suggest that the approach lays the foundation for a next generation diagnostic blood test for prostate-cancer.
Citation Format: Amin I. Kassis, Qi Wu, Maliackal Poulo Joy, Pichumani Balagurumoorthy, Massimo Loda, Carolyn Evan, Gillian Petrozziello, Philip W. Kantoff, S. James Adelstein. Novel WBC gene expression assay for prostate cancer detection. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-69. doi:10.1158/1538-7445.AM2013-LB-69
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.