bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5079: Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-Endoglin antibodies.
Authors: Nolan-Stevaux Olivier P. , Zhong Wendy , Wickramasinghe Dineli , Ruefli-Brasse Astrid 
Published: August 2014

Abstract
Endoglin (ENG), a co-receptor for several TGFβ-family cytokines, is expressed in activated endothelial cells alongside ALK1, the ACVRL1 gene product. ENG and ACVRL1 are both required for angiogenesis and mutations in either gene are associated with Hereditary Hemorrhagic Telangectasia, a rare genetic vascular disorder. ENG and ALK1 function in the same genetic pathway but the relative contribution of TGFβ and BMP9 to SMAD1/5/8 activation and the requirement of ENG as a co-mediator of SMAD phosphorylation in endothelial cells remain debated. Here, we show that BMP9 and TGFβ1 induce distinct SMAD phosphorylation responses in primary human endothelial cells and that, unlike BMP9, TGFβ1 only induces SMAD1/5/8 phosphorylation in a subset of immortalized mouse endothelial cell lines, but not in primary human endothelial cells. We also demonstrate, using siRNA depletion of ENG and novel neutralizing anti-ENG antibodies, that ENG is required for BMP9/pSMAD1 signaling in all human and mouse endothelial cells tested. Finally, anti-ENG antibodies that interfere with BMP9/pSMAD1 signaling, but not with TGFβ1/pSMAD3 signaling, including the TRC105 clinical candidate, also decrease in vitro HUVEC endothelial tube formation and inhibit BMP9 binding to recombinant ENG in vitro. Our data demonstrate that BMP9 signaling inhibition is a key and previously unreported mechanism of action of TRC105, an anti-angiogenic anti-ENG antibody currently evaluated in clinical trials.
Citation Format: Olivier P. Nolan-Stevaux, Wendy Zhong, Dineli Wickramasinghe, Astrid Ruefli-Brasse. Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-Endoglin antibodies. [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 5079. doi:10.1158/1538-7445.AM2013-5079
Abstract 5084: Overcoming the resistance to anti-angiogenic therapy: Itraconazole blocks blood vessel maturation and synergizes with anti-VEGF therapy.
Authors: Fu Chenglai , Gerber Stephanie , Castillo Richmond , van der Zwan Anita , Kachhap Sushant , Hammers Hans 
Published: August 2014

Abstract
Background: Anti-angiogenic drugs, such as sunitinib, have been used as a first line therapy for renal cell carcinoma and some other cancers. However, the development of resistance to angiogenesis inhibitors targeting the VEGF pathway is common and impedes the efficacy of cancer treatments. Previously, we found it that blood vessel maturation is a common feature of tumors resistant to sunitinib. Thus, we hypothesized that novel approaches of inhibiting pericyte coverage of the tumor vasculature could be a successful approach to sensitize resistant tumors to sunitinib. Approach: An in vitro angiogenesis model was developed for screening the pericyte recruitment inhibitors. Itraconazole, an anti-fungal drug, was found to block the association of pericyte with newly-formed blood vessel endothelial cells. A sunitinib resistance animal model of Myc-Cap prostate cancer xenograft was used for studying the in vivo effect of treatment. Animals were dosed with itraconazole, sunitinib or the combination when tumors were well established. Result: through the in vitro angiogenesis model, the association of pericyte with endothelial cells was significantly reduced by itraconazole treatment. Its mechanism of action involved inhibition of focal adhesion kinase activity, a protein that plays a central role in cell spreading, differentiation, migration and cell death. Moreover, itraconazole treatment showed reduced pericyte coverage of tumor vasculature in vivo, and synergized with sunitinib treatments. Conclusion: These findings indicated that itraconazole is effective in inhibiting the pericyte coverage of the tumor vasculature and broaden the efficacy of sunitinib. Our results support further preclinical and clinical evaluation of itraconazole combination therapies in cancer treatment.
Citation Format: Chenglai Fu, Stephanie Gerber, Richmond Castillo, Anita van der Zwan, Sushant Kachhap, Hans Hammers. Overcoming the resistance to anti-angiogenic therapy: Itraconazole blocks blood vessel maturation and synergizes with anti-VEGF therapy. [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 5084. doi:10.1158/1538-7445.AM2013-5084
Abstract 5085: Less tumor engraftment after anti-VEGF therapy in pediatric low grade astrocytoma.
Authors: Sie Mariska , Sikkema Arend H. , Scherpen Frank J.G. , ter Elst Arja , Kampen Kim R. , Hoving Eelco W. , den Dunnen Wilfred F.a. , de Bont Eveline S.j.m. 
Published: August 2014

Abstract
Introduction. Low grade astrocytomas are the most frequent brain tumors in children. Although children can benefit from treatments including neurosurgery, chemotherapy and radiotherapy, still children die due to tumor progression. Furthermore, morbidity can be serious. So new therapeutic strategies are warranted for these patients. Previously, we showed that angiogenesis is a characteristic of pediatric low grade astrocytoma (Sie et al, NAN 2010). Therefore, vascular endothelial growth factor (VEGF), the most critical angiogenic factor, may be a potential therapeutic target. The present study aimed to analyze the effect of VEGF inhibition in vitro and in vivo in pediatric low grade astrocytoma.
Materials and methods. Three different pediatric low grade astrocytoma cell lines were used: Res-186 (WHO grade I astrocytoma), Res-259 and UW-467 (WHO grade II astrocytoma). Effects in vitro of the anti-VEGF monoclonal antibodies, bevacizumab (0 - 50 ug/ml, Avastin®, anti human VEGF) and B20-4.1.1 (0 - 200 ug/ml, anti human and mouse VEGF) were studied using a WST-1 cell viability assay and a cell proliferation assay with BRDU. Res-259 cells were orthotopically implanted in NOD-scid IL2Rgnull mice. After 6 weeks of treatment intraperitoneal twice weekly with bevacizumab (15 mg/kg), B20-4.1.1 (5 mg/kg) or phosphate buffered saline as control group, mice were euthanized and tumor engraftment was studied in brain slides using Aperio's imagescope viewer.
Results. In vitro cell growth was not changed as measured by WST-1 and BRDU incorporation. In vivo results showed less tumor engraftment in bevacizumab (n = 10) and B20-4.1.1 (n = 9) treated mice compared with the control group (n = 10) (resp. 70%, 44%, 100%). In the bevacizumab and B20-4.1.1 treated mice tumor mass was lower as compared with controls (resp. P = 0.062, P = 0.001).
Conclusion(s). This study showed less tumor engraftment after anti-VEGF therapy in a newly developed pediatric low grade astrocytoma mouse model. In these tumors anti-VEGF seems to work especially on tumor microenvironment. Suggesting that anti-VEGF could have a potential role in the therapeutic strategy for children with low grade astrocytoma, thoughtfulness on possible tumor escape mechanisms that may arise will be crucial.
[W.F.A. den Dunnen and E.S.J.M. de Bont shared senior authorship.]
Citation Format: Mariska Sie, Arend H. Sikkema, Frank J.G. Scherpen, Arja ter Elst, Kim R. Kampen, Eelco W. Hoving, Wilfred F.a. den Dunnen, Eveline S.j.m. de Bont. Less tumor engraftment after anti-VEGF therapy in pediatric low grade astrocytoma. [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 5085. doi:10.1158/1538-7445.AM2013-5085
Abstract 5086: The side effects of sorafenib in treating hepatocellular carcinoma.
Authors: Sun Hui-Chuan , Zhang Wei , Zhu Xiao-Dong , Lu Lu , Zhang Qiang-Bo , Tang Zhao-You 
Published: August 2014

Abstract
Sorafenib, a tyrosine kinase inhibitor of VEGFR and B-Raf, is a standard treatment for advanced hepatocellular carcinoma (HCC). However, there are several clinical observations showing discontinuous sorafenib treatment associated with more metastasis or rapid relapse. We tested effect of sorafenib on tumor growth and metastasis in different dosing and schedules in liver cancer allograft or xenograft models. The results showed a lower dose sorafenib treatment will induce more intrahepatic or lung metastasis while the primary tumor growth is still inhibited in HCC with a higher expression of HTATIP2 but not in HCC with a lower expression of HTATIP2. Further studies showed sorafenib decreased HTATIP2 expression only in HCC with a higher expression of HTATIP2. The clinical data also supported the patients with lower HTATIP2 expression in tumor benefit from sorafenib treatment while patients with a higher HTATIP2 expression in tumor did not. We also observed the effect of sorafenib on host (mouse) immunity after we found pre-treatment by sorafenib before implantation of tumor resulted in more lung metastasis. We found interleukin 12 (IL12) was significantly inhibited by sorafenib, which is responsible for more lung metastasis. In conclusion, our study showed the side effect of sorafenib may promote tumor progression if sorafenib treatment is stopped or not given in a full dose. These findings may help to improve the efficacy of sorafenib by overcoming its side effects.
Citation Format: Hui-Chuan Sun, Wei Zhang, Xiao-Dong Zhu, Lu Lu, Qiang-Bo Zhang, Zhao-You Tang. The side effects of sorafenib in treating 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 5086. doi:10.1158/1538-7445.AM2013-5086
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5098: A mouse DLL4 cross-reactive variant of MEDI0639 disrupts functional vessel formation and inhibits tumor growth in preclinical models.
Authors: Cho Song H. , Jenkins David W. , Strout Patrick , Korade Martin , Zhong Haihong , Leow Ching Ching , Breen Shannon , Chesebrough Jon , Holoweckyj Nicholas , Inigo Ivan , Gololobov Gennady , Tsui Ping , Cook Kimberly , Damschroder Melissa , Czapiga Meggan , Brohawn Philip , Huang Jiaqi , Ricketts Sally-Ann , Maynard Juliana , Kamal Adeela 
Published: August 2014

Abstract
Delta-like ligand 4 (DLL4) is a membrane bound ligand for Notch receptors essential for functional vessel formation during development and angiogenesis. We have shown previously that MEDI0639, a human anti-DLL4 antibody, has potent in vitro and in vivo activity in blocking DLL4-Notch interaction. However, because MEDI0639 has low binding affinity to mouse DLL4, to enable in vivo pharmacology studies using xenograft tumor models in mice, MEDI0639 was engineered to bind more strongly to mouse DLL4. The resulting affinity-optimized variant antibody (anti-mDLL4 mAb) bound with high affinity to both human and mouse DLL4 and maintained binding specificity to DLL4. In a number of human cancer xenograft models in nude mice, the MEDI0639 variant antibody markedly inhibited the growth of tumors. qRT-PCR analysis using the Fluidigm platform showed decreases in mouse genes downstream of the Notch signaling pathway at efficacious doses, indicating on-target antibody effect on tumor vasculature. In addition, IHC and imaging analysis of xenograft tumors from the anti-DLL4 mAb dosed animals showed a dose-dependent increase in microvessel density and decrease in tumor perfusion compared to the control groups. In summary, we describe here the generation of mouse and human DLL4 cross-reactive antibody and the utilization of this antibody in demonstrating a positive correlation between the anticipated mechanism of action of DLL4 blockade on vasculature and inhibition of tumor growth.
Citation Format: Song H. Cho, David W. Jenkins, Patrick Strout, Martin Korade, Haihong Zhong, Ching Ching Leow, Shannon Breen, Jon Chesebrough, Nicholas Holoweckyj, Ivan Inigo, Gennady Gololobov, Ping Tsui, Kimberly Cook, Melissa Damschroder, Meggan Czapiga, Philip Brohawn, Jiaqi Huang, Sally-Ann Ricketts, Juliana Maynard, Adeela Kamal. A mouse DLL4 cross-reactive variant of MEDI0639 disrupts functional vessel formation and inhibits tumor growth in preclinical models. [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 5098. doi:10.1158/1538-7445.AM2013-5098
Abstract 5106: Circulating MACC1 transcripts are elevated in pancreatic cancer patient blood and correlate to locally advanced disease.
Authors: Stein Ulrike S. , Herrmann Pia , Fischer Christian , Schlag Peter M. , Detjen Katharina 
Published: August 2014

Abstract
Pancreatic cancer is a highly aggressive malignancy with a 5-year survival of &lt; 5%. Late diagnosis, lack of prognostic markers and poor response to radiation and chemotherapies all contribute to the dismal prognosis. Surgery represents the sole curative treatment option. However, success is limited by invasive growth and metastatic spread, which frequently precede the onset of clinical symptoms and hence diagnosis.
Recently, we identified the novel gene metastasis-associated in colon cancer-1 (MACC1). MACC1 is a prognostic indicator for metastasis formation linked to metastasis-free survival of colorectal cancer patients. Circulating MACC1 transcripts in colorectal cancer patient plasma predict metastasis and survival. Correlations of MACC1 expression levels with tumor progression, recurrence and metastasis have meanwhile been reported for several cancers, e.g. gastric, lung and hepatocellular cancer. Here, we addressed the role of MACC1 in pancreatic cancer.
Immunohistochemical analysis of MACC1 in cryosections of human pancreatic cancer revealed strong reactivity of tumour duct epithelial cells, but not in the desmoplastic stroma. In contrast, weak immunoreactivity was present in non transformed pancreatic tissues, suggesting an induction of MACC1 in pancreatic malignancy. We furthermore analyzed blood levels of circulating MACC1 transcripts in pancreatic cancer patients. Circulating MACC1 transcript levels were elevated in pancreatic cancer patients, when compared to healthy volunteers. MACC1 transcript levels furthermore correlated to peripancreatic infiltration, but not to tumour size, tumor grading or angioinvasion.
Thus, MACC1 expression is induced in pancreatic cancer, which is reflected by increased circulating transcript levels in blood as well as high protein levels in the primary tumors. The correlation of MACC1 transcript levels with peripancreatic infiltration suggests a distinct function of MACC1 in pancreatic cancer cell biology, which translates into distinct clinical features of disease progression. Circulating MACC1 might therefore help to personalize treatment decisions in situations such as (neo-)adjuvant chemotherapy.
Citation Format: Ulrike S. Stein, Pia Herrmann, Christian Fischer, Peter M. Schlag, Katharina Detjen. Circulating MACC1 transcripts are elevated in pancreatic cancer patient blood and correlate to locally advanced disease. [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 5106. doi:10.1158/1538-7445.AM2013-5106
Abstract 5107: Phenotypic characterization of circulating tumor cells (CTCs) in triple negative breast cancer patients.
Authors: Kallergi Galatea , Markomanolaki Haris , Mavroudis Dimitrios , Georgoulias Vassilis , Agelaki Sofia 
Published: August 2014

Abstract
Triple negative (ER-negative, PR-negative, HER2-negative) considered as poor prognosis breast cancer patients without many therapeutic options. Circulating Tumor Cells (CTCs) have been proposed as a “real time liquid biopsy” in breast cancer patients. CTCs are associated with disease relapse and could serve as a target for molecular cancer therapies. The aim of the present study was the phenotypic characterization of CTCs in triple negative patients to explore new therapeutic strategies for these patients. We evaluated peripheral blood mononuclear cells (PBMC) cytospins from 29 triple negative patients, before the initiation of adjuvant (19 early) and front-line (10 metastatic) treatment. The expression of Cytokeratins (CK) (marker for CTCs), Estrogen Receptor (ER), Progesterone Receptor (PR), EGFR and HER2 in CTCs was assessed using double immunofluorescent experiments. Our results revealed that median expression per patient for ER, PR, EGFR and HER2 was 16.7%, 0%, 42.9% and 91.4%. The respective numbers for early versus (vs) metastatic patients were 29.7% vs 0% for ER, 27.1% vs 0% for PR, 70.8% vs 52.3% for EGFR and 50% vs 48.7% for HER2. In addition ER, PR, EGFR and HER2 were expressed in 33.1%, 28%, 67.7% and 45.1%, respectively, of the total examined CTCs. Triple staining experiments with the Ariol system could not revealed any no co-expression of CK/EGFR/ER in CTCs; however, there was only one patient with CTCs co-expressing CK/HER2/ER.
Consequently in order to identify whether chemotherapy could induce phenotypic changes of CTCs, 18 patients were analyzed after the completion of adjuvant treatment. ER, PR, EGFR and HER2 median expression per patients was identified in 0.2%, 15.2%, 66.7%, and 50% suggesting that adjuvant chemotherapy does not significantly influence the phenotype of CTCs in triple negative patients.The majority of CTCs in triple negative patients revealed expression of HER2 and EGFR implying that these receptors could be a potential target for the limitation of metastasis in these patients.
Citation Format: Galatea Kallergi, Haris Markomanolaki, Dimitrios Mavroudis, Vassilis Georgoulias, Sofia Agelaki. Phenotypic characterization of circulating tumor cells (CTCs) in triple negative breast cancer 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 5107. doi:10.1158/1538-7445.AM2013-5107
Abstract 5110: Activation of Wnt/β-catenin, hedgehog and androgen receptor signaling pathways in solid pseudopapillary neoplasm of pancreas.
Authors: Park Minhee , Kim Minhyung , Hwang Daehee , Kim SangKyum , Park Eunsung , Paik Youngki , Park Jeonhan , Kim Hogeun 
Published: August 2014

Abstract
Solid pseudopapillary neoplasm (SPN), is an uncommon pancreatic tumor with distinct clinicopathologic features. Mutations in the exon 3 of β-catenin are characteristically identified in SPNs, however little is known about gene and microRNA expression characteristics. To investigate the molecular characteristics of SPNs, we analyzed mRNA and microRNA expression profiles of 14 SPNs and compared their expressions to that of 6 pancreatic ductal adenocarcinomas, 6 endocrine tumors of pancreas, and 5 non-neoplastic pancreas tissues. We demonstrated both mRNA and microRNA expression profiles completely distinguish SPNs to the other pancreatic tumors and non-neoplastic pancreas tissues. We found that Wnt/β-catenin, Hedgehog and androgen receptor signaling pathways are activated in SPNs by analyzing 1,686 genes that showed specific expression changes in SPN. We also found that 7 microRNAs were specifically down-regulated in SPNs, and miR-30a was most closely associated with the up-regulation of the genes belong to the three distinct activated pathways of SPN. We also demonstrated that genes involved in epithelial to mesenchymal transition (EMT) are up-regulated in SPNs than the other type of pancreatic tumors. SPN is characterized by increased expression of mesenchymal markers (N-cadherin, MMP9, Vercican, TIMP1) and decreased expression of epithelial markers (E-cadherin, Desmoplakin, Mucin1, Caveolin).
Considering that activated Wnt/β-catenin and Hedgehog pathways are related to the activation of the genes involved in EMT, these activated signaling pathways of SPNs can explain lack of epithelial cell differentiation, and the molecular mechanism of SPN tumorigenesis.
Citation Format: Minhee Park, Minhyung Kim, Daehee Hwang, SangKyum Kim, Eunsung Park, Youngki Paik, Jeonhan Park, Hogeun Kim. Activation of Wnt/β-catenin, hedgehog and androgen receptor signaling pathways in solid pseudopapillary neoplasm of pancreas. [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 5110. doi:10.1158/1538-7445.AM2013-5110
Abstract 5115: Inhibition of STAT-3 by piperlongumine induces anoikis in melanoma cells in vitro and blocks tumor formation potential in vivo.
Authors: Fofaria Neel M. , Srivastava Sanjay K. 
Published: August 2014

Abstract
The National Cancer Institute estimates that about 76,250 new cases of melanomas will be diagnosed in 2012 in the United States leading to at least 9810 related deaths. Metastasis of melanoma is the major challenge leading to the failure of its therapy. Hence, novel strategies to prevent metastasis are of prime importance. Anoikis is an anchorage independent cell death. Resistance to anoikis is one of the key features of a metastatic cell. In the current study, we show induction of anoikis by piperlongumine, a component of black pepper, by inhibition of STAT-3. Treatment of various melanoma cell lines in low attachment conditions with piperlongumine reduced the anoikis resistance in a concentration dependent manner. This decrease in anoikis resistance was associated with decrease in expression of STAT-3 and its phosphorylation at Y705. Significant down-regulation of Bcl-2 and Mcl-1, which are under the transcriptional regulation of STAT-3, was also observed by piperlongumine treatment indicating the role of STAT-3 in anoikis. Concentration dependent cleavage of poly (ADP-ribose) polymerase (PARP) was observed by piperlongumine treatment in melanoma cells. AG 490, an inhibitor of STAT-3 phosphorylation, alone induced anoikis in melanoma cells further indicating the role of STAT-3. IL-6 treatment not only increased the phophorylation of STAT-3 at Y05 but also abrogated the anoikis induced by piperlongumine. Silencing STAT-3 by shSTAT-3 sensitized the cells to piperlongumine treatment. On the other hand, over-expression of STAT-3 in SK-MEL28 and SK-MEL-2 cells conferred resistance to anoikis induced by piperlongumine. STAT-3 -/- SK-MEL-28 cells were highly sensitive to anoikis upon piperlongumine treatment. Finally, our in vivo studies established that melanoma cells treated with piperlongumine in suspension condition lost their potential to form tumors in mice. Taken together, our study suggests that the decrease in anoikis resistance induced by piperlongumine was mediated by STAT-3 inhibition. Notably, STAT-3 has been shown to be constitutively upregulated in melanoma rendering it resistant to chemotherapy and potential to metastasize. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Neel M. Fofaria, Sanjay K. Srivastava. Inhibition of STAT-3 by piperlongumine induces anoikis in melanoma cells in vitro and blocks tumor formation potential 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 5115. doi:10.1158/1538-7445.AM2013-5115