bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 685: Antagonism of sorafenib and regorafenib-mediated HCC growth inhibition by platelet factors
Authors: Carr Brian I. , D'Alessandro Rosalba , Refolo Maria Grazie , Lippolis Catia , Messa Caterina , Cavallini Aldo 
Published: May 2015

Abstract
Background. Circulating blood platelet numbers are frequently altered in hepatocellular carcinoma (HCC) patients. Thrombocytopenia is associated with smaller tumors and thrombocytosis with larger tumors (Oncology 2013;85:153-9). Recently, platelet extracts have been shown to enhance HCC cell growth and have anti-apoptotic effects.
Methods. Human HCC cell lines were used to evaluate the actions of time-expired mixed human platelet lysates on the inhibition of HCC growth by MTT assay, as well as on migration and Matrigel invasion mediated by Sorafenib or Regorafenib in vitro and Western blots were performed for cell signaling and apoptosis.
Results. Sorafenib or Regorafenib-mediated inhibition of cell growth, migration and invasion was antagonized by platelet extracts. The multi-kinase inhibitor-mediated induction of apoptosis and decrease in phospho-ERK levels were both blocked by the platelet extracts, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-XL levels.
Conclusions. In addition to their effects on coagulation and wound healing, platelet factors can antagonize growth inhibition and apoptosis induction by multi-kinase inhibitors Sorafenib or Regorafenib. This could be due to several growth factors or inflammatory cytokines that are produced by platelets. Targeting platelets might be a novel approach to increasing multi-kinase inhibitor actions.
Citation Format: Brian I. Carr, Rosalba D'Alessandro, Maria Grazie Refolo, Catia Lippolis, Caterina Messa, Aldo Cavallini. Antagonism of sorafenib and regorafenib-mediated HCC growth inhibition by platelet factors. [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 685. doi:10.1158/1538-7445.AM2014-685
Abstract 695: p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling
Authors: Axelrod Mark J. , Mendez Rolando E. , Gioeli Daniel G. , Jameson Mark J. , Weber Michael J. 
Published: May 2015

Abstract
Targeted cancer therapies often induce compensatory adaptive responses that blunt drug effectiveness, resulting in therapeutic resistance - intrinsic or acquired. Adaptive responses are characteristic of the complex nature of the cancer cell signaling network. Within this network, nodes of convergence between signaling modules are critical mediators of adaptive responses to targeted drugs. The critical nodes in an oncogenically-activated signaling network represent potential therapeutic vulnerabilities because their inhibition could result in collapse of the network and hence enhanced cytotoxicity. We have previously used high-throughput combinatorial drug screening to empirically identify adaptive survival responses to targeted therapies. We found that HER-family and PI3K represented compensatory signaling pathways, and combination therapy caused synergistic cytotoxicity in cases where inhibition of neither target was effective as a monotherapy. RPPA analysis identified ribosomal protein S6 as being synergistically down-regulated upon HER-family and PI3K co-inhibition. Expression of a constitutively active construct of the upstream activator of S6, p70S6K, was protective against apoptosis induced by combined HER-family and PI3K inhibition. Direct inhibition of p70S6K using small molecule inhibitors phenocopied the growth inhibition and apoptosis caused by HER-family and PI3K inhibition. These data implicate p70S6K as a critical node and druggable target in the HER-family / PI3K signaling network. The ability of direct inhibitors of p70S6K to phenocopy the co-inhibition of upstream signaling indicates that identification and targeting of critical nodes may be a way to overcome adaptive resistance to targeted therapies.
Citation Format: Mark J. Axelrod, Rolando E. Mendez, Daniel G. Gioeli, Mark J. Jameson, Michael J. Weber. p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling. [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 695. doi:10.1158/1538-7445.AM2014-695
Abstract 696: ASS1, ANXA4 and MVP underlie acquired multicellular resistance of mesothelioma 3D cell cultures
Authors: Barbone Dario , Dam Loes van , Zhang Shu-Dong , Puthen Jithesh , Fennell Dean , Broaddus V. Courtney 
Published: May 2015

Abstract
Cancer cells are usually studied in flat 2D monolayers however, solid tumors, such as malignant mesothelioma, grow as 3D masses. When tumor cells are grown as 3D structures, they acquire multi-cellular resistance to apoptosis, resembling the stubborn chemoresistance seen in patients. In this study, we have identified a gene expression signature that is specific for 3D spheroids, possibly underlying multicellular resistance. By comparing this signature with the data from two sets of publicly-available gene expression datasets of patients’ specimens we have identified three genes in common, genes that may play a role in multicellular resistance: ASS1, ANXA4 and MVP. Moreover, we have studied the levels of the proteins encoded by the three genes and have begun investigating how their ablation by RNAi influences the response to chemotherapy. Furthemore, by Connectivity Analysis, we have found two safe and patent-free candidate drugs that can reduce the expression levels of the three genes and undermine the acquired chemoresistance of spheroids. Such drugs would have potential as adjuncts to chemotherapy. These studies will not only clarify the role of ASS1, ANXA4 and MVP in mesothelioma and provide therapeutic insights but also advance the use of spheroids as a more realistic model for studying tumor biology.
Citation Format: Dario Barbone, Loes van Dam, Shu-Dong Zhang, Jithesh Puthen, Dean Fennell, V. Courtney Broaddus. ASS1, ANXA4 and MVP underlie acquired multicellular resistance of mesothelioma 3D cell cultures. [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 696. doi:10.1158/1538-7445.AM2014-696
Abstract 697: Development of spheroid based high-throughput screening of cell-cell adhesion inhibitors to reverse acquired multicellular resistance
Authors: Arai Kazuya , Itho Manabu , Mizuno Atsushi , Miura Hiromi 
Published: May 2015

Abstract
Background: Solid tumors are more resistant to chemo- and radio-therapy than in vitro cancer cells under conventional monolayer culture condition. This phenomenon can be explained by “multicellular resistance” (MCR). It is considered that one of approach for keeping out cancer cells from acquired MCR is inhibition of cell-cell/cell-matrix adherence. Several therapeutic approaches increasing effect of chemo- and radio-therapy by preventing MCR are proposed. However, reports of the approaches are still few. Therefore, we tried to develop a spheroid-based high-throughput screening method of cell-cell adherence inhibitor, for discovery of drug capable of reversing the acquired MCR.
Method: For spheroid formation, A549 cells were cultured under three-dimensional condition using NanoCulture® Plate, which is compatible with imaging and HTS systems. After 3 days culture, A549 spheroids were treated with library compounds for 4 days. To evaluate a degree of cell-cell adherence of the spheroids, we used Hypoxia Probe, which is a phosphorescence substrate for visualizing of intra-spheroid hypoxicity. And the signals were detected using Celigo® imaging cytometer.
Results: In NanoCulture® Plate, A549 cells formed a number of spheroids. Intra-spheroid hypoxicity was correlated with degree of cell-cell adherence. After screening of inhibitor of cell-cell adherence without cytotoxity, several candidates were evaluated the ability as chemosensitizing agent. Combination treatment with the hit compound and anticancer drug was more effective than each drug alone.
Conclusion: We developed a novel high throughput screening method of cell-cell adherence inhibitors. And we acquired several hit compounds capable of reversing the acquired MCR.
Note: This abstract was not presented at the meeting.
Citation Format: Kazuya Arai, Manabu Itho, Atsushi Mizuno, Hiromi Miura. Development of spheroid based high-throughput screening of cell-cell adhesion inhibitors to reverse acquired multicellular resistance. [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 697. doi:10.1158/1538-7445.AM2014-697
Abstract 7: Assessment of FSH receptor expression in the major molecular subtypes of breast cancer
Authors: Planeix François , Siraj Mohammad-Ahsan , Bidard François-Clément , Pierga Jean-Yves , Sastre Xavier , Antoine Martine , Ghinea Nicolae 
Published: May 2015

Abstract
Recent data from our laboratory show that the follicle-stimulating hormone receptor (FSHR) is expressed on the endothelial surface of tumor peripheral blood vessels in different types of tumors including breast cancer. The main goal of the present study was to determine differences in the endothelial FSHR expression level among the breast cancer types, and within the same tumor type, among tumor stages. We have also compared the FSHR expression with the receptor status of three most important markers for breast cancer diagnosis and therapy (estrogen receptor, progesterone receptor, and HER-2/neu). By using a highly specific monoclonal antibody raised against the human FSHR, we determined the density of FSHR-positive vessels in a band with a width of 10 mm (centered on the demarcation line between the tumor and the normal breast tissue) on the tissue sections by standard peroxidase-immunohistochemistry and immunofluorescent confocal microscopy. We examined 35 patients of Luminal A, 13 patients of Luminal B, 19 patients of HER-2 positive, and 16 patients of Triple negative/basal breast cancer. All four groups expressed almost similar densities of FSHR stained blood vessels with 36.7 ± 4.0/mm2 in Luminal A, 31.4 ± 5.2/mm2 in Luminal B, 39.6 ± 6.0/mm2 in HER-2 positive tumors, and 38.4 ± 8.0/mm2 in triple negative/basal group. A positive correlation has been observed between the percentage of FSHR-positive vessels and total blood vessels in the tumor periphery (r = 0.551; p = 7e-08). We have also noticed a tendency (not reaching statistical significance) towards an overall decrease in the extent of the vascular bed in elder patients as compared to younger patients. No correlation was found between the percentage of FSHR-positive vessels and the expression of receptors for estrogen, progesterone, and HER-2/neu.
In conclusion, our data show that: (i) FSHR is robustly expressed in breast cancer, and (ii) the main types of breast cancers and stages do not differ significantly in terms of vascular FSHR expression. These facts strongly increase FSHR potential relevance as a clinical target for breast cancer imaging and for therapy, especially for triple negative/basal breast cancers, a group with only chemotherapy options.
Citation Format: François Planeix, Mohammad-Ahsan Siraj, François-Clément Bidard, Jean-Yves Pierga, Xavier Sastre, Martine Antoine, Nicolae Ghinea. Assessment of FSH receptor expression in the major molecular subtypes of 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 7. doi:10.1158/1538-7445.AM2014-7
Abstract 70: Mouse models of human lung adenocarcinoma: Identification of potential tumor suppressors by functional in vivo shRNA screening
Authors: Yeddula Narayana , Xia Yifeng , Verma Inder 
Published: May 2015

Abstract
Lung cancer is one of the leading human cancer malignancies, and histopathologically divided into Non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Lung adenocarcinoma is a major form of NSCLC. We have developed a lentiviral-vector-mediated mouse model, which enables generation of lung adenocarcinoma from less than 100 alveolar epithelial cells, and investigated the role of IKK2 and NF-κB in lung-cancer development. IKK2 depletion in tumour cells significantly attenuated tumour proliferation and significantly prolonged mouse survival. We identified Timp1, one of the NF-κB target genes, as a key mediator for tumour growth by activating ERK signaling pathway. Knockdown of either Ikbkb or Timp1 by short hairpin RNAs reduced tumour growth in both xenograft and lentiviral models. Further, by utilizing lentiviral mediated mouse models, we performed a genome wide in vivo shRNA screen to findout tumor suppressors or tumor suppressor like genes that will cooperate with KRasG12D expression. The screen identified several novel molecules as potential tumor suppressor properties, which will cooperate with KRasG12D. Several of these molecules were also altered in human patient cohorts of The Cancer Genome Atlas. Ephrin receptor A2, EphA2, is one of the molecule knockdown of which cooperated with KRasG12D expression to generate lung adenocarcinomas comparable to knockdown of potent tumorsuppressor P53 thus validating our screen. The mechanisms underlying EPhA2 mediated tumorsuppression are being studied. Overall, our study identified novel potential tumorsuppressors.
Citation Format: Narayana Yeddula, Yifeng Xia, Inder Verma. Mouse models of human lung adenocarcinoma: Identification of potential tumor suppressors by functional in vivo shRNA screening. [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 70. doi:10.1158/1538-7445.AM2014-70
Abstract 701: In vivo anti-metastatic effects of uPAR retargeted oncolytic measles virus
Authors: Jing Yuqi , Zaias Julia , Merchan Jaime 
Published: May 2015

Abstract
The urokinase receptor (uPAR) is a clinically relevant target for novel biological therapies. Here, we investigated the antimetastatic effects of oncolytic measles virus retargeting uPAR (MV-uPA) in breast cancer metastases models. Species specificities of recombinant viruses retargeted against human (MV-h-uPA) or mouse uPA (MV-m-uPA) were demonstrated in vitro in human and murine breast cancer cell lines. MV-h-uPA and MV-m-uPA induced in vitro cytotoxicity and replicated in human breast cancer cells (MDA-MB231, MDA-MB436 and MCF-7) and murine mammary cancer cells (4T1), respectively. A syngeneic model of mammary cancer metastases was established by intravenous injection of 4T1 cells (5x10e4 per mouse) expressing highly efficient firefly luciferase into immunocompetent BALB/C mice. Seven days after tumor cell inoculation, MV-m-uPA or vehicle was administered into tumor-bearing mice via the tail vein (virus dose: 1×10e6 TCID50 per injection, three injections, every other day). Metastases progression was assessed by bioluminescence analysis. In this highly aggressive syngeneic model, MV-m-uPA treatment was associated with delay in metastases progression and improvement in survival, compared to controls. These effects were associated with detection of viable viral particles from lungs of mice treated with MV-m-uPA, as well as detection of MV-N staining in lung samples in tumor bearing treated mice. Finally, we validated the above effects in a model of human breast cancer metastases. This model was established by injection of 1×10e6 MDA-MB231-luc2 cells via tail vein into female nude mice. Ten days after tumor cell injection, mice were treated with three IV injections (every other day) of PBS or MV-h-uPA (1×10e6 TCID50). Metastases progression (by bioluminescence evaluation) was markedly inhibited in treated mice, compared to controls, resulting in improvement in survival. In conclusion, systemic administration of MV-uPA is effective in the treatment of breast cancer metastases in immune-competent and immune-deficient model, suggesting that measles virus mediated virotherapy may present a novel and promising strategy for treatment against metastatic breast cancer.
Citation Format: Yuqi Jing, Julia Zaias, Jaime Merchan. In vivo anti-metastatic effects of uPAR retargeted oncolytic measles virus. [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 701. doi:10.1158/1538-7445.AM2014-701
Abstract 705: In vivo audition of tumor homing peptides using high-throughput sequencing and q-PCR
Authors: Toome Kadri , Mölder Tarmo , Kõiv Kuldar , Säälik Pille , Sugahara Kazuki N. , Ruoslahti Erkki , Teesalu Tambet 
Published: May 2015

Abstract
In vivo peptide phage display has been widely used to explore tumor vascular heterogeneity and to develop targeting ligands for the delivery of anticancer drugs and imaging agents. Numerous tumor homing peptides with various targeting specificities have been identified. To select a suitable targeting ligand for a particular tumor from an existing peptide panel, it is crucial to perform unbiased quantitative assessment of in vivo peptide homing.
Here we describe an approach for parallel evaluation of in vivo tumor homing of peptide-displaying phage clones. Mice bearing orthotopic xenografts of gliomas, breast tumors, and prostate tumors were intravenously injected with equimolar mix of phage clones displaying 12 different tumor homing or control peptides. After 30 min circulation and removal of blood by perfusion, representation of each phage clone in tumors and control organs was determined by high throughput sequencing (HTS) and quantitative PCR (qPCR). The ratiometric analysis demonstrated a clear and reproducible homing signature for each tumor model. Calibrated copy number data obtained by qPCR correlated well with the HTS analysis. Selected phage clones were validated for tumor homing by conventional single-phage homing studies using immunofluorescence, phage titration, and qPCR.
Our study shows that the ratiometric in vivo phage biodistribution analysis can be used to rapidly identify peptides that efficiently deliver payloads to particular tumor types. As the peptides are evaluated side-by-side in a same animal, inter-animal variability is eliminated and the number of animals required is dramatically decreased.
The choice of analysis (HTS vs qPCR) depends on the complexity of phage pool to be audited. HTS enables the analysis of highly complex phage pools, but introduces a potential bias owing to multiple DNA amplification steps. On the other hand, qPCR allows precise quantification of the copy number of the target sequences, and is suitable for low complexity pools. Narrowing down a complex pool with HTS followed by precise evaluation with qPCR can be a potential combination of the two analytical methods.
Citation Format: Kadri Toome, Tarmo Mölder, Kuldar Kõiv, Pille Säälik, Kazuki N. Sugahara, Erkki Ruoslahti, Tambet Teesalu. In vivo audition of tumor homing peptides using high-throughput sequencing and q-PCR. [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 705. doi:10.1158/1538-7445.AM2014-705
Abstract 706: A novel photodynamic therapy with virus-mediated delivery of photosensitive cytotoxic fluorescent protein KillerRed for human cancers
Authors: Takehara Kiyoto , Tazawa Hiroshi , Hashimoto Yuuri , Kishimoto Hiroyuki , Fujiwara Toshiyoshi , Narii Nobuhiro , Mizuguchi Hiroyuki 
Published: May 2015

Abstract
Photodynamic therapy (PDT) is an antitumor strategy to induce tumor-specific cytotoxicity through accumulation of photosensitizers (PSs) and following light irradiation. Specific wavelength light irradiation induces the PS-mediated generation of reactive oxygen species (ROS) and subsequent cytotoxicity in tumor cells. Currently, some kinds of PSs, such as photofrin and laserphyrin, are used for PDT on clinical settings. However, the lack of sufficient and continuous accumulation of PSs in tumor tissues makes difficult to eradicate tumor cells by PDT. Therefore, the development of novel strategy for accumulation of PS in tumor tissues more efficiently and persistently is required to improve the antitumor effect of PDT. A bioengineered fluorescent protein KillerRed has been previously reported to generate ROS upon green light irradiation, suggesting a potential of KillerRed fluorescent protein as a novel PS. We recently confirmed that transient or stable transfection with KillerRed-expressing plasmid vector suppressed the cell viability through induction of ROS-mediated apoptosis in various types of human cancer cells when combined with light irradiation. In this study, we generated non-replicative adenovirus expressing KillerRed (Ad-KillerRed) and telomerase-specific conditionally replicating adenovirus expressing KillerRed (CRAd-KillerRed) to induce efficient accumulation of KillerRed in tumor cells. The in vitro antitumor effect of these viruses was investigated in human cancer H1299, HCT116 and HT29 cells in combination with light irradiation. Ad-KillerRed at high dose suppressed cell viability of human cancer cells when combined with light irradiation. In contrast, CRAd-KillerRed suppressed cell viability of human cancer cells more efficiently compared to Ad-KillerRed in combination with light irradiation. These results suggest that virus-mediated delivery system of KillerRed is a promising strategy for novel PDT. Now, in vivo experiments are under way to investigate antitumor effect of these viruses.
Citation Format: Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Hiroyuki Kishimoto, Toshiyoshi Fujiwara, Nobuhiro Narii, Hiroyuki Mizuguchi. A novel photodynamic therapy with virus-mediated delivery of photosensitive cytotoxic fluorescent protein KillerRed for human cancers. [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 706. doi:10.1158/1538-7445.AM2014-706