bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3684: Targeting Aurora kinase in peripheral T-cell non-Hodgkin's lymphomas
Authors: Mahadevan Daruka , Qi Wenqing , Liu Xiaobing , Cooke Laurence S. , Agarwal Amit , Persky Daniel O. , Miller Thomas P. 
Published: August 2012

Abstract
Aurora kinases (A and B) are oncogenic serine/threonine (S/T) kinases that play central roles in the mitotic phase of the eukaryotic cell cycle. Over-expression of Auroras during dysregulated cell cycling and their aberrant activation over-rides mitotic and spindle check points leading to anueploidy in many human cancers make Auroras attractive therapeutic targets. Gene expression profiling in mantle cell lymphoma [MCL] have shown the Auroras are over-expressed and is a poor prognostic marker within the ‘proliferative’ signature. PTCL (NOS) are a heterogeneous group of rare non-Hodgkin's lymphomas (NHL) derived from activated CD4+ or CD8+ T cells. PTCL and anaplastic large cell lymphoma (ALCL) both of T-cell phenotype and ALK negative have an aggressive clinical course with an inferior event free and overall survival relative to B-cell NHL counterparts. The biological explanation for the difference is unknown. Patients with PTCL have a poor prognosis due to a very aggressive disease course coupled to a lack of effective therapies. Therefore, the development of novel and effective treatments based on biologically validated targets is urgently needed for this disease. We hypothesized and investigated that (1). Auroras are over-expressed in human PTCL-NOS, (2). Aurora ATP-site small molecule inhibitor (SMI) is effective in inhibiting cell proliferation and promoting apoptosis in cell culture and (3). Aurora SMI will be safe and effective in treating patients with relapsed aggressive T-cell NHL in early phase clinical trials. In this study, we demonstrate that both aurora A and B are highly over-expressed in PTCL patients and cell lines. MLN8237 (alisertib), an ATP-site small molecule inhibitor of Aurora A had potent activity in inhibiting phosphorylation of Aurora A and histone H3 in PTCL cell lines. Cells treated with MLN8237 exhibited endoreduplication confirming the mechanism of action of an Aurora inhibitor. Also, treatment of PTCL cell lines with MLN8237 induced apoptosis in a dose and time dependent manner (flow cytometry and PARP-cleavage) and inhibited cell proliferation with an IC50 &lt; 0.1µM. Preliminary data from a phase II clinical trial using single-agent MLN8237 in patients with relapsed refractory aggressive NHL has demonstrated notable activity with 4 confirmed responses in 6 evaluable PTCL patients. Cytokine profiling on day 1 (pre-treatment) and day 8 (post-treatment) showed a profile consistent with aurora A activity. Together the data suggest inhibition of Auroras offers a promising treatment strategy for patients with aggressive T-cell NHL [Funded by the Lymphoma SPORE, P50 CAB0805501A1].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3684. doi:1538-7445.AM2012-3684
Abstract 369: Tumor detection and surgical navigation with fluorescence laparoscopy is enhanced with combinations of differently labeled fluorophore-conjugated antibodies and fluorescent proteins
Authors: Raimo Cristina A. Metildi , Kauhsal Sharmeela , Snyder Cynthia S. , Luiken George A. , Hoffman Robert M. , Bouvet Michael 
Published: August 2012

Abstract
The aim of this study was to improve detection of primary and metastatic lesions of human pancreatic cancer in mouse models with fluorescence laparoscopy by enhancing the fluorescence signal of tumor with different combinations of fluorophores without compromising background illumination. Human pancreatic cancer models were established with combinations of FG-RFP, MiaPaca2-GFP, BxPC-3-RFP, or BxPC-3 cancer cells implanted in 6-week-old female athymic mice. Two weeks post-implantation, diagnostic laparoscopy was performed with a Stryker L9000 LED light source 24 hours after tail vein injection of CEA antibodies conjugated with Alexa 488- and/or Alexa 555. Cancer lesions were detected and localized under the fluorescence light mode. Intravital images were obtained with the Maestro CRI Small Animal Imaging System, serving as a positive control. Tumors were collected for histologic review. Fluorescence laparoscopy with a 495-nm emission filter and an LED light source enabled real-time visualization of differently fluorescence-labeled tumors in the peritoneal cavity simultaneously. The combination of BxPC-3 RFP labeled with anti-CEA-Alexa 488 afforded the brightest signal of all established mouse models. We were able to reproduce this enhanced fluorescence signaling by doubly labeling non-color BxPC-3 tumor with anti-CEA-Alexa 488 and anti-CEA-Alexa 555. The doubly labeled tumor provided a greater signal intensity profile compared to tumors labeled with either anti-CEA-Alexa 488 or -Alexa 555 alone. This enhanced fluorescence signal permitted improved detection of sub-millimeter lesions without compromising background illumination. The ability to visualize tumor deposits expressing fluorescent proteins of different wavelengths simultaneously with an LED light source enabled us to establish the optimal combination of fluorophores that enhanced the signal intensity of fluorescence. With this optimal fluorophore combination, we improved the detection of sub-millimeter tumor lesions without impairing the visualization of surrounding structures necessary for surgical navigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 369. doi:1538-7445.AM2012-369
Abstract 3690: 19-nor-1α-25-dihydroxyvitamin D2 induces gastric cancer cell apoptosis and cell cycle arrest and inhibits STAT3 mediated inflammation
Authors: Bae Woo Kyun , Lee Ji Hee , Hwang Jun Eul , Shim Hyun Jeong , Cho Sang Hee , Chung Ik-Joo 
Published: August 2012

Abstract
The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), inhibits the growth of several types of human cancer cells in vitro, but its therapeutic use is limited because it causes hypercalcemia. Among its analogs, 19-nor-1,25-dihydroxyvitamin D2 has fewer calcemic effects and exhibits an activity that is equipotent to that of calcitriol in several in vivo and in vitro systems. This study demonstrated that paricalcitol has antitumor activity in gastric cancer cells. Treatment with paricalcitol inhibited gastric cancer cell growth, induced G0/G1 cell cycle arrest, and decreased the expression of cycle-dependent kinase 2 (CDK2). Additionally, paricalcitol led to apoptosis via induction of caspase-3 cleavage and decreased expression of anti-apoptotic Bcl-XL. Inhibition of STAT3, COX-2, and NF-κB activities was also observed. Moreover, growth of peritoneal metastases in vivo was significantly reduced in mice treated with19-nor-1,25-dihydroxyvitamin D2. These results suggest that the vitamin D analog (19-nor-1,25-dihydroxyvitamin D2) has anti-cancer and anti-inflammatory activity in gastric cancer cells, suggesting that it holds promise as a novel therapy for the prevention and treatment of gastric cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3690. doi:1538-7445.AM2012-3690
Abstract 3697: Phase II study of therapy selected by molecular profiling in patients with previously treated metastatic pancreatic cancer - SU2C-001
Authors: Barrett Michael T. , Lenkiewicz Elizabeth , Evers Lisa , Holley Tara , Aziz Meraj , Kiefer Jeffrey , Maitra Anirban , Hidalgo Manuel , Kumar Rajesh , Hlavacek William , Stites Edward , Posner Richard G. , Ramanathan Ramesh , Von Hoff Dan D. 
Published: August 2012

Abstract
We have completed a second line Phase II study of therapy to be selected by molecular profiling in 35 patients with previously treated metastatic pancreatic cancer. On this study all patients have a biopsy of a metastatic lesion (usually liver). Therapeutic targets are identified by profiling the metastatic biopsies with the combined use of immunohistochemistry (IHC), comparative genomic hybridization (CGH) on sorted tumor populations, and correlating gene expression microarray data to that of a panel of xenografts for which drug sensitivity has been previously determined. The IHC assays are performed in a CLIA certified laboratory and include the following therapeutic targets: MRP1, TOPO1, MGMT, PGP, Her2/Neu, PTEN, c-kit, RRM1, EGFR, BCRP, PDGFR, TOP2A, TS, ERCC1, SPARC, ER, PR, and AR. In addition each sample is screened by PCR for the presence of the most common K-RAS mutations. Gene expression microarray analysis is performed at John Hopkins University using Affymetrix U133 Plus 2.0 gene arrays. For CGH analysis flow sorted nuclei of diploid and aneuploid tumor cell populations are processed and hybridized to 400,000 feature CGH arrays. We have identified distinct high level focal amplicons targeting AKT2, LYN, RET, CDK6, K-RAS, MYCBP, BCL11A, RASA1 and WNT6, and gene specific homozygous deletions including CDKN2A, PTEN, MAP2K4, RASA1 and PARK2 in the sorted aneuploid tumor nuclei. In an effort to elucidate new targets and potential contexts of vulnerability based on the results of this trial, we have extracted combined gene level data for each patient and present these mapped to 32 pancreatic specific pathways and processes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3697. doi:1538-7445.AM2012-3697
Abstract 37: CCN6 downregulation in invasive breast carcinomas: In situ characterization of changes in EMT proteins and metastatic disease
Authors: Lorenzatti Guadalupe , Gonzalez María Elena , Toy Kathy A. , Cabanillas Ana M. , Kleer Celina G. 
Published: August 2012

Abstract
Background: The recognized heterogeneity of invasive breast carcinomas is a result of intrinsic characteristics of the tumor cells and their interaction with the microenvironment. CCN6, an extracellular matricellular protein involved in cell communication and epithelial-stromal interactions has a tumor suppressor role in breast cancer. CCN6 downregulation in benign breast cells induces an epithelial to mesenchymal transition marked by downregulation of E-cadherin and increased levels of the transcriptional regulators ZEB1 and Snai1. However, the relevance of these studies to human breast cancer needs further investigation. We hypothesized that CCN6 mRNA and protein levels in samples of breast cancer patients may be associated with metastasis and features of EMT. Methods: Forty clinical samples of invasive carcinoma and surrounding normal breast, frozen at the time of operation were collected. We extracted mRNA and protein from each sample and performed real time RT-PCR and Western blots for CCN6, respectively. All frozen samples were immunostained with antibodies against E-cadherin (BD Biosciences, 1:4000), ZEB1 (Santa Cruz Biotechnology, 1:400) and Snai1(Cell Signaling, 1:800). E-cadherin was analyzed as aberrant or normal. ZEB1 and Snai1 proteins were scored as positive or negative, either in the cancer or stromal cells. Results: Of the 40 frozen samples of breast cancer, 23 had high quality RNA and protein for further study. CCN6 mRNA and protein were both decreased in 18/23 (78%). Five of 23 (22%) samples exhibited normal or high expression. Low CCN6 was associated with the presence of distant metastasis. Four of 18 (22%) invasive carcinomas with low CCN6 had distant metastasis compared to none of the normal CCN6 expressing tumors (p&lt;0.05). Seventeen of 18 (94%) of invasive carcinomas with low CCN6 had aberrant E-cadherin protein expression. We noted that in the tumors with aberrant E-cadherin protein, the expression of ZEB1 or Snai1 was mutually exclusive in all cases (p&lt;0.05). We noted that 80% of the tumors exhibited ZEB1protein in the stromal cells. Conclusions: Our results show a direct link between levels of CCN6 mRNA and protein in breast carcinoma patient samples. A decrease in CCN6 expression in the primary breast cancer is associated with distant metastasis and decreased E-cadherin. We uncover a novel inverse relationship between ZEB1 and Snai1 proteins in breast cancer, which is under further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 37. doi:1538-7445.AM2012-37
Abstract 371: In vivo monitoring of metabolic inhibition in anaplastic thyroid carcinoma
Authors: Sandulache Vlad C. , Bankson James A. , Skinner Heath , Wang Yuan , Chen Yunyun , Dodge Cristina T. , Ow Thomas , Hazle John D. , Myers Jeffrey N. , Lai Stephen Y. 
Published: August 2012

Abstract
Purpose/Objective(s): Anaplastic thyroid carcinoma (ATC) accounts for over half of thyroid cancer related deaths and is generally refractory to conventional treatment. Development of novel therapeutic options is critical for the management of this deadly disease. Since tumor cells fulfill energy requirements primarily through aerobic glycolysis rather than mitochondrial respiration, metabolic inhibition represents an attractive treatment modality. In vivo real time imaging may be useful for evaluating the effectiveness of targeting tumor metabolism. Materials/Methods: A panel of ATC cell lines was evaluated for dependence on glucose and glutamine for cell proliferation and survival. Intracellular ATP levels and cellular reducing potential were measured in cells treated with 2-deoxyglucose (2-DG). Enhancement of the cytotoxic effects of cisplatin and radiation therapy (XRT) with 2-DG was evaluated. In a murine orthotopic xenograft model of ATC, real-time hyperpolarized magnetic resonance imaging (HP-MRI) was employed to assess the effects of 2-DG on tumor metabolism. Results: Glucose, but not glutamine starvation, resulted in significant ATC cell death, suggesting that glucose is the primary nutrient for ATC in vitro. Alterations in extracellular glucose levels affected ATP and cellular reducing potential and both were inhibited by 2-DG. Treatment of ATC cells with 2-DG potentiated the cytotoxic effects of cisplatin alone, XRT alone or cisplatin with XRT. Dynamic spectroscopy of HP-[1-13C]-pyruvate revealed differences in the rate of conversion of pyruvate to lactate in 2-DG treated animals compared to their controls (p=0.504). Analysis with a kinetic model accounting for chemical and physical exchange highlighted this difference (p&lt;0.001). Conclusions: Generalized dependence of ATC cells on glucose catabolism provides an opportunity to utilize metabolic inhibition to enhance sensitivity to radiation therapy and chemotherapy. HP-MRI may represent an effective means to assess metabolic targeting in vivo. Continued refinement of the kinetic parameters that relate the observed signal to multiple physical and chemical pools is necessary to facilitate interpretation of the observed changes. The synchronized optimization of metabolic inhibitors with complementary imaging agents in a preclinical platform may facilitate translation of these therapeutic options for ATC to the clinical setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 371. doi:1538-7445.AM2012-371
Abstract 372: Disease-free survival and overall survival from colon cancer is improved with fluorescence-guided surgery in metastatic mouse models
Authors: Raimo Cristina A. Metildi , Kaushal Sharmeela , Snyder Cynthia S. , Hoffman Robert M. , Bouvet Michael 
Published: August 2012

Abstract
The aim of this study was to improve disease-free survival and overall survival in orthotopic nude mouse models of human colon cancer with fluorescence-guided surgery (FGS). Fluorescent orthotopic or carcinomatosis models were established in nude mice using human colon cancer cell lines HCT-116 and HT-29 expressing either green fluorescent protein (GFP) or red fluorescent protein (RFP). The tumors were later resected by bright light surgery (BLS) or FGS. In orthotopic and carcinomatosis models, pre- and post-operative images were obtained with the OV-100 Small Animal Imaging System (Olympus Corp., Tokyo, Japan) to assess the extent of surgical resection. In the orthotopic model, whole body imaging of the mice was performed in the postoperative period to assess cancer recurrence and to follow subsequent tumor progression. The mice were sacrificed when they became premorbid and their abdomens were exposed for intravital and ex vivo imaging. Tumor burden was measured in mm2 using ImageJ v1.440. A greater extent of tumor resection in mice with carcinomatosis was achieved using FGS compared to BLS (99.9% vs. 76.9%, p = 0.006). Furthermore, all mice with localized disease had a complete surgical resection with FGS. In contrast, complete resection was achieved in only 56% of the mice undergoing BLS. (p=0.001) Fewer mice in the FGS group had evidence of tumor recurrence (33%) compared to mice in the BLS group (58%), lengthening disease-free survival from 9 weeks in the BLS group to 27 weeks in the FGS group. Overall survival of the mice also increased from 17 weeks in the BLS group to 29 weeks in the FGS group. The results of the present study demonstrate that improved surgical outcomes in the treatment of colon cancer can be achieved with FGS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 372. doi:1538-7445.AM2012-372
Abstract 3725: Combined cytotoxic effects of volasertib and cisplatin in urothelial carcinoma cells
Authors: Lin Chia-Chi , Lin Yu-Mine , Tsai Yu-Chieh , Pu Yeong-Shiau , Cheng Ann-Lii , Yang James C. 
Published: August 2012

Abstract
Purpose: Patients with advanced urothelial carcinoma (UC) are treated with cisplatin-based chemotherapy. Polo-like kinase 1 (PLK1) inhibitors (e.g. volasertib) have been shown to be effective in patients with refractory UC (AACR-NCI-EORTC Meeting 2008 abstr 36). We studied the combined cytotoxic effects of volasertib and cisplatin in UC cells in vitro. Materials and methods: The cytotoxicity of the two agents either alone or in combination were studied against UC cell lines with different genetic background: T24 (HRAS mutation), RT4, J82 (FGFR3 mutation), and BFTCC909 (TP53 mutation), using the sulforhodamine B colorimetric assay. Schedule-dependence of the two-drug combination was assayed using 3 different treatment schedules: concurrent and 2 sequential exposures. We examined the effects of volasertib on cell-cycle progression in unsynchronized UC cells by determining the DNA content. Results: The volasertib IC50s of T24, RT4, J82, and BFTCC909 were 13.4±0.13, 54.0±10.6, 14.1±1.3 and 62.4±4.46 nM, respectively and the cisplatin IC50s of the four cells were 2776±361, 8767±1018, 6270±1240 and &gt;10000 nM, respectively. With the median-effect analysis, the combined effects of the two agents when given concurrently were sub-additive in the low fraction affected (Fa) range (0.1-0.3) and additive in the median to high Fa range (0.4-1.0) for the four cells. The combined cytotoxicity was more synergistic if volasertib was given 24 hours earlier than cisplatin. The effects were less synergistic if cisplatin was given prior to volasertib. This phenomenon was seen in all four cells. UC cells in media with 50 nM volasertib arrested in G2/M and showed synchronization 24 hr after release. Conclusions: In our UC cell model, the combined effects may be optimized by sequential use of the two agents, preferably volasertib given 24 hours before cisplatin. Volasertib-treated UC cells arrested in G2/M and showed synchronization which may maximally sensitize UC cells to cisplatin. Our results have clinical implications for the treatment of UC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3725. doi:1538-7445.AM2012-3725
Abstract 3727: Targeting autotaxin to reduce chemotherapy resistance in ovarian cancer
Authors: Zhai Ling , Zamani Ali , Liu Ximeng , Wang Yimin , Maxuitenko Yulia , Alvarez Ronald , Estes Jacob , Li Rongbao , Qu Zhican 
Published: August 2012

Abstract
Development of resistance to chemotherapy presents the biggest challenge in the treatment of ovarian cancer. Autotaxin (ATX) is a secreted enzyme that catalyzes lysophosphatidic acid (LPA) production and is responsible for the up-regulation of LPA in ovarian cancer. The ATX-LPA axis has been identified to be one of the mechanisms of chemotherapy resistance in ovarian cancer. Thus, inhibition of autotaxin may be a potential strategy to increase the chemotherapy efficacy in this disease context. At Southern Research, we previously identified a known anti-parasitic small molecule, Bithionol as a potent antiangiogenic agent, which inhibits endothelial cell proliferation, migration and tubular morphogenesis in vitro and directly inhibits autotaxin enzyme activity. Our recent results have shown that Bithionol not only directly inhibits the enzyme activity; it also reduces autotaxin secretion from human endothelial and ovarian cancer cells. Recently, using a human ovarian cancer xenograft mouse model, Biothionol was shown to have in vivo anti-tumor activity as a single drug treatment. In addition, in combination therapy studies in mice, Bithionol significantly increased the efficacy of Paclitaxel and Cisplatin against ovarian tumor growth. These results suggest that Bithionol may provide a promising approach for reducing chemotherapy associated resistance in ovarian cancer. Additional preclinical studies are in progress to assess the potential clinical utility of Bithionol in combination with current ovarian cancer therapy. (This work is supported by a pilot grant from Norma Livingston Foundation and SRI SIP fund).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3727. doi:1538-7445.AM2012-3727