bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1461: The heparan sulfate mimetic PG545 potently inhibits spontaneous lung metastasis and significantly enhances overall survival in the 4T1 breast carcinoma model
Authors: Dredge Keith , Hammond Edward , Handley Paul , Rowley Jessica , Vincent Christina , Brandt Ralf , Bytheway Ian 
Published: June 2012

Abstract
PG545 is a fully synthetic heparan sulfate (HS) mimetic entering Phase I clinical trials for advanced cancer. PG545 inhibits key processes in tumor progression (a) angiogenesis – by interfering with growth factor binding and (b) metastasis – by inhibition of heparanase activity. The syngeneic 4T1 breast carcinoma murine model is a well known model of spontaneous metastasis and PG545 was assessed for effects on primary tumour growth, metastatic development in lung and overall survival. PG545 and the tyrosine kinase inhibitor (TKI) sorafenib (used as a comparative antiangiogenic agent) were investigated for their effect on primary tumour growth and the number of lung metastases after treatment for two weeks. PG545 significantly inhibited solid tumour growth and potently inhibited the formation of lung metastases when administered on a twice-weekly dosing schedule (2xqw). Although sorafenib inhibited primary tumour growth to a similar extent as PG545, sorafenib significantly increased the number of lung metastases. In a separate study to investigate overall survival, mice had their primary tumours resected (mastectomy) on day 11 post-inoculation and treatment with PG545 (1xqw), sorafenib (1xqd) or cisplatin (1xqw) was administered for 55 days. Interim data on day 30 using satellite animals confirmed the potent antimetastatic activity of PG545 by enumeration of lung metastases. This reduction in metastasis correlated with overall survival in the PG545-treated mice in the main study which was significantly enhanced compared to vehicle control or sorafenib (which had a similar survival profile as control). PG545 also outperformed cisplatin. Mice culled due to clinical signs associated with disease progression correlated with histological assessment of metastatic burden in lung tissue. The antimetastatic effects of PG545 were confirmed by histological assessment at the end of the study on day 55, with very few metastases observed in PG545-treated mice. In conclusion, PG545 has potent anti-metastatic activity that would appear to differentiate it from other antiangiogenic therapies such as TKI's which have also been recently reported by other groups to aggravate metastatic development under certain circumstances.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1461. doi:10.1158/1538-7445.AM2011-1461
Abstract 1615: Gene expression profile predicts response to smoothened inhibitors in epithelial cancers
Authors: Galimberti Fabrizio , Busch Alex , Chinyengetere Fadzai , Ma Tian , Sekula David , Memoli Vincent , Dragnev Konstantin , Liu Fang , Andrew Angeline S. , Greninger Patricia , Robbins David , Settleman Jeff , Benes Cyril , Dmitrovsky Ethan 
Published: June 2012

Abstract
The hedgehog (HH) signaling pathway is important for embryonic development as it controls cell fate and proliferation. Deregulation of the HH pathway is linked to the onset and maintenance of multiple cancers. Clinical trials revealed promising effects of targeting the HH pathway with smoothened (Smo) inhibitors, particularly in basal cell carcinomas and medulloblastomas where HH pathway activation occurs. This study sought to uncover a gene signature that would predict response to Smo inhibitors, such as cyclopamine or SANT-1. A panel of 705 human cancer cell lines from diverse epithelial cancers was interrogated for sensitivity to cyclopamine. A subset of cancer cell lines exhibited substantial growth inhibition across a broad array of epithelial cancers. Sensitivity was significantly linked to high Gli1, high cyclin E, and low insulin-like growth factor binding protein 6 (IGFBP6) expression levels (P &lt; 0.05). Cyclin E overexpression and IGFBP6 knockdown conferred increased sensitivity to either cyclopamine or SANT-1 Smo inhibitors in lung cancer cell lines. This functionally validated the importance of this gene signature. To ascertain the biological impact of this profile, cyclin E transgenic mice that spontaneously developed premalignant and malignant lung lesions were studied. These lung cancers expressed the gene signature profile that predicts sensitivity to Smo inhibitors. As expected, cyclopamine treatment of these transgenic mice caused substantial immunohistochemical repression of cyclin D1 and Ki-67 in both premalignant and malignant lung lesions. To confirm and extend these findings, cyclopamine antineoplastic effects were examined using a previously described murine syngeneic and transplantable lung cancer model. Cyclopamine treatment significantly repressed lung cancer formation in these mice (P &lt; 0.01). Notably, a subset of examined human lung cancers was found to express the same gene signature that predicted response to Smo inhibitors. Taken together, these findings reveal a gene expression profile that predicts response of diverse epithelial cancers to Smo inhibitors. Future work should discern whether this same gene signature also predicts response to HH inhibitors in epithelial cancers of patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2011-1615
Abstract 1658: STAT5b is expressed in human pancreatic cancer and serves as a target for anti-neoplastic therapy
Authors: Lang Sven Arke , Moser Christian , Schenk Hedwig , Ruemmele Petra , Hackl Christina , Geissler Edward K. , Stoeltzing Oliver , Schlitt Hans J. 
Published: June 2012

Abstract
The transcription factor STAT5b (signal transducer and activator of transcription 5b) is implicated in tumor growth and metastases in various cancer entities including breast and prostate cancer. Activation of STAT5 signaling can be mediated via oncogene mutation (e.g. src kinase), cytokines (e.g. IL-6) and growth factors (e.g. EGF). So far, the role of STAT5b in human pancreatic adenocarcinoma (HPAC) has not been elucidated. Hence, HPAC tissue samples were investigated for nuclear STAT5b expression by immunohistochemical staining. Results show that nuclear expression of STAT5b can be detected in 42/80 HPAC tissue samples. Since specific inhibitors of STAT5b are currently not available, a shRNA approach was chosen for stable knock-down in human pancreatic cancer cells (HPAF-II, BxPC-3, L3.6pl). In vitro, no differences regarding tumor growth were detected by MTT assays and cell counts. However, knock-down of STAT5b led to significant reduction of tumor cell motility as determined in Boyden Chamber assays (P&lt;0.05). Furthermore, upon stimulation with interleukin-6 (IL-6) and epidermal growth factor (EGF) as significant reduction in tumor cell migration was observed (P&lt;0.05). In addition, expression of prometastatic factors Cav-1, MMP-2 and uPAR were impaired upon STAT5b blockade as determined by RT-PCR. In vivo, blockade of STAT5b significantly reduced tumor growth in subcutaneous tumor models (P&lt;0.05). Immunohistochemical analyses of these tumors revealed no differences in tumor cell proliferation (BrdU) whereas vessel area (CD31) was significantly reduced (P&lt;0.05). In conclusion, STAT5b is expressed in almost 50% of HPACs investigated in our study. Since blockade of STAT5b impairs tumor growth and cancer cell motility, this might be an interesting novel target for therapy of human pancreatic adenocarcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1658. doi:10.1158/1538-7445.AM2011-1658
Abstract 1660: Cholesterol efflux transporter gene expression predicts clinical outcome in serous ovarian cancer
Authors: Henderson Michelle J. , Hedditch Ellen L. , Russell Amanda J. , deFazio Anna , Emmanuel Catherine , George Joshy , Chenevix-Trench Georgia , Bowtell David , Norris Murray D. , Haber Michelle ,   The Australian Ovarian Cancer Study Group
Published: June 2012

Abstract
Ovarian cancer is a devastating disease. More than half the women diagnosed with advanced disease will die within five years. Tumours displaying serous histology are the most common, and although initially responsive to current chemotherapy regimens, the disease is characterised by a frequent rate of relapse, often with disease that is resistant to further treatment. Tumours displaying serous histology are the most common and often have the worst prognosis. The ATP-binding cassette (ABC) transporter superfamily consists of 48 functional transmembrane proteins which are further classified into seven subfamilies according to sequence similarity, designated A through G. Various members of the B, C and G branches are well-known for their abilities to convey drug resistance to cancer cells in vitro, but their precise roles in determining clinical outcome are still unclear. In addition, ABC transporters have important and diverse physiological roles through active transport of a variety of endogenous substrates, which could also contribute to tumour phenotype and treatment response. This is the first study to explore the entire ABC transporter gene family in relation to clinical outcome of ovarian cancer. Using a Taqman low density array format for real-time PCR, we examined expression of all ABC transporter genes in a cohort of 150 serous ovarian cancers. Kaplan-Meier survival analysis revealed that expression of multiple ABCA family transporters was significantly associated with progression-free or overall survival and multivariate modelling identified ABCA1, ABCA5, ABCA6, ABCA8 and ABCA9 as new prognostic markers for serous ovarian cancer that are independent of established clinical indicators. The prognostic significance of ABCA family transporter expression was validated in an independent microarray dataset consisting of 350 serous tumours available through The Cancer Genome Atlas. These ABCA family transporters are not known to transport drugs but instead function in cellular lipid trafficking and cholesterol homeostasis, suggesting that treatment failure may involve mechanisms other than simple efflux of chemotherapeutic drugs. In light of accumulating evidence for the importance of cholesterol and bioactive lipids in several cancers, this study highlights an important area for investigation into the biology and treatment of serous ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1660. doi:10.1158/1538-7445.AM2011-1660
Abstract 2153: P34SEI-1 inhibits ROS-induced cell death through suppression of ASK1
Authors: Jin Dong-Hoon , Hong Seung-Woo , Shin Jae-Sik , Yoon Dok Hyun , Na Young-Soon , Hong Yong Sang , Lee Jae-Lyun , Ryu Min-Hee , Kim Tae-Won , Lee Won-Keun 
Published: June 2012

Abstract
Apoptosis signal-regulating kinase (ASK) 1 is a key factor for controlling cellular events including cell cycle, senescence or apoptosis, in response to reactive oxygen species (ROS). However, the mechanisms that regulate ASK1 protein remain largely unexplored. In this study we demonstrate that p34SEI-1 which is both a positive cell cycle regulator as well as an oncogenic protein, inhibits ROS-induced cell death by suppressing ASK1. We first found that p34SEI-1-expressing cells have enhanced resistance to hydrogen peroxide (H2O2). We found that ASK1 phosphorylation induced by H2O2 was clearly inhibited in two, colon cancer cells, i.e. HCT116 and SW620, which ectopically express p34SEI-1. Moreover transfection with p34SEI-1 resulted in a decrease in the ASK1 protein level. Surprisingly, p34SEI-1 induced the ubiquitination of ASK1, however, there is no interaction between p34SEI-1 and ASK1. These results suggest that p34SEI-1 inhibits ROS-induced cell death through the induction of ASK1 ubiquitination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2153. doi:10.1158/1538-7445.AM2011-2153
Abstract 2165: Identification of a novel pathway of castrate resistant prostate cancer (CRPCa) growth
Authors: Mehraein-Ghomi Farideh , Basu Hirak S. , Miyamoto Shigeki , Wilding George 
Published: June 2012

Abstract
Development of an effective therapy to prevent PCa occurrence, recurrence and/or progression remains an unmet medical need. This is mainly due to a poor understanding of the mechanism of PCa occurrence and progression.
There is accumulating evidence that ROS (Reactive Oxygen Species) such as hydrogen peroxide, superoxide, hydroxyl radical, etc. that are produced in high amounts in PCa cells may be a major factor in PCa occurrence and its progression to androgen-independence. One of the ROS (H2O2) plays a key role in triggering growth signals and expression of transcription factors to sustain growth of androgen-dependent PCa cells in the absence of androgen. One such factor is Nuclear Factor κB (NF-κB) that may sustain cell survival by preventing apoptosis and inducing cell proliferation. NF-κB activation kinetically correlates with androgen-induced ROS production in cultured LNCaP human PCa cells. This activation is also seen in resected PCa tissues from patients, who subsequently progressed to CRPCa.
Our published data show that androgen induces an up-regulation of spermidine/spermine acetyl transferase (SSAT) mRNA as well as enzyme activity that initiates polyamine oxidation in LNCaP cells after 72 h exposure. Because of the unusually high polyamine levels in the PCa cells, polyamine oxidation causes a large increase in ROS production that is abrogated by silencing SSAT expression in PCa cells stably transfected with shRNA against SSAT (siSSAT).
To determine whether SSAT is required for NF-κB activation following prolonged androgen stimulus, we transfected 3xκB-luciferase vector containing NF-κB consensus binding sites-luciferase reporter construct along with a β-gal expression vector (to control for the transfection efficiency) into both wild type LNCaP cells and its siSSAT clones. While 72 h androgen exposure causes an over 30-fold induction of luciferase activity in wild type LNCaP cells, no activation of NF-κB was observed in the siSSAT clones. These data clearly show a strong SSAT induction is required for a robust activation of NF-κB in androgen-treated PCa cells.
Multiple published reports show that NF-κB can also induce SSAT in several human cancer cells. Thus, our data suggest an intriguing mechanism of CRPCa progression, where androgen induced SSAT expression and consequent upregulation of NF-κB can set up an autocrine feed forward loop of SSAT-ROS-NFκB-SSAT that can sustain PCa cell proliferation in the absence of androgen that can lead to CRPCa growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2165. doi:10.1158/1538-7445.AM2011-2165
Abstract 2201: Involvement of somatic mutations in silencing cystatin E/M tumor suppressor gene in breast cancer
Authors: Venkatesan Natarajan , Issakhanian Shawnt P. , Ginther Charles G. , Slamon Dennis J. , Srivatsan Eri S. , Veena Mysore S. 
Published: June 2012

Abstract
Cystatin E/M is a cysteine protease inhibitor that has a tumor suppressive function in various cancers. Although promoter methylation is implicated in breast cancer, we wanted to determine whether the gene is also inactivated by somatic mutations. Thus, we analyzed breast cancer tissues and cell lines for the expression of Cystatin E/M and its effect on cancer cell growth and proliferation. RNA expression was observed in 3 (BT20, MB231 and ZR75.1) of 10 breast cancer cell lines by microarray and RT/PCR; however, the protein was not detectable in any of these cell lines by Western blotting indicating RNA and/or protein stability as a possible mechanism. Ectopic expression of cystatin E/M in MB435 cells, a cell line that did not show the RNA or protein expression, resulted in the inhibition of cell proliferation as studied by MTT assay. Western blotting and immunofluorescence studies indicated a reduced expression of its substrate cathepsin L with the reexpression of cystatin E/M. Varying expression of cystatin E/M (absent to strong) was also seen in a cohort of 24 human breast tumors; 8 of these tumors showed increased cathepsin L levels compared to a normal breast specimen. A mutation of Q47 to a stop codon in exon1 was observed in 2 tumor samples. These studies indicate that cystatin E/M may be inactivated by somatic mutations and the protein mediates tumor suppression by regulating its substrate cathepsin L in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2201. doi:10.1158/1538-7445.AM2011-2201
Abstract 2207: Functional interrogation of the colorectal cancer genome identifies numerous suppressors of anchorage-independent growth
Authors: Eskiocak Ugur , Kim Sang B. , Ly Peter , Roig Andres I. , Biglione Sebastian , Komurov Kakajan , Cornelius Crystal , Wright Woodring E. , White Michael A. , Shay Jerry W. 
Published: June 2012

Abstract
INTRODUCTION: High throughput cancer genome sequencing efforts are leading to the identification of frequently mutated genes in cancer. Unfortunately, the extreme diversity of lesions being detected presents a challenge to segment causal from coincidental mutations and to elucidate how causal lesions disrupt regulatory networks to drive cancer processes. AIMS AND METHODS: Given that a common early perturbation in solid tumor initiation is bypass of matrix-dependent proliferation restraints, we used immortalized human colonic epithelial cells (HCECs) to identify suppressors of anchorage-independent growth by conducting a soft-agar based shRNA screen within frequently mutated colorectal cancer (CRC) genes. RESULTS AND CONCLUSIONS: Remarkably, depletion of 65 of the 151 frequently CRC-mutated genes tested collaborated with K-RASV12 or TP53 knockdown to promote anchorage-independent proliferation of HCECs. These candidates fall under a variety of different signaling pathways, but in particular JNK signaling was found to be a master suppressor of anchorage-independent growth in normal HCECs. We have identified additional members of an extensive gene network specifying matrix-dependent proliferation, by constructing an interaction map of these confirmed progression suppressors with the ∼700 rare CRC-mutated genes and experimentally verifying soft-agar growth enhancement in response to depletion of these genes. Collectively, this study reveals a profound diversity of fragile nodes within a fundamental tumor suppressor network, perturbation of which leads to enhanced cell-autonomous proliferative fitness. These studies establish the importance of functionally annotating cancer genomes using biologically relevant assays.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2207. doi:10.1158/1538-7445.AM2011-2207
Abstract 2209: Downregulation of LKB1 in high-grade endometrial carcinoma
Authors: Co Ngai Na Chloe , Iglesias David A. , Schmandt Rosemarie , Lu Karen H. 
Published: June 2012

Abstract
Objective: LKB1/STK11 encodes a serine/threonine kinase that regulates cell polarity, proliferation and energy metabolism via the AMPK signaling pathway. Germline mutations of LKB1 are responsible for Peutz-Jeghers syndrome, which is characterized by hamartomatous polyps and increased incidence of several cancers. It has been demonstrated that LKB1 null mice develop invasive endometrial cancer. Our lab has previously shown that 5 of 26 (19%) of human endometrial cancers exhibited loss of LKB1 protein by Western blot analysis. The purpose of this study was to examine the expression of LKB1 in a larger set of endometrial cancers and to determine if mutations in LKB1 occur in these tumors.
Methods: LKB1 protein levels were evaluated in 20 normal endometrial tissues, 17 Grade 1, 24 Grade 2, and 28 Grade 3 endometrioid endometrial adenocarcinomas by immunohistochemical staining. Laser-capture microdissection (LCM) was used to isolate RNA from 22 Grade 1, 21 Grade 2 and 23 Grade 3 fresh frozen endometrioid endometrial tissues; and LKB1 mRNA expression levels in microdissected tumor samples were quantified by TaqMan quantitative PCR. Direct genomic DNA sequencing of LKB1 coding exons were performed on 20 microdissected high-grade tumors.
Results: While no significant difference in LKB1 expression was observed between normal endometrium, Grade 1 and 2 endometrial tumors, LKB1 staining was significantly lower in Grade 3 tumors when compared with normal endometrium (P&lt;0.0001), Grade 1 (P&lt;0.0001) and Grade 2 (P=0.016) tumors. Downregulation of LKB1 mRNA level was also demonstrated in microdissected Grade 3 endometrial tumor samples. Direct genomic DNA sequencing of LKB1 coding exons revealed a single amino acid change (L201Q) in only 1 of 20 Grade 3 endometrial tumors, suggesting that DNA mutation is not the major mechanism leading to the loss of LKB1.
Conclusion: Our findings of decreased expression of LKB1 in high-grade endometrial cancers supports the hypothesis that loss of LKB1 may contribute to the development of high-grade endometrioid endometrial cancer. We are currently evaluating the mechanisms by which LKB1 levels are regulated in endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2209. doi:10.1158/1538-7445.AM2011-2209