bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4151: Mutual feedback activation of PI3K and MAPK pathways support combining inhibitors of the two pathways to enhance efficacy
Authors: Zhang Theresa , Feldman Igor , Paweletz Cloud , Nebozhyn Michael , Shumway Stuart Shumway , Chen Albert Chen , Roberts Brian Roberts , Arthur William , Sathyanarayanan Sriram , Lutterbach Bart , Strack Peter , Huang Pearl , Dai Hongyue , Loboda Andrey , Watters James 
Published: February 2011

Abstract
There has been increasing interest in developing cancer therapies targeting PI3K pathway nodes. Unfortunately, the number of tumor types responding to PI3K pathway inhibitors as monotherapy has been limited, since most cancer cells accumulate genetic alterations that result in the constitutive activation of a complex network of proliferation and survival signals. As such, the inhibition of a single survival/proliferation pathway or node within this broader network may be circumvented by constitutive activation (or feedback activation) of an alternative survival pathway, and thus be insufficient for inducing a clinical response. Therefore, in most tumor types, dual pathway inhibition, guided by an in-depth understanding of feedback and cross-talk between pathways, may be required to induce tumor regression. Here we present a nonclinical study exploring mutual feedback activation of MAPK and PI3K pathways. Inhibition of the PI3K pathway by MK-2206 (AKT inhibitor) or MK-8669 (mTOR inhibitor) resulted in feedback activation of MAPK pathway nodes in subsets of lung cell lines. Similarly, inhibition of the MAPK pathway by a MEK inhibitor resulted in feedback activation of the PI3K pathway. Notably, a lack of such feedback activation was associated with sensitivity to the mono inhibitors. The strength of the feedback activation correlated with changes of several receptor tyrosine kinases, suggesting them as a part of the feedback mechanism. Finally, combined inhibition of both MAPK and PI3K pathways synergistically inhibited the feedback activation of both pathways and led to improved in vitro efficacy. Taken together, our findings identify mutual feedback activation of the PI3K and MAPK pathways in response to specific inhibitors and underscore the importance of combined therapeutic approaches with inhibitors to both pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4151.
Abstract 4154: Intratumoral heterogeneity of HER2/neu expression in diffuse-gastric carcinoma of European patients and its relevance for patients’ management
Authors: Tomasic Gorana , Malouf Gabriel G. , Marty Virginie , Malka David , Vielh Philippe , Ducreux Michel , Boige Valerie 
Published: February 2011

Abstract
Background: This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression, its relationship with gene amplification and its intra-tumoral heterogeneity in diffuse-gastric carcinoma, a subset of gastric carcinoma that might benefit from Trastuzumab in case of HER2 amplification according to recently reported ToGA trial (J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4509)
Patients and methods: The study included 51 European consecutive patients who underwent surgical resection in our institution between January 1991 and December 2007 for diffuse gastric carcinoma. A tissue-microarray was constructed using paraffin-embedded tissues of gastrectomy and matched lymph nodes. HER2 were evaluated by immunohistochemistry (IHC), using the same criteria than for breast cancer. All samples with a 2+ or 3+ HER2 overexpression were evaluated by FISH.
Results: HER2 overexpression was observed in 2 (4%) tumors and there was intratumoral heterogeneity. The first tumour shows 2+/3+ immunostaining in lymph nodes with negative immunostaining in the primary tumor. The second tumor shows a focal 3+ HER2 immunostaining in the primary tumor without evidence of positive immunostaining in lymph nodes and peritoneal metastasis. Using FISH, HER2 3+ tumour areas had a gene amplification, whereas no amplification was found in 2+ tumor. The 2 HER2 positive tumors showed the same heterogeneous pattern, with adjacent 3+ positive and negative areas by both IHC and FISH. There was a 100% concordance between TMA and the tissue-sections. Despite complete resection, the 2 patients with HER2 expression died within 15 months.
Conclusions: This study showed that 4% of resected diffuse gastric carcinoma had a heterogeneous distribution of HER2 gene amplification. These findings raise the question whether HER2 testing should be realized systematically in these patients and whether Trastuzumab may benefit in tumours with heterogeneous HER2 expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4154.
Abstract 4155: The small leucine-rich proteoglycan biglycan localizes to the nucleus of neoplastic cells in glioblastoma biopsies and tumor xenografts
Authors: deCarvalho Ana C. , Berezovsky Artem , Lemke Nancy , Mikkelsen Tom , Kalkanis Steven N. 
Published: February 2011

Abstract
Global molecular profiling efforts are leading to the identification of prognostic gene expression signatures for gliobastoma. Recently, several extracellular matrix (ECM) components typically expressed in mesenchymal tissues, have been shown to be overexpressed in a subgroup of high grade gliomas from poor prognosis patients, including the highly related small leucine-rich repeat proteoglycans (SLRPs) biglycan and decorin. These proteins were originally isolated from cartilage and are widely expressed in differentiated mesenchymal tissues, but their involvement in glioblastoma pathology is not understood. Biglycan expression in glioblastoma surgical specimens, cancer stem cells, and xenografts was assessed by RNA microarray, real-time PCR, Western blot and immunohistochemistry, and compared to decorin. Over 80% of the glioblastoma surgical specimens expressed both proteoglycans in the pericellular location of endothelial cells. In neoplastic cells, while decorin was observed in the pericellular location of discrete regions of about 40% of the samples, biglycan localized to the nucleus in most tumors analyzed. It has been previously reported that biglycan possess a nuclear localization signal, but in vivo nuclear localization in a glial tumor has not been shown. The unglycosylated core biglycan protein was ubiquitous, while the glycosylated form was less uniformly distributed among the tumor samples. Glioblastoma cancer stem cell enriched neurosphere cultures derived from the tumor specimens did not express biglycan or decorin in vitro. However, biglycan was re-expressed upon tumor formation, as nuclear staining was observed in the orthotopic tumor xenograft initiated by the neurospheres. Using the Rembrandt data base (http://caintegrator-info.nci.nih.gov/rembrandt) we observed a robust inverse correlation of biglycan expression in GBMs with survival. The nuclear localization in GBMs suggests an unconventional role for this proteoglycan in the pathology of this malignancy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4155.
Abstract 4160: Evaluating epithelial-to-mesenchymal transition (EMT) in the EL1-luc/EL1-SV40 T-antigen transgenic mouse model of pancreatic cancer
Authors: Franklin Maryland Rosenfeld , Krueger Joseph , Young G. David , Sennello Regina , Leary Lisa , Zhong Shaobin , Chen Hao , Lim Ed , Zhang Ning , Lassota Peter , Wild Robert 
Published: February 2011

Abstract
Epithelial-to-mesenchymal transition (EMT) is a biological function important in normal cellular processes such as embryonic development and wound healing. In cancer it is thought that the tumor cell machinery can re-activate these normal pathways resulting in more aggressive and invasive tumors. The loss of E-cadherin and the gain of vimentin are hallmarks which identify the process of EMT and have been shown to correlate with poor prognosis in multiple solid tumor types. While many preclinical models are utilized to evaluate mechanisms of tumorigenesis few in vivo models evaluating parameters of EMT have been described.
The EL1-luc/EL1-SV40 T-antigen transgenic mouse represents a model of pancreatic cancer whereby mice develop tissue specific, spontaneous and bioluminescent pancreatic tumors. To evaluate whether EMT occurs in the EL1-luc/EL1-SV40 T-antigen model in vivo, we collected primary pancreatic tissue from male mice between 10 and 21 weeks of age. The tissue was formalin fixed, paraffin embedded and then utilized for histopathological endpoints such as Hemotoxylin and Eosin staining as well as immunohistochemistry for markers known to be involved in EMT such as E-cadherin and vimentin. We found the tumors to express both markers and become very heterogeneous over time. In early tumors E-cadherin expression is membrane localized and very high. Over time there are areas of the tumors that have reduced or lost E-cadherin expression. Vimentin expression was highly variable but when present tended to be highly expressed. In many of the later stage tumors there was substantial heterogeneity reflected by the appearance of multiple cell types within a tumor. We utilized the Aperio (Aperio Technologies, Vista, CA) slide scanner and software system to evaluate serial sections of tumor samples and found that in some sections of the tumor E-cadherin is present and vimentin is absent, whereas in other areas of the tumor vimentin is present in the absence of E-cadherin. Additionally, we identified areas of the tumor that seem to be expressing both markers which suggests that the EL1-luc/EL1-SV40 T-antigen transgenic mouse may recapitulate many aspects of EMT observed in vivo, thus offering a model system to study the signaling and molecular changes necessary for this process during cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4160.
Abstract 4161: Synergistic effects of aflatoxin B1 exposure and glycine N-methyltransferase deficiency in hepatocarcinogenesis
Authors: Liu Shih-Ping , Li Ying-Shiuan , Lee Cheng-Ming , Yen Chia-Hung , Liao Yi-Jen , Huang Shiu-Feng , Chien Chau-Heng , Chen Yi-Ming Arthur 
Published: February 2011

Abstract
In both humans and rodents, males are known to be more susceptible than females to hepatocarcinogenesis. We have previously reported that glycine N-methyltransferase (GNMT) interacts with aflatoxin B1 (AFB1) and reduces both AFB1-DNA adduct formation and hepatocellular carcinoma (HCC) in mice. We also reported that 50% of the males and 100% of the females in a small group of Gnmt null (Gnmt−/−) mice developed HCC, with first liver nodules detected at mean ages of 17 and 16.5 months, respectively. In this study we tested our hypothesis that male and female Gnmt−/− mice are susceptible to AFB1 carcinogenesis, and that the absence of Gnmt expression may accelerate AFB1-induced liver tumorigenesis. We inoculated Gnmt−/− and wild-type mice intraperitoneally with AFB1 at 7 days and 9 weeks of age and periodically examined them using ultrasound. Liver nodules were detected in 6 of 8 males and 5 of 5 females at 12.7 and 12 months of ages, respectively. Liver nodules from 5/8 (62.5%) male and 4/5 (80%) female Gnmt−/− mice were diagnosed as having HCC, approximately 6 months earlier than AFB1-treated wild-type mice. Results from microarray and real-time PCR analyses indicate that five detoxification pathway-related genes were down-regulated in AFB1-treated Gnmt−/− mice: Cyp1a2, Cyp3d44, Cyp2d22, Gsta1 and Abca8a. In summary, we observed a synergistic relationship between GNMT deficiency and AFB1 exposure in hepatocarcinogenesis, further evidence that GNMT over-expression is an important contributing factor to female liver cancer resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4161.
Abstract 417: Tax-interacting protein 1 (TIP-1) as one biomarker of invasive astrocytomas
Authors: Wang Hailun , Hallahan Dennis , Han Zhaozhong 
Published: February 2011

Abstract
Despite the comparatively low incidence of astrocytomas to other human cancers, mortality rates of cancer patients with invasive astrocytomas are extremely high. Despite decades of therapeutic research, curative intervention is still nonexistent for high grade astrocytomas; patient care ultimately focuses on palliative management. Even with aggressive surgical, radio- and chemo- therapies, highly invasive astrocytomas have poor prognosis with an average survival time of 12 months. We intend to identify and characterize new biomarkers or molecular targets for effective diagnostics or therapeutics development. In our previous study of recombinant peptide for tumor imaging, we found that tumor xenografts formed with D54 glioma cells had relatively higher binding to HVGGSSV peptide than other tumor models. It was further elucidated that Tax-interacting protein 1 (TIP-1) contributes to the HVGGSSV peptide binding within tumors. Immunohistochemistry study of human brain tissues revealed significantly elevated expression of TIP-1 within astrocytomas, while compared to normal brain tissue or oligodendrogliomas that showed faint to negative staining of TIP-1. More interestingly, the highest expression of TIP-1 was found in glioblastoma multiforme, the highly invasive astrocytomas. To elucidate biological relevance of TIP-1 expression in invasive astrocytomas, human glioma cell line D54 was genetically engineered to have elevated or down-regulated expression of TIP-1. Tumorigenesis studies indicated that TIP-1 positively regulated tumor formation in nude mice. Knocking-down TIP-1 within D54 cells resulted in delayed tumor formation and decreased tumor growth rate. However, over-expression of TIP-1 within D54 cells lead to fast growing tumors in vivo, histological examination showed the TIP-1 over-expressing D54 tumors were sporadic with presence of necrotizing tissues surrounded by anaplatic cells, one characteristic of glioblastomas multiforme. In vitro characterization further demonstrated that the TIP-1 over-expressing cells had improved invasion capability, TIP-1 is dominantly expressed in invasion front of D54 cells. Biochemical studies indicated that the TIP-1 modulates cytoskeleton organization by interacting with multiple proteins. In summary, this study demonstrated that TIP-1 is one biomarker of invasive astrocytomas, and might be one potent molecular target for therapeutics development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 417.
Abstract 4173: In vivo and in vitro propagation of Intraductal Papillay Mucinous Neoplasms
Authors: Kamiyama Hirohiko , Kamiyama Mihoko , Hong Seung-Mo , Karikari Collins , Lin Ming-Tseh , Griffith Margaret , Young Angela , Kirby Alexis , Borges Michael , Lubek Conrad , Mizuma Masamichi , Feldman Georg , Shi Chanjuan , Liang Hong , Goggins Michael , Maitra Anirban , Hruban Ralph , Eshleman James 
Published: February 2011

Abstract
Background
Intraductal Papillary Mucinous Neoplasms (IPMNs) are one of the 3 known curable precursor lesions (IPMN, MCN (Mucinous Cystic Neoplasm), and PanIN (Pancreatic Intraepithelial Neoplasm)) of invasive pancreatic ductal adenocarcinoma, an almost uniformly fatal disease.
Methods
To advance the study of the biological features of IPMNs, we attempted in vivo and in vitro growth of selected IPMNs, based on the hypothesis that IPMNs could be grown in the most severely immunodeficient mice. We examined fourteen cases by implanting them into nude, severe combined immunodeficient (SCID), and NOD/SCID/IL2Rγnull (NOG) mice, in addition to direct culture, to generate tumor xenografts and cell lines.
Results
Thirteen tumors were implanted into the 3 types of mice, including 10 tumors implanted into the triple immunodeficient NOG mice, where the majority (8 of 10) grew including 5 IPMNs lacking invasive components. One of the explanted IPMNs, with an associated invasive carcinoma, was successfully established as a cell line. Growth in soft agar, growth in mice and homozygous deletion of P16/cdkn2a confirmed its tumorigenicity. The expression of cytokeratin confirmed the epithelial differentiation of the cell line, and DNA fingerprinting confirmed its human origin.
Future directions
Isolating cell lines from IPMNs and their invasion counterparts should be valuable to identify gene mutations critical to IPMN carcinogenesis, and permit drug screening to identify compounds that cause regression of those lesions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4173.
Abstract 4180: The L360R point mutation in the DNA repair gene XRCC1 suppresses tumor progression
Authors: Pettan-Brewer Christina , Goh Jorming , Coil Rebecca , Enns Linda , Morton John , Ladiges Warren 
Published: February 2011

Abstract
Variations in the DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) have been increasingly reported in cancer epidemiology investigations, but have yielded conflicting results and are lacking biological data. XRCC1 is an essential scaffolding protein that interacts with many proteins associated with base excision repair and single-strand break repair. Several polymorphisms and point mutations have been shown to be in the BRCT1 binding domain, where critical binding with the DNA damage sensor gene Poly (ADP-ribose) polymerase (PARP) occurs. The point mutation L360R interferes with PARP binding in cell culture systems. In order to further investigate the biological effects of L360R, we constructed a gene-targeted mouse line and showed the homozygous genotype to be embryonic lethal. We therefore used the heterozygous genotype to determine tumor susceptibility and showed that subcutaneously implanted B16 melanoma tumors developed more slowly in L360R mutant mice compared to wild type littermates (tumor volume 116±11 mm3 vs 263±21 mm3, respectively, p≤0.05) suggesting host mediated affects. We conducted a second experiment using azoxymethane (10mg/kg once a week for 6 weeks) to induce colon tumors and showed that after six months the tumor burden was 14.2±3 mm3 in mutants compared to 22.5±5 mm3 in wild type littermates (p≤ 0.05). These findings suggest that the XRCC1 L360R point mutation acts as a tumor suppressor, possibly through host mediated events. The molecular mechanism for the suppression is not yet known, but the XRCC1 L360R mouse line is a promising animal model to further investigate and determine the clinical relevance of this novel observation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4180.
Abstract 4186: Development of a novel, genetically faithful model of pediatric glioblastoma
Authors: Ihrie Rebecca A. , Huillard Emmanuelle , Petritsch Claudia , James David , McMahon Martin , Gutmann David H. , Rowitch David H. , Alvarez-Buylla Arturo 
Published: February 2011

Abstract
Gliomas are among the most lethal human cancers, with high-grade tumors exhibiting a dismal 5-year survival rate. Mutations and amplifications of receptor tyrosine kinases such as PDGFR and EGFR, which drive Ras-MAPK pathway activity, are among the hallmark mutations of adult gliomas. However, pediatric glioblastomas often do not exhibit the oncogenic mutations found in adult tumors, suggesting that these tumors may have distinct mechanistic origins. The unique genetic characteristics of pediatric brain tumors may also affect their response to conventional treatment. Therefore, there is a need to generate mouse models that faithfully recapitulate the genetics of pediatric glioblastomas to identify potential avenues for improving treatment of these tumors. Recent genetic profiling of pediatric brain tumors has found activating mutations of the BRaf kinase in higher grade tumors but not low-grade juvenile pilocytic astrocytomas. By contrast, BRaf is not frequently altered in adult gliomas, suggesting that cells in the developing brain may be particularly susceptible to this mechanism of Ras pathway activation. In addition, BRaf mutation is closely linked to the loss of the tumor suppressor Ink4a/Arf, indicating a possible requirement for loss of this tumor suppressor in the development of high-grade gliomas.
Here, we describe the generation of a model system allowing expression of oncogenic BRaf in spatially and temporally defined populations of neural stem cells. In BRaf CA/+; R26YFP animals, Cre-mediated recombination induces expression of the oncogenic V600E mutant form of Braf from the endogenous gene locus and simultaneously labels these cells via expression of YFP. By stereotaxically injecting Cre-expressing adenovirus into the neonatal or adult brain in these mice, we can induce oncogene expression in specific populations of neural progenitors and track its effects on infected cells.
Data from multiple tumor types suggests that the activation of Ras-MAPK signaling via BRaf mutation is tightly linked to loss of the Ink4a/Arf tumor suppressor locus. We are also using viral introduction of Cre to activate oncogenic BRaf when Ink4a/Arf expression is absent. The phenotype of these mice will be compared to human pediatric gliomas to determine if this system provides an accurate model of the human disease. Such a model would provide a platform for testing targeted therapies against BRaf - a critical step in designing new treatments for pediatric glioblastoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4186.