bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4805: Distinctive phospho-proteome signatures in non-small cell lung carcinoma tumors
Authors: Wei Yuhong , Taylor Paul , Tong Jiefei , Pham Nhu-An , Li Ming , Panchal Devang , To Christine , Chui Michael H. , Tsao Ming-Sound , Kislinger Thomas , Moran Michael F. 
Published: August 2012

Abstract
Non-small cell lung carcinoma (NSCLC) is a major, lethal cancer worldwide. Various molecular and cellular abnormalities are found in NSCLC, and an established theme is the alteration of protein phosphotyrosine (pY), as exemplified by elevated epidermal growth factor receptor (EGFR) activity recognized in a subset of NSCLC. In order to gain a broad perspective of pY-mediated signaling networks in NSCLC, mass spectrometry was used to analyze pY-containing peptides affinity purified from protease-digested xenograft tumors. Seventeen tumors representing the major NSCLC subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were characterized. The major classes of pY proteins detected were cytoskeletal, protein kinases, and adhesion proteins. Pathways and cellular functions enriched in the data set included focal adhesion, adherens junction, and ErbB signaling. Five receptor tyrosine kinases (RTKs) were detected, with EGFR and EPHA2 most prevalent. Src-family kinases (YES, LYN, FRK and LCK) and focal adhesion kinase (FAK) comprised the majority of non-receptor tyrosine kinases measured. Analysis of individual pY sites on 14 tyrosine kinases indicates their activation by kinase domain activation loop phosphorylation, but also revealed additional pY sites suggestive of regulation by trafficking/endocytosis and inter- and intra-molecular protein-protein interactions involving, for example, SH2 and SH3 domains, and extra-kinase domain regions. Analysis of tumors based on protein-pY suggested subtypes distinguished by their activated tyrosine kinase networks. Genetic analysis of 3 tumors that displayed EGFR-associated phospho-proteome signatures confirmed that they carried either EGFR activating mutations (in two ADCs) or increased gene copy number (in one SCC). Western blot analysis of protein pY confirmed different patterns of cellular protein pY among the tumor phospho-types in agreement with the phospho-proteomic analysis. Quantification of kinase and substrate pY sites, according to their integrated extracted ion currents, revealed a set of phosphorylations that constituted a molecular signature that differentiated between the ADC and SCC subtypes. In summary, quantitative phospho-proteomic profiling of NSCLC tumors is feasible and may have utility in the categorization of individual tumors according to their networks of activated tyrosine kinases and substrates.
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 4805. doi:1538-7445.AM2012-4805
Abstract 4807: Identification of pre-invasive pancreatic cancer serum biomarkers using genetically engineered mouse models and mass spectrometry techniques
Authors: Ludwig Michael R. , Kojima Kyoko , Grizzle William , Mobley James A. , Klug Christopher A. 
Published: August 2012

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. Surgery is the only curative treatment approach if the tumor is diagnosed early at an organ confined stage. Therefore, serum biomarkers specific for early stage pancreatic neoplasia would be of tremendous value in the treatment of this disease. Genetically engineered mouse models (GEM) of pancreatic neoplasia have been generated that closely recapitulate the molecular and biological properties of human PDAC. Here we take advantage of these GEMs and a high-throughput proteomics approaches to “dig deep” into the serum proteome of these mice to identify representative biomarkers of early stage pancreatic neoplasia. Methods: Serum was collected from 9 Pdx1-Cre (control) and 9 Pdx1-Cre;LSL-RasG12D (pre-invasive PDAC model) mice at 4 months of age. Serum was then pooled into 3 sets of 3 samples for each arm. The top 7 most abundant proteins were depleted from each pooled sample prior to labeling with a tandem mass tag (TMT) sixplex isobaric labeling system and long-column MudPIT analysis. Data were searched in SEQUEST, and quantified in ProteoIQ. Candidate proteins were accepted only with 97-99% confidence, and at least 2 unique TMT tagged peptides. Only biomarkers with &gt;2 fold change and passing 2 non-parametric statistical tests were further evaluated. The same samples were also analyzed with a 1D MALDI-TOF MSMS approach to survey the low-mass serum proteome. In addition, a multi-dimensional MALDI-TOF approach was carried out on whole protein serum samples using spectral counting to quantify proteins instead of TMT labeling. Results/Discussion: Long-column MudPIT analysis resulted in identification of 3001 proteins with high confidence. Seventy of these proteins passed fold change and statistical filters, with 25 of these having known biological connections to pancreatic disease or function. A number of these proteins are currently being validated by immune assays. Multi-dimensional MALDI-TOF analysis resulted in identification of 8 differentially abundant proteins. Two of these proteins have been validated by Western blot. Taken together, these mass spectrometry techniques allow for a relatively in-depth survey of the serum proteome with accurate quantitation of potentially novel early stage pancreatic neoplasia biomarkers. Ultimately, the biomarkers identified in this study will be validated in human studies with the expectation that high risk patients will benefit from the application of these biomarkers for early diagnosis and improved treatment of disease.
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 4807. doi:1538-7445.AM2012-4807
Abstract 4815: Cytomegalovirus enhances glioblastoma via PDGF-B/STAT3 pathway activation
Authors: Price Richard L. , Song Jieun , Bingmer Katherine , Yi JiYeun , Rivera Andreana , Ogelsbee Michael , Cook Charles , Kwon Chang-Hyuk , Chiocca E. Antonio 
Published: August 2012

Abstract
Recently several groups have demonstrated cytomegalovirus (CMV) protein and DNA in a large majority of glioblastomas (GBMs), though the exact role of CMV in tumors remains controversial. Although CMV is capable of activating several oncogenic pathways, it has never been shown to be a transforming virus. Because of this, we hypothesize that CMV infection can modify the rate of gliomagenesis in the context of genetic mutations known to predispose to tumor formation. To test this, we used the Smith strain mouse CMV (MCMV) to infect Mut3 (GFAP-cre; Nf1loxP/+; Trp53-/+) mice that develop normally but eventually develop spontaneous gliomas at an adult age After intraperitoneal viral inoculation, mice exhibited multisystemic infection throughout the body, including the brain. Mut3 mice infected perinatally (103 plaque forming units) developed gliomas significantly sooner than mock-infected Mut3 mice. MCMV-infected mice developed GBMs (WHO grade IV) at a higher rate than less severe tumors, whereas, mock-infected mice developed less severe gliomas (WHO grade III). Since MCMV preferentially infected the neural stem cell (NSC) niche, an area shown to generate gliomas, we interrogated changes in signaling in this population via microarray of cultured NSCs in MCMV- versus Mock-infected mice. Ingenuity Pathway Analysis identified a PDGF-B network as the highest scoring differentially regulated network between MCMV-and Mock-infected neurospheres. In vitro infection of mouse tumorspheres and human GBM tumorspheres with CMV validated the observed upregulation of PDGF-B, a molecule shown to cause gliomas de novo. Additionally, in vitro infection of human glioma stem cells with HCMV (Towne strain) or exogenous PDGF-B activated STAT3, a key regulator of gliomas. In mice infected with MCMV, PDGF-B is upregulated in CA2/3 neurons and STAT3 is activated in the subventricular zone and dentate gyrus suggesting a paracrine effect of MCMV-induced PDGF-B. Also, infected human brain tumor stem cells demonstrated an increase in proliferation via flow cytometry. Taken together, our data suggest that CMV in gliomas may accelerate GBM progression by activating PDGF-B/STAT3 signaling in the NSC population.
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 4815. doi:1538-7445.AM2012-4815
Abstract 4821: Biomarker evaluation In phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors
Authors: Spoerke Jill , O'Brien Carol , Wu Jenny , Desai Rupal , Patel Rajesh , Raja Rajiv , Koeppen Hartmut , Amler Lukas , Hampton Garret , Yan Yibing , Lackner Mark R. 
Published: August 2012

Abstract
Background: The PI3K/Akt pathway is frequently activated in cancer by multiple mechanisms including PI3K activating mutations, PTEN loss, RTK activation, and other means. GDC-0941 and GDC-0980 are selective PI3K and dual PI3K/mTOR inhibitors, respectively, which are currently in phase II clinical development. Assays for candidate predictive and pharmacodynamic biomarkers were conducted on patient samples collected from phase I studies of GDC-0941 and GDC-0980. The purpose was to confirm pathway inhibition at tolerable doses, as well as look for association between anti-tumor activity and candidate predictive biomarkers. Methods: Archival tumor tissue samples were analyzed using a 6 gene mutation assay (PIK3CA, EGFR, KRAS, BRAF, NRAS, AKT1), an immunohistochemistry assay for PTEN, and a fluorescence in situ hybridization (FISH) assay for PIK3CA. Select samples were analyzed for an expanded mutation panel and genome-wide copy number alterations using the Oncoscan platform (Affymetrix). For pharmacodynamic biomarker assays, analyses were initially limited to pre and post treatment phospho-AKT levels in platelet rich plasma. Once substantial downmodulation of pAKT in surrogate tissue was observed, pre- and post treatment biopsies were collected from a subset of patients and analyzed for phospho-S6 levels by immunohistochemistry. Results: Predictive biomarker assays were conducted on over 150 samples from the phase I study. Overall we found a prevalence of 7% PIK3CA mutations and 15% loss of PTEN in these samples. PIK3CA amplification was observed in several samples from ovarian cancer patients. Overall there were five confirmed partial responses in the studies, and two of these occurred in patients with activating mutations in PIK3CA. Robust PD knockdown of pAKT in surrogate tissue was observed in the early stage of dose-escalation. Moreover, substantial knockdown of pS6 was seen in tumor tissues in patients treated at or below the recommended phase II dose. Conclusions: Pharmacodynamic assays confirmed effective pathway knockdown at safe and tolerated clinical doses of GDC-0941 and GDC-0980. Anti-tumor activity was observed in patients with PIK3CA mutations, as well as some patients whose tumors did not harbor pathway alterations. These data support patient stratification in phase II clinical studies to determine whether a predictive biomarker will be useful in identifying responsive patients.
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 4821. doi:1538-7445.AM2012-4821
Abstract 4827: Humanized hepsin neutralizing antibody RO5486055 inhibits tumor growth and leads to accumulation of hepsin substrate laminin-332
Authors: Daouti Sherif , Filipovic Zoran , Stern Alvin , Tardell Christine , Zhang Xiaolei , Lucas-McGady Debra , Higgins Brian , Huang Kuo-Sen , Gubler Ueli , Li Ying , Berkofsky-Fessler Windy , Hang Julie , Samokhin Gennady , Seidl Annette , Niu Huifeng , Cai James , Hilton Holly , Thomas Markus , Pamulapati Chandra , Mundigl Olaf , Hansen Silke , Heimbrook David C. , Packman Kathryn E. 
Published: August 2012

Abstract
Hepsin is overexpressed in prostate and other cancers where it is implicated in promoting tumor growth, invasion, and metastasis. To further our understanding of the role of hepsin in prostate and breast cancer, a fully humanized monoclonal antibody that recognizes human and cynomolgus hepsin has been developed. RO5486055 selectively binds to hepsin but not related type II transmembrane serine proteases, and neutralizes hepsin serine protease activity with an IC50 in the single digit nM range. In LNCaP prostate cancer cells, both shRNA knockdown of the hepsin gene and RO5486055 treatment cause a similar accumulation of the β3 chain of laminin-332, a known hepsin substrate. With ip administration in mice, RO5486055 demonstrates dose-dependent exposure and a long serum half-life of 168-406 hours. RO5486055 attenuates tumor growth in the LNCaP prostate cancer and T-47D breast cancer xenograft models, but not in the CRW-22Rv1 prostate or MCF-7 breast cancer xenografts. In these models, it has been shown that the level of the β3 chain of laminin-332 detected by Western blot analysis predicts sensitivity to RO5486055-mediated growth inhibition. Moreover, accumulation of the β3 chain during RO5486055 treatment correlates with antitumor activity. In 8/10 hepsin-expressing patient-derived prostate tumors, an inverse correlation between hepsin and β3 chain expression is observed. The β3 chain of laminin-332 may therefore be useful as both a predictive and response biomarker for anti-hepsin therapy. RO5486055-mediated tumor growth inhibition is enhanced by combination with the EGFR-targeted antibody cetuximab in LNCaP prostate cancer xenografts, and by combination with hormone withdrawal in T-47D breast cancer xenografts. These preclinical results suggest that hepsin-directed therapy could be effective in prostate and breast cancer treatment.
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 4827. doi:1538-7445.AM2012-4827
Abstract 4844: A novel mechanism of immune escape in cancer and its regulation by nitric oxide
Authors: Barsoum Ivraym B. , Hamilton Thomas K. , Miles Ellen , Siemens Robert , Graham Charles H. 
Published: August 2012

Abstract
One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Previously, we showed that hypoxia induces resistance to natural killer (NK) cell-mediated lysis in tumour cells through a mechanism that involves the shedding of the NK cell-activating ligand, MHC Class I Chain Related molecule A (MICA), from the cell surface. Additionally, we reported that activation of NO signalling in the tumour cells was able to block this hypoxia-induced shedding of MICA, as well as resistance to NK-mediated lysis. Here, we show that hypoxia-induced tumor resistance to lysis is mediated by a HIF-1-dependent increased expression of the metalloproteinase ADAM10, which is required for the hypoxia-induced shedding of MICA. Our findings demonstrate that HIF-1α knock down attenuated the hypoxia-induced expression of ADAM10 and MICA in tumour cells. Also, siRNA-mediated knockdown of HIF-1α or ADAM10 prevented the hypoxia-induced resistance of DU145 cells to innate immune effector cell-mediated lysis. Treatment with nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF-1α, and with the hypoxia-induced up-regulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. To validate the in vitro results, we adopted a model in which human DU145 cells were injected subcutaneously into Swiss nude mice (T and B cell-deficient). Continuous transdermal delivery of nitroglycerine (1.8 µg/h for up to 62 days) significantly attenuated attenuated the tumor growth (P &lt; 0.05). This tumor growth-inhibitory effect of nitroglycerine was absent in mice depleted of innate immune effector cells. Within the tumours, areas of hypoxia co-localized with the metalloproteinase ADAM10 expression. Our results demonstrate a novel mechanism by which hypoxia contributes to immune escape in tumor cells and provide evidence that activation of nitric oxide signalling interferes with this mechanism. The findings described here are important because they indicate that nitric oxide mimetics could potentially be used as immunosensitizers in the treatment and/or prevention of 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 4844. doi:1538-7445.AM2012-4844
Abstract 4846: Manipulation of autophagy during tumor cell killing regulates the growth of neighboring tumor cells
Authors: Thorburn Jacqueline , Morgan Michael , Thorburn Andrew 
Published: August 2012

Abstract
Many anti-cancer agents induce macroautophagy (hereafter “autophagy”) and it is widely thought that autophagy can regulate tumor chemosensitivity. Most work in this area asks if autophagy increases or decreases tumor cell killing. Using a targeted anti-cancer agent (DT-EGF, an EGF receptor-targeted diphtheria toxin), we demonstrated that autophagy can also control the characteristics of dying glioma cells. DT-EGF induces autophagy in glioma cells, however this autophagy has little impact on whether or not the cells die. Instead its major effect is to determine how the cells die. When autophagy is allowed, the cells die by a non-apoptotic mechanism that has little caspase activation, whereas if autophagy is inhibited, the glioma cells die by inducing caspase-dependent apoptosis. Here, we present data showing that the effects of this switch in death mechanism change the growth of other tumor cells that did not die in response to the drug. By mixing DT-EGF-sensitive and DT-EGF-resistant cells such that 99% of the tumor cells in the population die, we found that manipulation of autophagy in the dying cells affects the growth rates of the surviving 1% of tumor cells. If caspase-dependent apoptosis is allowed by inhibiting autophagy, the surviving tumor cells grow faster to repopulate the tumor. Conversely if autophagy is allowed in the dying cells, the resistant cells grow more slowly. We propose that cancer therapy should take account not just of how many tumor cells are killed but also the way that they are killed and that manipulating autophagy during cancer treatment could be used to improve outcomes by regulating the mechanism of tumor cell death as well as the amount of tumor cell death.
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 4846. doi:1538-7445.AM2012-4846
Abstract 4854: Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion positive and fusion negative prostate cancer
Authors: Krohn Antje , Stahl Phillip , Burkhardt Lia , Gerhäuser Clarissa , Huang Joseph , Mader Malte , Sirma Hüseyin , Plass Christoph , Sauter Guido , Minner Sarah , Simon Ronald , Schlomm Thorsten 
Published: August 2012

Abstract
The PTEN (Phospatase and Tensin Homolog deleted on chromosome Ten) gene is frequently altered in prostate cancer. To determine the prevalence and clinical significance of different mechanisms of PTEN inactivation, we analyzed 4,699 hormone-naïve and 57 hormone-refractory prostate cancers by fluorescence in situ hybridization for PTEN deletion. In addition, PTEN mutations and promoter methylation were analyzed in subsets of 149 and 34 tumors. PTEN deletions were present in 20.2% (458/2,266) of prostate cancers harboring and heterozygous (8.1%) and homozygous (12.1%) deletions. Deletions of PTEN were linked to advanced tumor stage (p&lt;0.0001), high Gleason grade (p&lt;0.0001), presence of lymph-node metastasis (p=0.0002), hormone refractory disease (p&lt;0.0001), presence of ERG gene fusion (p&lt;0.0001), and nuclear p53 accumulation (p&lt;0.0001). PTEN deletions were also associated with early PSA recurrence in univariate (p&lt;0.0001) and multivariate analysis (p=0.0158) if compared to the established risk factors pT stage, Gleason grade, and preoperative PSA level. The PTEN deletion had the identical prognostic impact in both in ERG fusion-positive and -negative tumors. PTEN mutations were found in 4 of 26 (15%) of cancers with heterozygous PTEN deletion, but in only 1 of 59 (2%) of cancers without PTEN deletion (p=0.0183). Analysis of the PTEN promoter for methylation changes in 34 tumors revealed no aberrations. The results of this study demonstrate that biallelic inactivation of PTEN, either by homozygous deletion or by deletion of one allele and mutation of the second one, occurs in the majority of prostate cancers with PTEN alteration and is characteristic feature for a particularly aggressive subset of metastatic and hormone-refractory prostate cancers.
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 4854. doi:1538-7445.AM2012-4854