bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CN07-04: Patient-specific pathway analysis using PARADIGM identifies key activities in multiple cancers.
Authors: Stuart Joshua M. 
Published: June 2012

Abstract
While common pathways are believed to be shared within specific cancer types, the mechanisms of why particular patients respond differently to treatment is not fully understood. Current - omics studies such as The Cancer Genome Atlas (TCGA) give us powerful tools to search for pathways universal or specific to cancers. Our integrated approach makes use of multiple measurements including large-scale whole-genome mRNA expression, DNA copy number, and epigenetic features. Typical analysis of these measurements relies on integrating data from multiple samples to distinguish signal from noise. However, few analytical methods allow for sample-specific differences to identify features and pathways that are significant for prognosis and clinical treatment classifications.
Using our pathway analysis method PARADIGM (PAthway Recognition Algorithm using Data Integration on Genomic Models) (Bioinformatics (2010) vol. 26 (12) pp. i237) we computed pathway activities for the approximately 1685 available TCGA samples with both copy-number and gene expression data across 10 tissues to identify both common and differential pathway features When clustered together using hierarchical clustering methods, we see well-known associated cancers as clustering together such as Colon adenocarcinoma (COAD) with Rectum adenocarcinoma (READ) and Ovarian serous cystadenocarcinoma (OV) with invasive Breast carcinoma (BRCA). Interestingly Glioblastoma multiforme (GBM) and both types of Kidney (KIRC, KIRP) tend to cluster together, apparently driven by relatively low integrin signals and lower DNA damage response levels shared among the three tissues. Using this global cancer dataset we find striking similarities between subtypes of cancers from different tissues of origin. In particular, we find that a signature trained to recognize Lung adenocarcinoma (LUAD) versus Lung squamous cell carcinoma (LUSC) can be used to classify breast cancer subtypes Luminal A versus Basal with a surprising accuracy of 0.972. This analysis illustrates the molecular similarities between these cancers and warrants further characterization to assess the viability of bridging treatments between these and other cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN07-04.
Abstract PL02-02: BRAF and RAS signaling in cancer: From biology to therapeutics.
Authors: Marais Richard 
Published: June 2012

Abstract
The RAS proteins are small G-protein that are activated downstream of cell surface receptors. The RAF proteins are protein kinases that are activated by RAS. RAF proteins then activate the MEK/ERK signalling pathway, which stimulates cell proliferation and drives tumorigenesis. There are three RAS proteins (HRAS, KRAS, NRAS) in humans and the NRAS isoform is mutated in about 25% of melanomas. There are also three RAF proteins in humans (ARAF, BRAF and CRAF) and BRAF is mutated in a further 50% of melanomas. Critically, drugs that target BRAF achieve impressive objective responses in patients with BRAF mutant melanoma, but are ineffective in patients whose melanomas express wild-type BRAF. These data validate mutant BRAF as a therapeutic target in melanoma.
An unexpected property of RAF inhibitors is that they drive paradoxical activation of the MEK/ERK pathway in cells that express oncogenic RAS. This is because when they bind to RAF in cells in the presence of oncogenic RAS, these inhibitors drive the formation of CRAF:BRAF heterodimers and CRAF:CRAF homodimers in which one partner is drug-bound and the other is drug-free. Critically, the drug-bound partner acts as a scaffold, or induces a conformation change that hyper-activates the drug-free partner and this partner then drives pathway signalling. Notably, a quarter to a third of patients on BRAF inhibitors develop cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas. We have used a two-stage skin carcinogenesis model in mice that is driven by oncogenic HRAS to show that while BRAF inhibitors accelerate the development of RAS-driven cuSCC in mice, they do not initiate the formation of these lesions. We found that about 60% of BRAF-inhibitor driven cuSCC in melanoma patients harbour mutations in RAS genes and furthermore show that in mice cuSCC development driven by BRAF inhibitors can be blocked by co-administration of a MEK inhibitor. Thus, we conclude that RAS inhibitors do not act as tumor promoters per se; rather they accelerate the inevitable in susceptible patients and we provide a rational approach to blocking this side effect in BRAF mutant melanoma patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL02-02.
Abstract 1006: TP53-induced glycolysis and apoptosis regulator (TIGAR) induces NADPH production and growth in nasopharyngeal carcinoma cells
Authors: Lam Emily KY , Lui Vivian WY , Wong Elaine YL , Lau Cecilia PY , Wong Cesar SC , Hui Edwin P , Chan Andrew SK , Tsao Sai Wah , Mills Gordon B , Chan Anthony TC 
Published: June 2012

Abstract
TIGAR (TP53-induced glycolysis and apoptosis regulator) is a novel dual regulator of glycolysis and apoptosis regulated by p53. TIGAR was first found to protect normal cells from oxidative stress by inducing cellular production of NADPH, a powerful reducing agent in the cell, via the pentose phosphate shunt.
Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer prevalent in Southeast Asia. Our previous studies demonstrated that overexpression of TIGAR rescued NPC cells from growth inhibition induced by c-Met kinase inhibitors and an RNA anti-metabolite (ECyd), suggesting an anti-apoptotic function of TIGAR in NPC. Here, we demonstrated by Western blotting and immunohistochemistry that TIGAR was expressed in primary tumor biopsies of NPC. Moreover, NPC cell lines from various differentiation status also expressed TIGAR. Using an Epstein-Barr virus-associated NPC cell line, HONE-1-LMP1 cells, we showed that specific knockdown of TIGAR by siRNA inhibited cell proliferation (∼45%) at 48 hrs. Moreover, TIGAR overexpression markedly increased NPC cell proliferation (&gt;300%), which was accompanied by significant induction of cellular NADPH production (&gt;200%). This indicates that TIGAR-induced generation of NADPH, which is an important building block for major cellular metabolites for proliferation (including DNA, RNA and fatty acids, etc), may be involved in NPC carcinogenesis. Furthermore, TIGAR overexpression induced the expression of a pro-survival protein, Mcl-1 in NPC cells, which supports an anti-apoptotic function of TIGAR in NPC. Our results implicate that TIGAR may confer survival benefits to NPC cells via metabolic alteration.
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 1006. doi:10.1158/1538-7445.AM2011-1006
Abstract 1023: Social stress modulates beta-adrenergic and potassium channel-mediated signaling in lung adenocarcinoma
Authors: Plummer Howard , Al-Wadei Hussein A.N. , Unger Benjamin , Schuller Hildegard M. 
Published: June 2012

Abstract
Small airway epithelial cell-derived adenocarcinoma is the most common human lung cancer. Previous research from our laboratory has indicated the importance of stress neurotransmitters in cancer signaling in these cells in vitro. In the current study, we have assessed the potential modulation of cancer progression by social stress in xenograph models. The adenocarcinoma cell lines NCI-H322 (with activating point mutations in K-ras) and NCI-H441 (without ras mutations) were injected into nude mice 4 weeks after induction of social stress. The social stress continued for an additional 4 weeks when the tumors were removed. RNA was isolated, and PCR microarrays were used to identify genes that could be affected by stress. Using real-time PCR, we investigated some of these genes. We saw significant decreases in β1-adrenergic (0.49 fold), β2-adrenergic (0.55 fold) and calmodulin (0.16 fold) gene expression in the NCI-H322 xenographs. In the NCI-H441 xenographs, only calmodulin was changed (1.59 fold increase). The immortalized normal human small airway epithelial cell HPL1D was chosen for in-vitro studies. Treatment of HPL1D cells for 7 days with 10 μM acetylcholine led to a significant 0.48 fold decrease in β1-adrenergic gene expression. Previous research from our laboratory has indicated the significance of potassium channels in both lung cancer and breast cancer. Therefore, we determined if a potassium channel could be involved in these stress-induced responses. The voltage-dependent human ether à go-go (EAG) potassium channel has been shown to be important in cellular signaling, cancer progression and calcium signaling/calmodulin binding. After assay by real-time PCR, the NCI-H322 xenographs showed a significant 0.51 fold decrease in EAG gene expression, but there was no change in gene expression in the NCI-H441 xenographs. Treatment of HPL1D cells for 7 days with 10 μM acetylcholine led to a significant 0.36 fold decrease in EAG gene expression. Our data indicate social stress modulates beta-adrenergic and potassium channel-mediated signaling in lung adenocarcinoma. Supported by 1RC1CA144640 with the National Institutes of Health.
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 1023. doi:10.1158/1538-7445.AM2011-1023
Abstract 1027: Bcl-2 protected HNSCC cells from dasatinib-induced apoptosis
Authors: Lin Yu-Chin , Wu Meng-Hsuan , Chen Kuen-Feng , Cheng Ann-Lii , Chen Ching-Chow 
Published: June 2012

Abstract
Introduction: Head and neck squamous cell carcinoma (HNSCC) is a worldwide prevalent cancer with aggressive clinical courses and dismal outcomes. Incorporation of cetuximab, an antibody against epidermal growth factor receptor, had led to advance of treatment, but showed a modest efficacy. Therefore, new treatment for HNSCC is needed. Dasatinib, a Bcr-Abl and Src inhibitor, approved for treatment of chronic myeloid leukemia, was demonstrated to have activities for solid tumors. Here, we report the differential sensitivity of dasatinib for HNSCC cells and identify the possible molecular events.
Material and method: HNSCC cells including Ca9-22, HSC3, UMSCC1, FaDu, and SAS were treated with dasatinib. Cell viability, apoptosis, and underlined signal transduction were evaluated by MTT assay, flow cytometry and Western blotting, respectively.
Results: Five HNSCC cells treated with dasatinib displayed differential sensitivities. Ca9-22 and HSC3 cells are the most sensitive cells in response to dasatinib and showed significant growth inhibition and apoptosis. In contrast, FaDu and SAS cells are resistant to dasatinib-induced growth inhibition and apoptosis. UMSCC1 cells showed intermediate sensitivity to dasatinib; their growth was inhibited without induction of apoptosis. Src inhibition (Y416 dephosphorylation) was observed in all 5 cells treated with dasatinib. The growth inhibition of Ca9-22, HSC3, and UMSCC1 cells was correlated with inhibition of Akt and Erk activities, which is not observed in SAS and FaDu cells. In addition, anti-apoptotic protein bcl-2 was increased in UMSCC1, FaDu, and SAS cells, but decreased in Ca9-22 and HSC3 cells. Therefore, the increases of bcl-2 in UMSCC1 may protect cells from dasatinib-induced apoptosis.
Conclusion: Bcl-2 plays a crucial role in dasatinib-induced apoptosis in HNSCC cells, providing a new therapeutic approach to target bcl-2 in HNSCC treatment.
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 1027. doi:10.1158/1538-7445.AM2011-1027
Abstract 1031: Protein kinase c ∈ regulates tumor necrosis factor-α induced nuclear factor-κB signaling in prostate cancer
Authors: Garg Rachana , Benavides Fernando , Blando Jorge , Wang Hongbin , Caino Maria Cecilia , Kazanietz Marcelo G. 
Published: June 2012

Abstract
Protein Kinase C epsilon (PKC∈), a member of the PKC family of phorbol ester/diacylglycerol receptors, has been shown to be up-regulated in human prostate cancer specimens. As PKC∈ plays an important role in prostate cancer cell survival and cooperates with other oncogenic insults, we hypothesized that PKC∈ may regulate NF-κB signaling pathway, known to be highly dysregulated during prostate tumorigenesis. Similar to human tumors, we observed high PKC∈ overexpression in prostate cancer cell lines compared to normal immortalized RWPE-1 cells. PKC∈ depletion using siRNA or its pharmacological inhibition in LNCaP cells resulted in decreased TNFα-induced IκBα phosphorylation and degradation, as well as decreased NF-κB nuclear translocation and transactivation of NF-κB reporter activity. Conversely, significant enhancements in these TNFα-induced responses were observed in LNCaP cells upon PKC∈ overexpression using an adenoviral approach. Interestingly, TNFα treatment led to activation of PKC∈ in LNCaP cells, as analyzed by enhanced translocation from cytosolic to membrane fractions. Furthermore, TNFα-mediated PKC∈ translocation and IκBα phosphorylation were found to be dependent on phosphatidylcholine- but not phosphatidylinositol-specific phospholipase C. As determined by co-immunoprecipitation, PKC∈ associates with TNF receptor-1 (TNFR1) in response to TNFα and has important regulatory consequences in the assembly of TNFR-1 signaling complex. PKC∈ depletion by siRNA decreased the TNFα- mediated recruitment of receptor interacting protein (RIP) and TNFR-associated factor-2 (TRAF2), which are both known to mediate NF-κB activation. In accordance with the co-immunoprecipitation results, siRNA-mediated PKC∈ depletion inhibits TNFR1, TRADD, TRAF2, IKK-β- mediated NF-κB reporter activity. Furthermore, effects of PKC∈ overexpression on NF-κB transcriptional activity correlated well with the increased mRNA levels of known NF-κB regulated genes involved in cell survival, inflammation, invasion and angiogenesis (Cox2, VEGF, MMP9, and IL8). Finally, we found that in preneoplastic lesions from transgenic mice overexpressing PKC∈ in the prostate there is enhanced NF-κB activation. In summary, our study established a molecular link between PKC∈ and NF-κB in prostate cancer and suggests a prominent role for this pathway in prostate cancer cell survival.
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 1031. doi:10.1158/1538-7445.AM2011-1031
Abstract 1091: ShcA-mediated ERK signaling contributes to the tumor-promoting activity of TGF-beta in the presence of mutant p53
Authors: Lin Shu , Yu Lan , Yang Junhua , Sun Lu-Zhe 
Published: June 2012

Abstract
Transforming growth factor-beta (TGF-β) signaling has been shown to inhibit tumorigenesis at the early stage and promote metastasis at the late stage. However, biomarkers for identifying the complicated molecular alterations mediating the switch of TGF-β from a tumor suppressor to a tumor promoter still remain obscure. Published studies have shown that the presence of mutated tumor p53 can switch TGF-β to becoming tumor-promoting. However, we found that in the p53-null PC-3 prostate cancer cell line, the ectopic expression of the mutant p53 R175H (mp53) enhanced the Smad-dependent signaling, but inhibited TGF-β-induced cell migration by downregulating the active ERK. Since TGF-β is known to activate MAPK/ERK pathway to induce cell migration, EMT and survival through direct phosphorylation of adaptor protein ShcA isoform p52, we investigated how the expression of the mp53 inhibited ERK activation. We found that the expression of mp53 led to downregulation of phospho-p52ShcA and upregulation of ERK antagonist p66ShcA isoform. Interestingly, we found partial depletion of p52ShcA by using siRNA enhanced the TGF-β/Smad signaling and inhibited the TGF-β/ERK signaling in PC-3 cells and spontaneously immortalized and non-tumorigenic human mammary epithelial MCF-10A cell line, suggesting ShcA may act as an additional switcher of the TGF-β. Furthermore, reactivation of ERK by the expression of its activator, MEK1, restored active ERK level and TGF-β-induced cell migration in PC-3/mp53 cell. Those findings show that mp53 expression alone is not sufficient to promote the malignant phenotype of TGF-β in certain cells and the cooperation of mp53 and ShcA-mediated ERK signaling may switch TGF-β to be a tumor promoter.
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 1091. doi:10.1158/1538-7445.AM2011-1091
Abstract 1110: Differential expression of cholecystokinin receptors and their ligands in normal and neoplastic pancreas
Authors: Ortega Emily , Smith Jill P. 
Published: June 2012

Abstract
Background: The gastrointestinal peptide gastrin has been identified in fetal pancreas up until week 14 where it is thought to play a role in growth and differentiation. Gastrin has also been identified as an important growth factor that stimulates pancreatic cancer through the CCK-B and CCK-C receptors by an autocrine mechanism.
Hypothesis: It is hypothesized that gastrin re-expression is important to pancreatic carcinogenesis.
Methods: The mRNA from normal human pancreas tissue was isolated and endpoint RT-PCR was performed to detect RNA levels of gastrin and CCK peptide, using gastrin specific and CCK peptide specific primers, respectively. PCR products were visualized on an ethidium bromide stained gel after electrophoresis. Normal human pancreatic tissue samples were evaluated for gastrin and CCK by immunohistochemistry. Tissues were flash frozen and sectioned at a thickness of 8-10uM. Non-specific sites were blocked, followed by exposure to either gastrin or CCK antisera. Peptide presence was assessed using AF568 (Alexa Fluor) goat anti-rabbit secondary antibody.
Results: The end-point RT-PCR showed significant levels of CCK-B receptor and CCK peptide in normal pancreas samples. The gastrin end-point RT-PCR showed extremely low levels in all of the normal pancreas samples. Gastrin immunoreactivity was not detected in normal pancreas, however, staining of the positive control, an islet cell tumor, was reactive. The negative control, a GIST tumor, showed no staining as well.
Conclusions: Normal pancreas possesses the receptor CCK-B and the peptide CCK. Gastrin is not present in normal pancreatic tissues, but is detected in neoplastic pancreatic samples. Therefore, the re-expression of gastrin plays a pivotal role in the development of pancreatic cancer and could be a potential trigger to pancreatic carcinogenesis.
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 1110. doi:10.1158/1538-7445.AM2011-1110
Abstract 1111: Preclinical evaluation of CP868,596, a novel PDGFRα Inhibitor for treatment of glioblastoma
Authors: Yang Xiao-Li , Mashimo Tomoyuki , Su Yang , Vemireddy Vamsidhara , Guntipalli Prathima , Ramachandran Abhijit , Chaudhary Preeti , Mickey Bruce , Hatanpaa Kimmo , Maher Elizabeth , Bachoo Robert M. 
Published: June 2012

Abstract
Background: Recent large scale genomic studies have shown that ∼13% of glioblastoma (GBM) have a copy number gain of the gene encoding for platelet-derived growth factor receptor alpha (PDGFRα). Animal studies have shown that PDGFRα signaling can drive tumor growth. Clinical studies, however, have failed to show efficacy when patients with recurrent GBM were treated with non-specific PDGFR inhibitors (Imatinib, Sunitinib). Drawing firm conclusions from such studies is limited by lack of patient stratification by PDGFRα expression and lack of biological data demonstrating effective target inhibition. CP-868,596 is a benzimidazole which is orally bioavailable, and has IC50s of 0.9 nM and 1.8 nM for PDGFRα and PDGFRb, respectively. Phase I trials of CP-868,596 have shown a favorable safety profile and serum concentrations up to 2000 nM. We are pursuing a systematic in vitro and in vivo preclinical evaluation to assess potential clinical efficacy of CP-868,596 for the treatment of glioma.
Methods: To evaluate IC50 for CP868,596, we have genetically engineered conditional Ink4a/Arf-/- mouse astrocytes to stably co-express both the human PDGFRα and its cognate ligand, PDGF-AA. Expression levels of PDGFRα and PDGF-AA levels were adjusted so they are comparable to those we have found in GBM tumors.
Results and Discussion: Immunoblot analysis shows that PDGFRα phosphorylation and its downstream signaling pathway (pAKT, phospho-S6 ribosomal protein, and p-4EBP1) activated either by autocrine and/or exogenous PDGF-AA ligand (1um) is completely blocked by CP868,596 (concentrations 0.1-1um). INK4a/Arf-/-, PDGFRα/PDGF-AA astrocytes, when implanted into the NOD-SCID mouse brain or subcutaneous space (flank), form orthotopic /heterotopic tumors, respectively. Using these glioma models, intratumoral CP868,596 levels and the ability of the drug to block PDGFRα phosphorylation is being evaluated (dose range 0.1-5 ug/kg/hr IV). While multiple signal transduction pathways are implicated in pathogenesis of GBM, CP868,596 may only be effective in those GBM where PDGFR is the dominant ‘driver’ of tumorigenesis. To test this hypothesis we have established a panel of primary GBM orthotopic mouse tumor lines which overexpress PDGFRα/PDGF-AA with and without EGFR and/or cMet gene overexpression and will evaluate response to treatment with CP868,596. In addition, a Phase II treatment trial in adult glioma patients is being initiated. Data from the in vitro and in vivo studies will be presented.
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 1111. doi:10.1158/1538-7445.AM2011-1111