bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A17: A role for the endocytic regulators Rab25 and Rab coupling protein (RCP) in K-Ras dependent colorectal cancer cells
Authors: Rooney Claire , Barry Simon 
Published: June 2012

Abstract
Endocytic transport impacts a wide range of cellular functions, including growth factor signaling, cell polarity, and cell-cell and cellmatrix adhesion. As such, deregulated endocytosis is emerging as a key feature of tumorigenesis. Growth factors and their receptors are important regulators of normal cell survival and proliferation and aberrant growth factor signaling is one of the fundamental elements of tumor growth and progression. Upon activation at the plasma membrane, growth factor receptors are internalized and either trafficked to the lysosome for degradation, or returned to the cell surface via the process of endosomal recycling. Furthermore, growth factor receptors can signal from endocytic compartments en route to the lysosome, and throughout the recycling process. Downstream of growth factor stimulation, signaling from Ras GTPases to effectors such as the mitogen activated protein kinase (MAPK) pathway has also been shown to occur at endocytic compartments. Elucidation of the key regulators of the endocytic process therefore presents a novel opportunity to target certain growth factor signaling pathways. Two such key regulators are the small GTPase Rab25, and its interacting partner Rab coupling protein (RCP). Rab25 and RCP are amplified in certain breast and ovarian cancers, and this amplification is associated with increased aggressiveness of these cancers. Additionally, in mutant p53 cells RCP has been implicated in enhanced EGFR and integrin signaling, resulting in increased invasion. Here, we provide evidence for the importance of Rab25 and RCP in colorectal cancer (CRC) cell lines. Using siRNA to specifically knockdown RCP and Rab25 in a panel of CRC cell lines we have found that RCP and Rab25 knockdown significantly impacts on the proliferation of these lines. Within the panel of CRC cell lines, we have identified subpopulations of K-Ras dependent and K-Ras independent lines. K-Ras dependency appeared to be independent of K-Ras mutation status, and those lines which depend on K-Ras for proliferation also require RCP and Rab25. We are currently investigating the consequences of RCP knockdown on growth factor receptor signaling and subsequent Ras activation. These findings highlight the importance of the regulation of recycling endocytosis in colorectal cancer, and indicate a dependence of colorectal cancer cells on this process.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A17.
Abstract A2: Receptor status in breast cancer and reproductive history: Is there any relation?
Authors: Basu Chinmay K. , Pandey Ritwik , Mukhopadhyay Soma , Mukhopadhyay Ashis 
Published: June 2012

Abstract
Objective: Molecular profiling studies using immunohistochemistry have identified subtypes of breast cancer that can be approximately classified by estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER-2) expression. These molecular subtypes and their combinations taken together with reproductive history of woman may help prognostication of breast cancer cases. We report a series of 102 cases of breast cancer treated in our institution over last five years (2004-08).
Methods: Paraffin-embedded primary breast cancers from 102 patients with invasive and ductal carcinoma were studied immunohistochemically. Markers along with reproductive history were analysed.
Result: 78 ductal 12 lobular cases were found. 43 cases were postmenopausal. Hormone receptor positive cases were 63 (61.7%), ER+ 34 (33.3%), and PR+ 29 (28.4%). HER-2/neu + cases were 34 (33.3%). There were 11 cases of triple negative (basal-like) breast cancer. Significant inverse correlation was found between HER-2/neu and hormone receptor. Early age at menarche was only found to be associated with risk of HER-2neu+, whereas breastfeeding had protective effect. Both late ages at menopause, hormone therapy was associated with poor prognosis. Higher age at first child birth was significantly associated with poorer outcome and no difference in risks with parity was noticed. HER-2/neu was not associated with response rate but their prognosis was worse. Triple negative had 3 survivors at three years. Significant associations were observed between HER-2/neu and increasing number of involved and metastases (p = 0.01). Analysis demonstrated that HER-2/neu overexpression (p = 0.02) and age (p = 0.01) were independent predictors for disease-free survival (DFS).
Conclusion: Hormone receptor positive cases are associated with better prognosis than HER-2/neu positive cases. For node positive patients, HER-2/neu overexpression was a significant predictor of DFS. Reproductive history had significant bearing in prognosis and receptor expressing subsets of breast cancer which may be clear by further study.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A2.
Abstract A20: FGFR1-amplified squamous cell lung cancers depend on FGFR1
Authors: Sos Martin L. , Thomas Roman K. 
Published: June 2012

Abstract
In lung adenocarcinomas of never-smokers EGFR mutations or EML4-ALK gene fusions are frequent genomic events that both expose prime therapeutic targets. By contrast, squamous cell lung cancer (SQLC) is almost invariably associated with smoking; in this subgroup of patients, no attractive therapeutic target has so far been identified. In order to identify such a therapeutically exploitable target in SQLC, we performed high-resolution genomic analyses of over 300 lung tumor specimens. Using 6.0 Affymetrix SNP-arrays we identified high-level focal amplifications of FGFR1 in 10% of over 150 primary SQLC specimens. Importantly, FGFR1 amplification was almost exclusively restricted to SQLC of smokers and almost never observed in adenocarcinomas. We also performed high-throughput cell line screening of 82 genomically annotated lung cancer cell lines using the FGFR inhibitor PD170374 and identified the presence of focal FGFR1 -amplifications as the strongest predictor of PD170374 activity. Biochemical kinase profiling across 108 kinases suggested that PD170374 was highly selective with only one of the kinases being inhibited to a similar extend as FGFR1 itself. Treatment with PD173074 induced apoptosis and inhibited MAPK- and, to a lesser extend, PI3K signaling in cell lines with focal amplification of FGFR1. In order to validate FGFR1 as a critical target in FGFR1 -amplified cells we employed retroviral expression of the gatekeeper mutant allele of FGFR1 (V561M) and thus the PD173074-sensitive cells were rendered resistant. Additionally, lentiviral-mediated knockdown of FGFR1 in FGFR1 -amplified cell lines confirmed FGFR1 as a critical target for FGFR1 inhibition in these cells. Finally, successful treatment of mice engrafted with FGFR1 -amplified lung cancer cell lines with PD173074 confirmed its on-target activity in vivo. Overall, our work demonstrates the functional relevance of amplification of FGFR1 in lung cancer and suggests that inhibition of FGFR with targeted therapeutics might be an effective strategy in squamous cell carcinoma patients with focal amplification of FGFR1.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A20.
Abstract A21: Expression of placental growth factor in hepatocellular carcinoma and peritumoral liver and its prognostic significance
Authors: Sun Hui-Chuan , Xu Hua-Xiang , Zhu Xiao-Dong , Tang Zhao-You 
Published: June 2012

Abstract
Vascular endothelial growth factor targeted therapy is a promising treatment for hepatocellular carcinoma (HCC), but its clinical benefit is often accompanied by acquired resistance. Antiplacental growth factor (PlGF) therapy is effective in animal study with less resistance. Role of PlGF in the progression of HCC is not clear. In this study, we investigated PlGF expression in tumor and peritumoral liver tissues from 105 HCC patients by immunohistochemistry in tissue microarrays. Intratumoral and peritumoral PlGF mRNA expression was analyzed in another cohort containing 37 patients. Peritumoral PlGF expression was significantly higher than intratumoral PlGF expression (P &lt; 0.001). Intratumoral PlGF expression was not associated with patients’ overall survival (OS) or time to recurrence (TTR). However, peritumoral PlGF expression, which was associated with tumor size (P = 0.002), presence of intrahepatic metastasis (P = 0.005), TNM stage (P = 0.048), and BCLC stage (P = 0.001), was an independent risk factor for OS (P &lt; 0.001) and TTR (P = 0.001). Prognostic value of peritumoral PlGF expression was validated in a validated cohort. Furthermore, we inferred that elevation of PlGF in peritumoral liver might be induced by hypoxia. And we found that peritumoral PlGF expression was associated with hypoxia-inducible factor 1α (HIF-1α) (P = 0.003) and PlGF expression was elevated in hepatic cell line L02 under hypoxia in vitro. These findings indicate that high peritumoral PlGF expression was associated with tumor recurrence and survival after resection of HCC. PlGF could be a target of adjuvant therapy and deserves further investigations.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A21.
Abstract A23: Frequent ASS1 deficiency in bladder cancer and sensitivity to pegylated arginine deiminase (ADI-PEG20): A potential novel therapeutic strategy
Authors: Allen Michael , Syed Nelofer , Crook Tim , Jones Louise , Lemoine Nicholas R. , Berney Dan , Szlosarek Peter 
Published: June 2012

Abstract
Tumors deficient in argininosuccinate synthetase (ASS1), a key enzyme involved in arginine synthesis, are auxtrophic for arginine and sensitive to amino acid deprivation. Based on reports of ASS1 negativity and arginine auxotrophy of prostate and renal cancers, we investigated the role of ASS1 and arginine depletion in bladder cancer, a common urological malignancy with limited treatment options for advanced disease. First, we screened 8 bladder cancer cell lines revealing very low mRNA levels and low or absent ASS1 protein in 4 of 8 cell lines. The ASS1 negative cell lines were all hypermethylated at the ASS1 promoter, compared with the ASS1 – positive cell lines, which were hypomethylated. An analysis of 48 patients with bladder cancer revealed 65% were ASS1 -negative by immunohistochemistry, with evidence for ASS1 methylation as a mechanism for ASS1 inactivation. There was no correlation between ASS1 loss and the type, grade or stage of bladder tumor. Next, we exposed two ASS1 -negative and two ASS1 -positive bladder cancer cell lines to pegylated arginine deiminase (ADI-PEG20), an arginine depleting agent that is currently undergoing evaluation in several clinical trials in patients with solid malignancies. The ASS1-negative, but not the ASS1 -positive, bladder cancer cell lines were sensitive to ADI-PEG20 treatment. Current work is focussed on determining whether there is enhanced cell killing when ADI-PEG20 is combined with cisplatin-based chemotherapy. In summary, ADI-PEG20 is a potential novel therapeutic approach in the treatment of ASS1 – negative bladder cancer and warrants further investigation in the clinic.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A23.
Abstract A25: Variations of human papillomavirus type 16 in cervical, lung, and skin cancers in Sichuan, China
Authors: Zhang Jian , Wang Tao , Han Min , Yang Zhihui , Zhang Min , Liu Lunxu , Zhou Bin , Chen Yue , Hou Qiannan , Wang Yanyun , Lai Ting , Zhang Lin , Hu Huaizhong , Xi Mingrong 
Published: June 2012

Abstract
Human papillomavirus (HPV) is closely related with many kinds of cancers such as cervical, lung, and skin cancers, etc. HPV 16 showed intratypic variations that were known to differ in oncogenic potential and geographic distribution. This study was designed to analyze sequence variants in oncogenes E6, E7 and L1 of HPV 16 in cervical, lung, and skin cancers in Sichuan, China. Materials from 138 non-malignant controls, 122 cervical cancer patients, 104 lung cancer patients and 104 skin cancer patients were analyzed by PCR and direct sequencing. The infection rates of HPV 16 in cervical, lung, skin cancers were respectively 68.9%, 17.3%, 5.8%. The Asian prototype was the most prevalent variant in cervical cancer in Sichuan (40%). Compared with that detected in cervical cancer, lung and skin cancers showed more monotonous variations, but several mutations on L1 genes existed only in lung or skin cancers such as G6818C, C7011A, and C7017A.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A25.
Abstract A28: Multiplexed immunofluorescence in formalin-fixed paraffin-embedded prostate cancer
Authors: Sevinsky Christopher , Dinn Sean , Pang Zhengyu , Li Qing , Sarachon Brion , Rothney Megan , Colligan Bruce , Douglass Larry , Carter Julia , Graff Jeremy , Ginty Fiona 
Published: June 2012

Abstract
Traditional immunohistochemistry serves as a vital diagnostic assay as it allows for semiquantitatively probing the magnitude and spatial distribution of protein expression and posttranslational modifications. Unfortunately, an accurate portrayal of disease often requires several immunohistochemical stains, which are run on separate tissue sections. The application of transcriptomics analyses in cancer classification has led to the generation of multivariate index analyses that confer diagnostic, prognostic, and predictive signatures of disease. However this method is limited by the inability consider target expression in the context of tissue (stroma, epithelium) or cell (e.g. stem/progenitor cells) type. A unifying platform that would allow for the quantitative spatial analysis of multiplexed in situ target measurements promises to exploit the best features of both systems. To this end, we have developed a novel multiplexed fluorescence immunohistochemistry assay that is capable of quantitative analysis of &gt;25 antigens in a single formalin-fixed paraffin-embedded tissue section, as well as image and data analysis capabilities for analyzing the multidimensional data. By inclusion of targets for cell and tissue compartments, including nuclei, cytoplasm and membrane, we have demonstrated the ability to investigate subcellular protein expression, phosphorylation and co-localization in individual cells. In the present study we have stained a cohort of 79 prostate cancer patients of varying Gleason grades for a total of 24 antigens, representing key mediators of cell signaling, tumor suppressors and oncogenes, tumor associated phenotypic targets, and structural proteins. The images are precisely registered and segmented into individual cells nuclear, cytoplasmic and membrane regions and the underlying expression of a given antigen is then quantitatively determined in each compartment by automated algorithms. With the advent of this new tool, we aim to define new prognostic molecular signatures in prostate cancer.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A28.
Abstract A29: Discovery and preclinical to clinical evaluation of biomarkers for Anti-DLL4, a monoclonal antibody targeting cancer stem cells
Authors: Kapoun Ann M. , Wang Min , O'Young Gilbert , Beviglia Lucia , Liu Yu-Wang , Yeung Pete , Fischer Marcus , Smith Dave , Lewicki John , Hoey Tim 
Published: June 2012

Abstract
Blockade of DLL4 signaling reduces tumor growth in preclinical human xenograft models by disrupting productive angiogenesis and reducing proliferation of tumor cells. Importantly in these models, blocking DLL4 also reduces cancer stem cell (CSC) frequency in multiple solid tumor types. Currently, there exists an important need to identify and evaluate pharmacodynamic biomarkers that indicate the biological activity of agents, such as anti-DLL4, that are in clinical studies. Towards this aim, we used numerous human xenograft models derived from primary human tumors to identify and characterize biomarkers for anti-DLL4. Here, we present data from these studies and describe anti-DLL4 biomarkers in tumors, in hair follicles, and in blood. We show that several vascular-related genes are significantly upregulated by anti-DLL4 in tumors including, Egfl7, Apln, Cldn5, and Notch4. We also demonstrate significant downregulation of CSC gene signatures and modulation of differentiation genesets. A subset of the identified markers were validated at the protein level and also tested in a human skin graft model, where the human tumor is engrafted in a human microenvironment/vasculature. Finally, a DLL4-Notch gene signature was identified that showed a significant association with breast cancer survival using publicly available cancer gene sets. In surrogate tissues, we identified anti-DLL4 biomarkers in blood and in hair follicles. These markers from surrogate tissues were translated into a phase I trial of Anti-DLL4 antibody (OMP-21M18), and an interim analysis of this data demonstrates that OMP-21M18 affects the Notch pathway in patient samples.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A29.
Abstract A3: The human epidermal growth factor receptors in gastric carcinomas: A study using fluorescence in situ hybridization and immunohistochemistry
Authors: Fukuda Emy , Soares Fernando , Fregnani Jose H. , Begnami Maria D. 
Published: June 2012

Abstract
The human epidermal growth factor receptors (EGFR) family consists of four members: ErbB-1 (HER1), ErbB-2 (HER2), ErbB-3 (HER3) and ErbB-4 (HER4). These receptors activate numerous downstream pathways in response of extracellular ligands, regulating diverse processes including differentiation, migration, proliferation, and survival. Alterations in EGFR family members play a role in the development and progression of many human cancers. In gastric carcinomas (GC), HER1 and HER2 overexpressions are thought to be prognostic factors and targets of novel biological agents. The effect of HER3 or HER4 expression in GC has not been sufficiently studied. HER3 expression is observed frequently in advanced GC with poor prognosis and HER4 gene expression seems to be higher in GC tissue in comparison with adjacent gastric mucosa. In this study, we explored gene and protein expression of the EGFR family in GC in order to establish new potentially prognostic factors. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were carried out in 221 GC using tissue microarray. IHC positivity for EGFR was defined by score 2+ or 3+ according with intensity and frequency of membranous staining. In addition, the intensity of the cytoplasm staining was also determined for HER3 and HER4 overexpression. HER1, HER2, HER3, and HER4 overexpression was found in 3/197 (1.5%), 24/207 (12%), 121/193 (64%) and 41/183 (22%) cases respectively. FISH assay was performed according to the protocol previous described. In each case, 100 tumor nuclei were evaluated. Cases showing a gene/CEN fluorescence ratio ≥ 2 were considered positive for gene amplification. FISH detected HER1 and HER2 amplification in 1.3% and 8% of the cases. Amplifications for HER3 and HER4 were not observed. Overall, alterations of the 4 members of EGFR were significantly associated with parameters involved with tumor progression, including the depth of tumor invasion, involved lymph nodes, and tumor stage. We herein showed a strong correlation between HER2, HER3 and HER4 overexpression and low-grade tumors, corresponding to the intestinal type GC according to Lauren's classification. In addition, HER2 amplification was significantly related with worse survival. These results reveal that members of EGFR family are activated in GC. The exact molecular mechanisms involved in the HER3 or HER4 alterations in gastric cancer, especially in the intestinal type, remain unclear since amplifications of these genes were not found. Gaining further understanding into the oncogenic mechanism of EGFR family may not only help in the development of targeted therapy in gastric patients but might accelerate the acceptance of a novel taxonomy of cancer which is based on the genomic perturbations in cancer genes and cancer gene families and their response to targeted agents.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A3.
Abstract A31: Prognostic microRNA biomarkers for recurrence of stage II colorectal cancer
Authors: Sanford Tiffany , Adai Alex T. , Doleshal Martina , Langfield Laura , Choudhury Bhavna , LeBourgeois Paul , Pappas Todd , Mambo Elizabeth 
Published: June 2012

Abstract
Reliable prediction of recurrence in stage II colorectal cancer (CRC) patients is a major unresolved clinical need as recurrence is often the ultimate cause of death in these individuals. Several mRNA and DNA prognostic markers have been evaluated and, to date, none have been recommended by oncology groups due to poor specificity and sensitivity. MicroRNA (miRNA) have been shown to regulate fundamental cellular processes and have been implicated in several cancer types, including CRC. We used a microarray platform to examine the expression of more than 600 miRNAs in tumors from stage II patients with or without recurrence. Using an exploratory sample set of 12 tumors (6 nonrecurrent and 6 recurrent), we identified several miRNAs that were significantly deregulated in tumors from recurrent patients compared to non-recurrent patients. We used RT-qPCR to interrogate the differentially expressed miRNAs on the original 12 samples plus an additional set of 39 stage II CRC tumors that were not used in the initial miRNA discovery process. Using cross-validation, we derived a miRNA-based classifier that was strongly associated with recurrence (hazard ratio (HR), 3.83; p=0.005). We further evaluated associations of MSI status and mutations in KRAS, BRAF and PIK3CA genes with recurrence (n=39). Multivariate Cox analysis revealed that only the miRNA classifier was significantly associated with recurrence (HR 3.08; p=0.03). Interestingly, the combination of the miRNA classifier and mutant KRAS status was highly predictive of recurrence (p&lt;0.0001). These data provide strong support for miRNAs as prognostic biomarkers for stage II CRC and warrant further validation.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A31.