tbuckley/cabot-search huggingface dataset:
Abstract 1225: Proteome-wide analysis of gain-of-function mutant p53 targets in breast cancer implicates PARP, PCNA and MCM4 as oncogenic drivers
Authors: Alla Polotskaia, Gu Xiao, Katherine Reynoso, Che Martin, Wei-Gang Qiu, Ronald Hendrickson, Jill Bargonetti
Journal: Cancer Research (2015)

Abstract Gain-of-function mutant p53 (mtp53) changes the cancer cell transcriptome. However no analysis of mtp53-associated proteome diversity has been carried out. We coupled cell fractionation with stable isotope labeling with amino acids in cell culture (SILAC) and inducible knockdown of endogenous mtp53 to determine the mtp53 driven proteome. Using SILAC followed by tandem mass spectrometry (LC-MS/MS) we identified that R273H mtp53 expression in MDA-MB-468 breast cancer cells both up and down-regulated multiple proteins and metabolic pathways. We sequenced 73,154 peptide pairs that corresponded to 3010 proteins detected under reciprocal labeling conditions. Importantly the high impact regulated targets included the previously identified transcriptionally regulated mevalonate pathway proteins but also identified two new levels of mtp53 protein regulation for non-transcriptional targets. Interestingly, mtp53 depletion profoundly influenced poly (ADP-ribose) polymerase 1 (PARP1) localization, with increased cytoplasmic and decreased chromatin-associated PARP1. An enzymatic PARP shift occurred with high mtp53 expression resulting in increased poly-ADP-ribosylated proteins in the nucleus. Mtp53 increased the level of PCNA and MCM4 protein without changing the amount of pcna or mcm4 transcript. Pathway enrichment analysis ranked the DNA replication pathway above the cholesterol biosynthesis pathway as an R273H mtp53 activated proteomic target. Knowledge of the proteome diversity driven by mtp53 suggests DNA replication and repair pathways are major targets of mtp53 and highlights consideration of combination chemotherapeutic strategies targeting cholesterol biosynthesis and PARP inhibition. Acknowledgements. This work was supported by a grant to JB from the Breast Cancer Research Foundation. Citation Format: Alla Polotskaia, Gu Xiao, Katherine Reynoso, Che Martin, Wei-Gang Qiu, Ronald Hendrickson, Jill Bargonetti. Proteome-wide analysis of gain-of-function mutant p53 targets in breast cancer implicates PARP, PCNA and MCM4 as oncogenic drivers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1225. doi:10.1158/1538-7445.AM2015-1225
Cetuximab Resistance in Head and Neck Cancer Is Mediated by EGFR-K521 Polymorphism
Authors: Friederike Braig, Malte Kriegs, Minna Voigtlaender, Beate Habel, Tobias Grob, Karina Biskup, Veronique Blanchard, Markus Sack, Anja Thalhammer, Isabel Ben Batalla, Ingke Braren, Simon Laban, Antje Danielczyk, Steffen Goletz, Elzbieta Jakubowicz, Bruno Märkl, Martin Trepel, Rainald Knecht, Kristoffer Riecken, Boris Fehse, Sonja Loges, Carsten Bokemeyer, Mascha Binder
Journal: Cancer Research (2016)

Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K521 (K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K521 was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K521 that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K521 expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform. Cancer Res; 77(5); 1188-99. ©2016 AACR.
Abstract 3968: Identification of microRNAs markers in patients with oral squamous cell carcinomas for the presence of lymph nodes metastasis
Authors: Fernando Tadeu Zamunér, André Lopes Carvalho, Luiz Paulo Kowalski, André Luiz Vettore
Journal: Cancer Research (2015)

Abstract Introduction: Oral cancer is the most common subset of head and neck squamous cell carcinomas (OSCC). These tumors often have an aggressive clinical outcome hallmarked by a propensity for local invasion and regional nodal metastasis. The presence of metastatic disease in cervical lymph nodes is an important prognostic factor and it influences in the choice of the therapeutic strategy to be adopted. Thus, the identification of molecular markers able to select patients who are at high risk for lymph node metastasis and/or locoregional recurrence could be of great value. Recent studies have shown that microRNAs can be regulators of the tumor metastasis process by the activation of various signaling pathways involved in this process being useful in diagnosis, determination of disease prognosis and prediction of therapeutic response. PURPOSE: to identify microRNAs expressed in OSCC associated with the presence of lymph node metastasis. METHODS: Tumor samples were obtained from patients diagnosed with OSCC at the Head and Neck Surgery Department, Cancer Hospital of Barretos. For microRNA microarrays experiments, total RNA from 32 tumor samples (12 without lymph node metastasis and 12 with metastasis) was extracted labelled and hybridizated Analysis of microarray data was performed using GeneSpring GX 12.0 and R program. RESULTS: This analysis allowed the identification of 10 microRNAs differentially expressed in the comparison between metastatic and non-metastatic OCCS cases. These microRNAs will be validate and selected by qRT-PCR in an independent cohort of OSCC patients and correlate the molecular data with the clinical features of the patients. Citation Format: Fernando Tadeu Zamunér, André Lopes Carvalho, Luiz Paulo Kowalski, André Luiz Vettore. Identification of microRNAs markers in patients with oral squamous cell carcinomas for the presence of lymph nodes metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3968. doi:10.1158/1538-7445.AM2015-3968
Abstract 5401: TGF-β signaling inhibition as a potential approach to target suboptimally debulked ovarian tumors
Authors: Wei Wei, Michael J. Birrer
Journal: Cancer Research (2015)

Abstract The current standard of care for all patients with high-grade, advanced-stage serous ovarian cancer is surgery followed by adjuvant chemotherapy. Resection of all visible residual disease to less than 1 cm is associated with a favorable prognosis, but this optimal debulking can only be achieved in ∼70% of patients. Patients with suboptimal cytoreduction are presumed to have lower response rates to subsequent chemotherapy and are known to have a poor prognosis. Recently, we performed a meta-analysis of 1,525 publicly available expression profiling assays and identified a 200-gene expression signature of primary ovarian tumors to predict the outcome of debulking surgery. The signature was validated using two independent sets of tumors. This debulking signature consists of transcripts positively regulated by TGF-β, indicating that hyperactivation of TGF-β signaling may be responsible of the aggressive biological and clinical behavior of suboptimally debulked tumors. In this study, we evaluated the potential anti-tumor effect of TGF-β signaling blockade in ovarian cancer cells in vitro and in vivo. Integrated TGF-β signaling was observed in 8 of 10 ovarian cancer cell lines tested by a SMAD-binding element based luciferase assay. The potential anti-tumor effect of a small molecular TGFBR1 kinase inhibitor LY2157299 was further investigated in SKOV3 cell line, which presents both endogenous and inducible TGF-β signaling and is highly disseminative when inoculated into immunodeficient mice. Although imposing minimum effect on in vitro cellular proliferation, LY2157299 significantly inhibited tumor-dissemination related biological processes in SKOV3 cells including migration, invasion and mesothelial cell adhesion. In an interperitoneal SKOV3 xenograft model, administration of LY2157299 significantly increased cisplatin related cytotoxicity and tumor burden reduction. Taken together, our study has provided evidence for the potential clinical use of LY2157299 to improve the treatment and survival of women with suboptimal surgery. Citation Format: Wei Wei, Michael J. Birrer. TGF-β signaling inhibition as a potential approach to target suboptimally debulked ovarian tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5401. doi:10.1158/1538-7445.AM2015-5401
Abstract LB-052: Kinase identification of proximal substrates (KIPS): A novel chemical genetics approach for kinase substrate identification
Authors: jon roffey, Andrew Turnbull, Christian Dillon, Susan Boyd, Philippe Riou, Mark Linch, Peter Parker, Sven Kjaer, Neil McDonald
Journal: Cancer Research (2015)

Abstract Protein kinases are attractive targets for pharmacological intervention through their frequent disease associated aberration of cellular signalling networks. In this context an understanding of the myriad of substrates on which a protein kinase operates can help to reveal potential pharmacodynamic and patient stratification biomarkers. Kinase Identification of Proximal Substrates (KIPS) utilises an innovative chemical genetics approach to identify novel proximal biomarkers of kinase target response. This approach relies on the generation of a desensitized mutant protein that retains its kinase function, but loses sensitivity to small-molecule mediated inhibition. Comparative phospho-proteomics is performed on immuno-complexes of tagged wild type and mutant protein kinases in the presence and absence of inhibitor to isolate specific phospho-proteomic changes in proximal substrates. To exemplify the KIPS approach we have focused on the identification of novel substrates of the atypical protein kinase C isoform, PKCι. Through structure based design we identified two acidic amino acid residues in the PKCι nucleotide binding site that are crucial for efficacy of a previously characterized PKCι inhibitor, CRT0066854. Upon mutation to non-acidic alanine residues the PKCι protein is rendered insensitive to compound-mediated inhibition, allowing a comparison of wild type and mutant responses to PKCι inhibition to be made. Using HCT116 cells, we identified Myosin X as a putative substrate for PKCι, and demonstrated its specificity to the PKCι signalling axis through alanine-scanning peptide arrays and generation of phospho-specific antibodies. We show that the key acidic amino acids utilised in KIPS are highly conserved across the AGC and CAMK kinase super families. Furthermore, extensive compound SAR, diverse kinome profiling and structural biology have identified a tool box of inhibitor compounds with a broad range of activities across these kinase families leading to broader applicability of KIPS to enable the identification of individual kinase specific substrates and response across approximately 20% of the human kinome. Citation Format: jon roffey, Andrew Turnbull, Christian Dillon, Susan Boyd, Philippe Riou, Mark Linch, Peter Parker, Sven Kjaer, Neil McDonald. Kinase identification of proximal substrates (KIPS): A novel chemical genetics approach for kinase substrate identification. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-052. doi:10.1158/1538-7445.AM2015-LB-052
Stroma-Derived Exosomes Mediate Oncogenesis in Multiple Myeloma
Authors: Aldo M Roccaro, Antonio Sacco, Abdel Kareem Azab, Yu-Tzu Tai, Patricia Maiso, Yong Zhang, Yang Liu, Michaela Reagan, Feda Azab, Ghayas C Issa, Hai T Ngo, Phong Quang, Kenneth C Anderson, Riccardo Dalla-Favera, Irene M. Ghobrial
Journal: Blood (2011)
Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD
Authors: Hoeke A. Baarsma, Wioletta Skronska-Wasek, Kathrin Mutze, Florian Ciolek, Darcy E. Wagner, Gerrit John-Schuster, Katharina Heinzelmann, Andreas Günther, Ken R. Bracke, Maylis Dagouassat, Jorge Boczkowski, Guy G. Brusselle, Ron Smits, Oliver Eickelberg, Ali Ö. Yildirim, Melanie Königshoff
Journal: The Journal of Experimental Medicine (2016)

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT-β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy.
Obesity and colorectal cancer: adiponectin and tumor necrosis factor alfa a representative link between inflammation and cancer
Authors: R. Divella, A. Daniele, R. De Luca, P. Casamassima, E. Savino, A. Casamassima, G. Micelli, D. Carbonara, C. Caliandro, E. Ruggieri, S. Montemurro, F. Giotta, F. Giuliani, C.S. Sasanelli, L. Cataldo, I. Abbate
Journal: Annals of Oncology (2015)
Abstract 4431: Musashi enhances GS3K-beta and promotes stemness-related chemoresistance in glioblastoma
Authors: Hsiao-Yun Chen, Shih-Hwa Chiou
Journal: Cancer Research (2015)

Abstract Glioblastoma multiforme (GBM), one of the deadly malignant brain tumor, and is easily to recur and develop resistance to clinical chemotherapeutics. It has been demonstrated that cisplatin treatment select for resistance but also for a more oncogenic phenotype characterized by high self-renewal and oncogenic resistance. Musashi (MSI), a neural stem cell marker, is found to be elevated in several cancer tissues and positively regulates cancer progression. In this report, we found that MSI promoted tumourigenicity and enhances drug resistance of human GBM cells in response to cisplatin, a chemodrug. We further showed that MSI could activate and interact with phosphorylated-GS3K-β, and lead to a protective effect against mitigating cisplatin-induced cell death. Knockdown of MSI effectively suppressed the phosphorylation of GS3K-β and blocked β-catenin translocating into nucleus in cisplatin-resistant GBM cells, while overexpressing MSI reversed these effects. Notably, MSI could further upregulate β-catenin-driven stemness signature, and expression of Oct-4, Nanog, and ABCG2, thereby enhanced tumorigenicity and chemoresistance of GBM cells. Moreover, the result of in vivo animal study demonstrated that knockdown MSI effectively suppressed stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in GBM-transplanted immunocompromised mice. Taken together, our findings indicated that MSI-1 may provide a positive contribution to oncogenic resistance, in partly, through interplaying with GS3K-β and modulating WNT/stemness mechanism. Note: This abstract was not presented at the meeting. Citation Format: Hsiao-Yun Chen, Shih-Hwa Chiou. Musashi enhances GS3K-beta and promotes stemness-related chemoresistance in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4431. doi:10.1158/1538-7445.AM2015-4431
Oral Tipifarnib (R115777) Has Single Agent Anti-Tumor Activity in Patients with Relapsed Aggressive Non-Hodgkin Lymphoma (NHL): Results of a Phase II Trial in the University of Iowa/Mayo Clinic Lymphoma SPORE (CA97274).
Authors: Thomas E. Witzig, Matthew J. Maurer, Patrick B. Johnston, Joseph P. Colgan, Scott H. Kaufmann, David J. Inwards, Ivana N. Micallef, Stephen M. Ansell, Clive S. Zent, Cristine Allmer, George J. Weiner, James E. Wooldridge, Brian K. Link, Thomas M. Habermann
Journal: Blood (2006)
Evaluation of Human Leukocyte Antigen (HLA) Matching Requirements for Unrelated Peripheral Blood Stem Cell (PBSC) Transplantation
Authors: Ann E Woolfrey, John Klein, Michael D Haagenson, Stephen R Spellman, Minoo Battiwalla, James L. Gajewski, Gregory A. Hale, John Horan, Carolyn K Hurley, Craig Kollman, Susana Marino, Machteld Oudshoorn, Effie W Petersdorf, Olle Ringdén, Michelle Setterholm, Stephanie J. Lee
Journal: Blood (2008)
Abstract 1057: Characterization of methylation patterns in cancer tissue shown by targeted Next-Gen bisulfite sequencing
Authors: Jessica Alexander, Ryan Drennan, Ann Meyer, Jessica Xu, Matthew L. Poulin, Winston Timp
Journal: Cancer Research (2015)

Abstract Continuing research demonstrates an ever increasing number of genes with measurable dysregulation in their DNA methylation state.We have developed a panel of targeted NextGen bisulfite sequencing amplicon assays (TGBS) centered on cancer genes with altered DNA methylation. This cancer panel includes tumor suppressor genes (BRCA1, RASSF1, RUNX3), DNA methyltransferases (DNMTs and MGMT), DNA repeats (LINE1 and Sat2), oncogenes (MYC,ERBB2), receptor genes (EGFR, ESRRA, NR2E1), Homeobox genes (HOXA10, HOXA11, EN1) and detoxification genes (GSTM1, GSTM2) among others. A total of 80 genes covering over 1500 CpG sites were selected and assays for these regions were developed and validated using PCR/Pyrosequencing. 10 pairs of DNA samples (tumor vs adjacent normal) for four cancer types (ovarian cancer, breast cancer, cervical cancer, and colorectal cancer) were sequenced using this panel on an Ion Torrent PGM™ system. We have used this data to characterize the general behavior of these cancer samples as compared to normal in three specific ways. First, we have assayed the change in overall methylation level between normal and cancer samples using these multiplexed amplicons, using these values for both an unsupervised hierarchical clustering and principal component analyses. We have then attempted to establish a per tissue normal methylation profile, and measured the distance to this normal profile for each of the cancer samples. As has been discussed in previous work, cancer has more of an anti-normal profile than a characteristic pattern per se. Finally, we have examined the methylation patterns within individual reads, and assessed the measured methylation entropy or randomness of these patterns in normal versus cancer samples Citation Format: Jessica Alexander, Ryan Drennan, Ann Meyer, Jessica Xu, Matthew L. Poulin, Winston Timp. Characterization of methylation patterns in cancer tissue shown by targeted Next-Gen bisulfite sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1057. doi:10.1158/1538-7445.AM2015-1057
Dacetuzumab (SGN-40), Lenalidomide, and Weekly Dexamethasone in Relapsed or Refractory Multiple Myeloma: Multiple Responses Observed in a Phase 1b Study.
Authors: Edward Agura, Ruben Niesvizky, Jeffrey Matous, Nikhil Munshi, Mohamad Hussein, Ramakrishnan V Parameswaran, Stefano Tarantolo, Nancy C Whiting, Jonathan G Drachman, Jeffrey A Zonder
Journal: Blood (2009)
22. Post-Exposure Vaccination by Capsid-Modified AdC7 Vector Expressing Pseudomonas aeruginosa OprF in Chronic P. aeruginosa Lung Infection
Authors: Anurag Sharma, Rika Gomi, Wenzhu Wu, Biin Sung, Stefan Worgall
Journal: Molecular Therapy (2016)

Chronic infections by Pseudomonas aeruginosa are a common problem in cystic fibrosis and other chronic lung diseases associated with bronchiectasis. With antimicrobial resistance of P. aeruginosa becoming more common, alternate prophylactic and therapeutic approaches are needed. Despite extensive efforts, a vaccine against P. aeruginosa is not yet available. A post-exposure vaccine that eliminates already established P. aeruginosa from the respiratory tract, could be useful in the management of chronic P. aeruginosa colonization. Replication-deficient adenoviral (Ad) vectors are an attractive platform for vaccines against respiratory pathogens. We have previously found that, in addition to circumvent pre-existing anti-human Ad immunity, a non-human primate-based AdC7 vector expressing outer membrane protein F (OprF) of P. aeruginosa (AdC7OprF) was more potent in inducing lung mucosal and protective immunity compared to a human Ad5-based vector. In addition, genetic modification of the AdC7 fiber to display an integrin-binding arginine-glycine-aspartic acid (RGD) sequence can further enhance mucosal protective immunogenicity of AdC7OprF. In this study we investigated if post-exposure vaccination by AdC7OprF. RGD can clear the already established P. aeruginosa in a mouse model. Intratracheal inoculation of P. aeruginosa (clinical strain RP73) encapsulated in agar beads (10^6 cfu/mouse) was used to establish persistent infection. Intranasal immunization of P. aeruginosa infected mice with AdC7OprF. RGD (10^10 pu/mouse) induced significantly high serum anti-OprF IgG antibodies as early as 1 week of immunization that further increased to higher levels after 2 week of immunization compared to AdC7Null or PBS inoculated mice (p<0.05; all comparisons). In addition to robust humoral response, immunization with AdC7OprF. RGD induced OprF-specific T-cell responses, as indicated by the higher secretion of IFN-γ or IL-4 from the OprF-stimulated cultured splenocytes compared to AdNull or PBS inoculated mice (p<0.05; all comparisons). Importantly, the AdC7OprF. RGD immunized mice showed significantly higher clearance of P. aeruginosa from the infected lungs after 1 week or 2 weeks of immunization (p<0.05; all comparisons). In fact, after 2 weeks of immunization, 50% of AdC7OprF. RGD immunized mice (3 out of 6) completely cleared the P. aeruginosa from the infected lungs. These data suggest that immunization with AdC7OprF. RGD induced robust humoral and cellular anti-P. aeruginosa immunity that could clear established pulmonary P. aeruginosa infections.