bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-235: Therapeutic human papillomavirus vaccine design based on epitopes identified on the tumor cell surface by mass spectrometry
Authors: Hoppe Stephanie , Blatnik Renata , Schessner Julia P. , Dressler Lisa , Steinbach Alina , Winter Jan , Wuehl Martin , Klevenz Alexandra , Khallouf Hadeel , Riemer Angelika B. 
Published: August 2015

Abstract
Detailed knowledge about T cell epitopes, which are bona fide presented on the surface of human papillomavirus (HPV)-transformed cells, is essential for rational design of therapeutic HPV vaccines. HPV affects the cellular antigen processing machinery, thus not every epitope derived from viral proteins is presented on human leukocyte antigen (HLA) molecules. Even the presented epitopes are displayed in low abundance.
In this study, we developed a highly sensitive nano-UPLC-ESI-MS3 multiple-reaction monitoring mass spectrometry (MS) approach for direct detection of low-abundant epitopes on the cell surface. Several web-based prediction algorithms were used to predict prospective epitopes from the HPV16 E6 and E7 proteins. These candidate epitopes were tested for actual HLA binding in cellular binding assays. The presence of binding peptides on HPV16-transformed cells was analyzed by our MS technology. Immunogenicity of candidate peptides was assessed in vitro with short-term and long-term T cell line experiments, generated from peripheral blood mononuclear cells of healthy donors, and in vivo for a selected HLA-A2-restricted epitope in HLA-A2/DR-1 transgenic mice.
To ensure &gt;95% population coverage, prospective HPV epitopes were predicted for the HLA supertypes HLA-A1, A2, A3, A11, A24, B7, and B15. Close to 500 peptides were tested in competition-based binding assays and multiple novel binders were identified. MS epitope detection was first established for HLA-A2 epitopes, and is now extended to the other supertypes. In the immunogenicity assays, several peptides induced robust IFN-γ responses.
In conclusion, several new HPV16 E6 and E7 epitopes were identified and validated in this study. They represent promising candidates for inclusion into a therapeutic HPV vaccine. Validated epitopes are the basis of rational therapeutic vaccine design and are also important for immunomonitoring purposes.
Citation Format: Stephanie Hoppe, Renata Blatnik, Julia P. Schessner, Lisa Dressler, Alina Steinbach, Jan Winter, Martin Wuehl, Alexandra Klevenz, Hadeel Khallouf, Angelika B. Riemer. Therapeutic human papillomavirus vaccine design based on epitopes identified on the tumor cell surface by mass spectrometry. [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-235. doi:10.1158/1538-7445.AM2015-LB-235
Abstract LB-239: The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies
Authors: Lin Luping , Sabnis Amit , Chan Elton , Olivas Victor , Cade Lindsay , Pazarentzos Evangelos , Asthana Saurabh , Neel Dana , Yan Jenny Jiacheng , Lu Xinyuan , Pham Luu , Wang Mingxue , Karachaliou Niki , Cao Maria G. , Manzano Jose L. , Ramirez Jose L. , Torres Jose M. , Buttitta Fiamma , Rudin Charles M. , Collisson Eric A. , Algazi Alain , Robinson Eric , Osman Iman , Munoz-Couselo Eva , Cortes Javier , Frederick Dennie T. , Cooper Zachary A. , McMahon Martin , Marchetti Antonio , Rosell Rafael , Flaherty Keith T. , Wargo Jennifer A. , Bivona Trever G. 
Published: August 2015

Abstract
Resistance to RAF-MEK targeted therapy is a major clinical challenge. RAF-MEK inhibitors are initially but only transiently effective in some but not all BRAF mutant patients, and largely ineffective in RAS mutant patients because of resistance. Through a genetic screen in BRAF mutant tumor cells, we show that the Hippo pathway effector YAP acts as a parallel survival input to promote resistance to RAF-MEK inhibitor therapy. Combined YAP and RAF-MEK inhibition was synthetically lethal not only in several BRAF mutant tumor types but also in RAS mutant tumors. Increased YAP in BRAFV600E patient tumors was a biomarker of worse initial response to RAF inhibition in patients, establishing the clinical relevance of our findings. Our data uncover YAP as a novel mechanism of resistance to RAF-MEK targeted therapy. The findings unveil the synthetic lethality of YAP and RAF-MEK co-suppression as a promising strategy to enhance response and patient survival.
Citation Format: Luping Lin, Amit Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue Wang, Niki Karachaliou, Maria G. Cao, Jose L. Manzano, Jose L. Ramirez, Jose M. Torres, Fiamma Buttitta, Charles M. Rudin, Eric A. Collisson, Alain Algazi, Eric Robinson, Iman Osman, Eva Munoz-Couselo, Javier Cortes, Dennie T. Frederick, Zachary A. Cooper, Martin McMahon, Antonio Marchetti, Rafael Rosell, Keith T. Flaherty, Jennifer A. Wargo, Trever G. Bivona. The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies. [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-239. doi:10.1158/1538-7445.AM2015-LB-239
Abstract LB-241: HGF promotes resistance to MET inhibitor AMG337 in MET-amplified gastric cancer cells
Authors: Gordon Marcia , Croft Alexandra , Li Chi-Ming , Taylor Sean , Caenepeel Sean R. , Quon Kim 
Published: August 2015

Abstract
The MET oncoprotein is a tyrosine kinase that is the only known receptor for its ligand, HGF (Hepatocyte Growth Factor). In approximately 5% of gastric cancers, MET is activated by focal amplification, rendering it constitutively active and ligand independent. MET-amplified cancer cell lines and xenografts are typically dependent on MET signaling for proliferation or survival. To test this dependency in patients, a number of small molecule MET inhibitors, including AMG337, are currently undergoing clinical evaluation for the treatment of MET-amplified tumors.Here we characterize resistance mechanisms to MET inhibitor AMG337 in vitro. We show that under standard culture conditions, resistance does not readily arise in MET-amplified gastric cell lines SNU620 and MKN45 treated with a therapeutic dose (&gt;IC90) of AMG337. Surprisingly however, exogenous recombinant human HGF enables resistance to readily appear, with emergent cultures possessing resistance mutations in the MET activation loop at positions D1228 and Y1230. Phosphoprotein analysis shows that HGF increases autophosphorylation and activation of mutant MET sufficiently to drive cell proliferation even in the presence of AMG337.Notably, deep sequencing and clonal analysis of individually barcoded cells show that pre-existing mutant clones are likely present in cultures prior to drug treatment. However, such clones are unable to robustly proliferate in drug-containing media unless HGF is present. Based on copy number analysis, we propose that a single or small number of pre-existing mutant MET alleles in an individual cell is sufficient to drive resistance in the presence of exogenous HGF. In contrast, in HGF-negative media, a single mutant MET allele is insufficient and thus resistance does not readily arise unless gradual drug dose escalation protocols that select for increased mutant MET copy number are employed.Our results identify a key mechanism by which HGF can promote resistance to MET inhibitors in MET-amplified cancer cell lines. Because HGF is present in tumor microenvironments, combining anti-HGF antibodies with maximally-tolerated doses of small molecule MET inhibitors such as AMG337 may be beneficial in preventing resistance and in promoting durable responses.
Citation Format: Marcia Gordon, Alexandra Croft, Chi-Ming Li, Sean Taylor, Sean R. Caenepeel, Kim Quon. HGF promotes resistance to MET inhibitor AMG337 in MET-amplified gastric cancer cells. [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-241. doi:10.1158/1538-7445.AM2015-LB-241
Abstract LB-248: Protein arginine methyltransferase 5 (PRMT5) inhibition as a therapeutic strategy in B-cell lymphoma
Authors: Barbash Olena , Gerhart Sarah , Soong David , Thompson Christine , Montes de Oca Rocio , Zhang Ping , McHugh Charles , Kuplast Kristy , Majer Christina , Chesworth Richard , Smith Jesse , Copeland Robert , Penebre Elayne , Duncan Kenneth , Johnson Neil , Carpenter Chris , Kruger Ryan 
Published: August 2015

Abstract
PRMT5 is responsible for symmetric dimethylation of arginine residues in glycine and arginine rich (GAR) motifs on a variety of cytosolic and nuclear proteins including histones, spliceosome components, regulators of translation, transcription factors, kinases and others. PRMT5 driven methylation of some of these proteins has been implicated in tumorigenesis. For example, PRMT5 deposits repressive marks on histones and silences a subset of tumor suppressor genes, such as RB and ST7. PRMT5 methylation of non-histone substrates (such as E2F1 and p53) also contributes to cancer cell growth and death. PRMT5 driven methylation of spliceosome subunits and components of translational machinery has been well described but its connection to PRMT5's role in cancer has not been established. We have identified first-in-class small molecules that are highly potent, selective, reversible inhibitors of PRMT5. Cellular mechanistic studies revealed that PRMT5 inhibition decreases symmetric arginine dimethylation on a variety of cellular proteins including spliceosome components, histones and transcription factors. PRMT5 inhibition leads to gene expression and splicing changes ultimately resulting in the induction of p53 in lymphoma cell lines. In addition to impacting the p53 pathway, PRMT5 inhibition leads to attenuation of the expression of cell cycle related genes, genes involved in ribosome and spliceosome homeostasis, as well as genes important for cellular metabolism. PRMT5 inhibitor attenuates proliferation and induces cell death in a subset of mantle cell and diffuse large B-cell lymphoma cell lines and inhibits tumor growth in xenograft models of mantle cell lymphoma. These data underline the potential of PRMT5 inhibitors as a therapeutic strategy in mantle cell and diffuse large B-cell lymphoma.
Citation Format: Olena Barbash, Sarah Gerhart, David Soong, Christine Thompson, Rocio Montes de Oca, Ping Zhang, Charles McHugh, Kristy Kuplast, Christina Majer, Richard Chesworth, Jesse Smith, Robert Copeland, Elayne Penebre, Kenneth Duncan, Neil Johnson, Chris Carpenter, Ryan Kruger. Protein arginine methyltransferase 5 (PRMT5) inhibition as a therapeutic strategy in B-cell lymphoma. [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-248. doi:10.1158/1538-7445.AM2015-LB-248
Abstract LB-254: High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism
Authors: Bunch Kristen , Goldlust Ian , Thomas Craig , Hernandez Lidia , Guha Rajarshi , Annunziata Christina 
Published: August 2015

Abstract
Background: Inhibitors of apoptosis (IAPs) are attractive anti-cancer therapeutic targets as a mechanism to sensitize cancer cells to apoptosis. IAPs are overexpressed in ovarian cancer and portend a poor prognosis. SMAC- mimetics are IAP antagonists that have shown in vitro and in vivo antitumor activity in ovarian cancer, but preclinical and clinical studies suggest SMAC mimetics may be more effective in combination therapies.
Methods: Birinapant (B) was initially screened in combination with each of 1,912 compounds using an automated acoustic drug dispensation system in 6×6 matrices. Seventy compounds were chosen from the initial screen, based on synergistic characteristics, and verified in 10×10 matrices. The most clinically rational drug combinations with B were further evaluated in 8 high-grade serous ovarian cancer cell lines (CAOV3, CAOV4, OV-90, OVCAR4, OVCAR5, OVCAR8, PEO1, PEO4), focusing on 3 synergistic (docetaxel, panobinostat, volasertib) and 2 antagonistic combinations (cisplatin, olaparib) for exploration of mechanism. Combination index was determined using Compusyn software.
Results: Specific classes of drugs were identified to have synergism with B, including taxanes, HDAC inhibitors, and PLK1 inhibitors, while platinum agents and PARP inhibitors were found to be antagonistic. Four of the 8 cell lines were sensitive to B. Caspase-Glo 3/7 assay was performed in B-sensitive cell lines and confirmed increased caspase-3 activity in the combination treatments. Ongoing studies include genomic analysis, mechanistic interrogation, and in vivo xenograft studies.
Conclusions: B is a promising novel therapy for use in combination treatment for ovarian, fallopian tube, or primary peritoneal cancers. Our findings provide insight on optimal therapies to combine with B, and constitute a foundation for further evaluation of predictive and pharmacodynamic biomarkers to select the patient population most likely
to respond to this targeted therapeutic approach.
Citation Format: Kristen Bunch, Ian Goldlust, Craig Thomas, Lidia Hernandez, Rajarshi Guha, Christina Annunziata. High-throughput drug matrix screen with SMAC (second mitochondria-derived activator of caspases)-mimetic birinapant in high-grade serous ovarian cancer cell lines identifies synergism. [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-254. doi:10.1158/1538-7445.AM2015-LB-254
Abstract LB-268: Black rapsberries induced protection in pancreatic cancer mouse models
Authors: Pan Pan , Skaer Chad , Wang Hsin Tzu , Tsai Susan , Oshima Kiyoko , Huang Yi-Wen , Stoner Gary , Lechner John , Wang Li-Shu 
Published: August 2015

Abstract
Backgrounds and objectives Pancreatic ductal adenocarcinoma (PDAC) is the 12th most common cancer worldwide with 338,000 new cases diagnosed in 2012. The estimated 5-year survival rate of diagnosed PDAC patients is less than 4%, making it the 7th leading cause of cancer death. Over-expression of epidermal growth factor (EGF) receptors and ErbB2 receptors has been associated with the development and progression of human PDAC. Diets rich in fruits and vegetables have been reported to reduce the risk of PDAC incidence and its recurrence. Our current study aimed to investigate the effects of dietary black raspberries (BRBs) on pancreatic carcinogenesis..
Methods 4-5 weeks old pancreas-specific (Pdx-1-cre) mutant mice that carry constitutively-activated oncogene K-ras (G12D) and loss-of-function tumor-suppressor gene Trp53 (R172H), hereafter refers to KPC mice, were fed with control (n = 26) or 5% BRB (n = 29) diet. In addition, orthotopic pancreatic cancer xenografts were injected with luciferase transfected human Panc-1 cells. Four weeks after Panc-1 cells were injected, these mice were given control (n = 8) or 5% BRB (n = 19) diet for 6 weeks.
Results Kaplan-Meier survival analysis showed that BRBs prolonged survival of KPC mice with a medium survival of 124 days in comparison to 79 days from mice fed with control diet (p = 0.03). Molecular studies suggest that BRBs decreased the activation of EGF receptor and ErbB2 receptor signaling pathways. Further, BRBs significantly suppressed growth of Panc-1 tumors and it was associated with decreased EGF receptor activation.
Conclusion These results suggest that BRBs might protect against carcinogenesis of PDAC through regulating EGF receptor and ErbB2 receptor signaling pathways. Further investigation of the downstream pathways of EGF receptor and ErbB2 receptor activation is warranted.
Citation Format: Pan Pan, Chad Skaer, Hsin Tzu Wang, Susan Tsai, Kiyoko Oshima, Yi-Wen Huang, Gary Stoner, John Lechner, Li-Shu Wang. Black rapsberries induced protection in pancreatic cancer mouse models. [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-268. doi:10.1158/1538-7445.AM2015-LB-268
Abstract LB-275: Beneficial regulation of metabolic profiles by black raspberries in human colorectal cancer patients
Authors: Pan Pan , Skaer Chad , Stirdivant Steven , Young Matthew R. , Stoner Gary , Lechner John , Huang Yi-Wen , Wang Li-Shu 
Published: August 2015

Abstract
Objectives: Dietary intervention of freeze-dried black raspberries (BRBs) in a group of human colorectal cancer patients has demonstrated beneficial effects, including pro-apoptosis, anti-proliferation and anti-angiogenesis. The aim of this study was to investigate BRB-mediated metabolite changes from this same cohort of patients.
Methods: 28 colorectal cancer patients were given 60 g BRB powder daily for 1-9 weeks. Urine and plasma specimens were collected before and after BRB intervention. A comprehensive mass spectrometry-based nontargeted metabolomic analysis was conducted on each specimen.
Results: A total of more than 400 metabolites were annotated in each specimen. Of these 69 and 58 metabolites were significantly changed by BRBs in urine and plasma, respectively. An increased level of 4-methylcatechol sulfate was correlated with a higher apoptotic marker (TUNEL) in post-BRB tumors, while a decreased level of N-acetylglycine was correlated with a lower cell proliferation marker (Ki67) in post-BRB tumors. Cis-aconitate and isocitrate, two tricarboxylic acid (TCA) cycle metabolites, were increased in post-BRB urine. Fatty acid β-oxidation and synthesis were decreased in post-BRB plasma. In addition, BRB-derived polyphenols were absorbed and metabolized to various benzoate species, which were significantly increased in post-BRB specimens. Increased benzoate levels were positively correlated with enhanced amino acid and carbohydrate metabolism but were negatively correlated with decreased fatty acid metabolism.
Conclusion: These results suggest that BRBs may induce systemic changes that affect energy generating pathways. This study supports the hypothesis that BRBs might be beneficial to colorectal cancer patients through altering multiple intrinsic metabolic pathways.
Citation Format: Pan Pan, Chad Skaer, Steven Stirdivant, Matthew R. Young, Gary Stoner, John Lechner, Yi-Wen Huang, Li-Shu Wang. Beneficial regulation of metabolic profiles by black raspberries in human colorectal cancer patients. [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-275. doi:10.1158/1538-7445.AM2015-LB-275
Abstract LB-295: Analysis of miR-21 isomiRs in lung cancer
Authors: Leikin Jennie D. , Zingone Adriana , Brown Derek , Mitchell Khadijah , Khan Mohammed , Vidal Oscar , Ryan Brid 
Published: August 2015

Abstract
microRNAs (miRNA) are small non-coding RNAs that target mRNA transcripts. Primarily, they bind to the 3′UTR of mRNA sequences and repress protein translation. They are involved in the regulation of over 60% of human genes. miRNAs are deregulated in cancer and expression signatures have been correlated with cancer diagnosis, progression and prognosis. Thus, they are being pursued for clinical application. isomiRs, or miRNA variants that are generated post-transcriptionally, were originally classified as experimental error in cloning and next generation sequencing studies. However, over the past five years it has become increasingly clear that isomiRs are evolutionarily conserved, prevalent and functional. miR-21 is overexpressed and associated with poor prognosis in multiple malignancies and as such it is currently under development as a therapeutic target. Thus, we examined the isomiR landscape of miR-21 in lung cancer using data from The Cancer Genome Atlas (lung adenocarcinoma n = 420 and squamous cell carcinoma n = 296). Raw sequence files were extracted from TCGA, cleaned and analyzed using STATA 13. We observed that there are significantly more isomiRs of miR-21 in both lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) compared to non-involved adjacent lung tissue. Specifically, LUAD had total of 244 5p variants and LUSC had 232 5p variants, compared with 74 and 105 in non-involved tissue, respectively. The most prevalent isomiR of miR-21 was not the canonical ‘miRBase’ isomiR and the most common edit was a 5′ deletion with 3′ addition. There were 15 miR-21-5p isomiRs in LUAD and 12 in LUSC that were prevalent (defined as detected in more than 50% of patients) and were expressed at a significantly higher level defined as detected with a FPKM value greater than 50) in tumor versus non-involved tissue samples. The average fold change was 5.7 in LUAD (range 2.8-21.1) and 2.7 in LUSC (range 1.7-5.6). Of the prevalent miR-21-5p isomiRs, 6 in LUAD and 4 in LUSC had a change in the canonical miR-21 seed sequence. An analysis of the targets of these isomiRs using the target prediction algorithms Targetscan and Diana revealed limited overlap in gene targets (0% to 54%) compared with canonical miR-21-5p targets. Our work highlights a high complexity of miRNA sequence heterogeneity in lung cancer. Combining the characterization of miR-21 isomiRs and pursuing translational laboratory studies will allow us to determine the functionality of these isomiRs and their relevance for human cancer diagnosis and treatment.
Citation Format: Jennie D. Leikin, Adriana Zingone, Derek Brown, Khadijah Mitchell, Mohammed Khan, Oscar Vidal, Brid Ryan. Analysis of miR-21 isomiRs in lung cancer. [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-295. doi:10.1158/1538-7445.AM2015-LB-295
Abstract PL02-03: Early detection and prevention of liver cancer: Leveraging lessons learned from liver repair
Authors: Diehl Anna Mae E. 
Published: August 2015

Abstract
Liver cancer is currently among the top causes of cancer mortality worldwide and is increasing in both incidence and prevalence.The fact that cirrhosis is the strongest known risk factor for primary liver cancer suggests that injured liver is carcinogenic. The presentation will summarize evidence indicating that liver injury is carcinogenic because it stimulates regenerative responses (e.g., activation of developmental morphogenic signaling pathways) that relax forces which normally constrain the inherent multi-potency of adult liver cells. There are two main take-home messages. First, cirrhosis reflects defective regulation of these normal regenerative responses and thus, sustained tissue enrichment with permissive signals for multi-potency. Second, this cirrhotic microenvironment is particularly advantageous for liver cells with epistatic genetic/epigenetic events which enable escape from counter-regulatory signals that antagonize multi-potency.
Citation Format: Anna Mae E. Diehl. Early detection and prevention of liver cancer: Leveraging lessons learned from liver repair. [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 PL02-03. doi:10.1158/1538-7445.AM2015-PL02-03