bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-002: A novel c-Met/EGFR bispecific targeting antibody drug conjugate for NSCLC
Authors: Chen Gang , Li Lingna , Muyot Pia , Gros Edwige , Zhang Yanliang , Sun Yingqing , Zhang Hong , Fu Yanwen , Lee Alice , Cao Jian , Kaufmann Gunnar , Miao Zhenwei 
Published: August 2015

Abstract
c-Met and EGFR are both widely and highly expressed, share and cross talk common signaling pathways in a variety of carcinomas including lung, breast, ovary, kidney, colon, thyroid, liver, and gastric carcinomas. Therapeutics like tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, targeting EGFR and c-Met are on the cutting-edge of cancer therapy. In preclinical studies and clinical trials, though these anti-c-Met and EGFR therapeutics showed promising anti-tumor activities but usually not sufficient for sustained treatment efficacy, their individual efficacies are limited due to the development of resistance. c-Met amplification has been considered to be a major escape route for EGFR-targeted therapies. We believe that antibody drug conjugates (ADCs) offer the promise and potential of delivering potent anti-tumor activity with the advantage of reduced side effects. We generated a novel bispecific antibody drug conjugate containing a proprietary human anti-c-Met antibody and anti-EGFR antibody, and a potent toxin by our novel C-lock conjugation method. The conjugate retained high binding affinity and targeting both c-Met and EGFR on tumor cell surface. The ADC showed potent cell killing in a lower nM range in a variety of c-Met and EGFR positive cell lines in vitro and strong in vivo anti-tumor efficacy in several c-Met and EGFR positive human NSCLC xenograft models without significant toxicity. The in vivo anti-tumor growth efficacy of bispecific c-Met/EGFR targeting antibody conjugates is superior to either single anti-c-Met or EGFR ADC.
Citation Format: Gang Chen, Lingna Li, Pia Muyot, Edwige Gros, Yanliang Zhang, Yingqing Sun, Hong Zhang, Yanwen Fu, Alice Lee, Jian Cao, Gunnar Kaufmann, Zhenwei Miao. A novel c-Met/EGFR bispecific targeting antibody drug conjugate for NSCLC. [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-002. doi:10.1158/1538-7445.AM2015-LB-002
Abstract LB-006: Receptor tyrosine kinase EphA5 is a functional molecular target in human lung cancer
Authors: Staquicini Fernanda , Dobroff Andrey , Ferrara Fortunato , D'Angelo Sara , Bradbury Andrew RM , Arap Wadih , Pasqualini Renata 
Published: August 2015

Abstract
The concept of targeted cancer therapy is predicated on the assumption that tumors have unique and sustained genetic abnormalities, and that direct targeting of such distinctive biological features can only be accomplished through the identification and validation of certain specific molecular markers. These principles are particularly relevant to lung cancer, the leading cause of cancer-related death worldwide. For patients with early-stage disease, surgical resection or primary radiotherapy are generally the standard treatments, whereas combined-modality therapy (radiation plus chemotherapy, with or without surgery) is preferred for locally advanced disease. However, most patients with lung cancer develop metastatic tumors and resistance to therapy, and ultimately die of their disease. Here, we identify EphA5 as a molecular target of lung cancer, and as a novel regulator of IR-induced cell cycle checkpoint and DNA damage repair, with unexpected roles in the resistance of lung cancer to radiotherapy. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ataxia-telangiectasia mutated (ATM) at sites of DNA repair. In addition, we produced a new monoclonal antibody against EphA5 that sensitizes lung cancer cells to IR in vitro and improves the overall survival of mice bearing human lung cancer xenografts in combination with radiation therapy. These findings present a readily available and potentially effective strategy for the detection and treatment of lung cancer.
Citation Format: Fernanda Staquicini, Andrey Dobroff, Fortunato Ferrara, Sara D'Angelo, Andrew RM Bradbury, Wadih Arap, Renata Pasqualini. Receptor tyrosine kinase EphA5 is a functional molecular target in human 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-006. doi:10.1158/1538-7445.AM2015-LB-006
Abstract LB-007: Synergistic inhibition of human gastric and colorectal cancers by Bromelain and N-acetylcysteine: An in vivo study
Authors: Amini Afshin , Masoumi-Moghaddam Samar , Ehteda Anahid , Liauw Winston , Akhter Javed , Pilai Krishna , Morris David L. 
Published: August 2015

Abstract
Mucin is well understood to be an adverse prognostic factor in some cancers. We previously reported that a combination of Bromelain (BR) and N-acetylcysteine (NAC) were synergistic in dissolving pseudomyxoma peritonei mucin, had direct in vitro cytotoxic effects on some gastrointestinal cancer cells and sensitized them to some chemotherapy agents. In the present study, we aimed to evaluate the growth-inhibitory effect of BR and NAC as single agent or combination therapy in nude mice models of gastrointestinal cancer.
Nude mice received 2 million and 1 million cells of MKN45 (gastric) and LS174T (colorectal) by intraperitoneal injection. At day 14 and 7 post inoculation for MKN45 and LS174T cells, respectively, animals were intraperitoneally administrated BR (3, 6 mg/kg), NAC (300, 500 mg/kg) or their combination every other day over 12 days for MKN45 and 17 days for LS174T models. At the end of the study, the animals were euthanized, the number of peritoneal nodules and their weight were collected, and the peritoneal tumors were subjected to immunohistochemistry for evaluation of MUC2.
No toxicity was observed during the experiment. At necropsy, highly significant reductions in the number of tumor nodules and tumor burden were observed, in particular in the combination group, where almost complete inhibition in LS174T group was found. There was more than 95% and 70% decreases in tumor burden and tumor nodules, respectively, in LS174T group after combination treatment. For MKN45 model, the reductions in tumor burden and tumor nodules in combination groups were more than 60% and 70%, respectively. Performing immunohistochemistry on tumor samples, MUC2 staining of the LS174T xenografts showed a greater than 60% reduction of cytoplasmic staining.
To the best of our knowledge, this is the first report of the in vivo use of this combination with synergistic inhibition of human gastric and colorectal cancers. The combination of BR and NAC in mucin secreting gastrointestinal tumors is interesting and could be of potential value in peritoneal cancer.
Citation Format: Afshin Amini, Samar Masoumi-Moghaddam, Anahid Ehteda, Winston Liauw, Javed Akhter, Krishna Pilai, David L. Morris. Synergistic inhibition of human gastric and colorectal cancers by Bromelain and N-acetylcysteine: An in vivo study. [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-007. doi:10.1158/1538-7445.AM2015-LB-007
Abstract LB-029: Signal transduction in EGFR-amplified and NFKBIA-deleted human gliomas
Authors: Mishra Alok , Kong Jun , Brat Daniel J. 
Published: August 2015

Abstract
Nuclear factor Kappa B (NF-κB)- a nuclear transcription factor that is retained in the cytoplasm by IKBα (encoded by NFKBIA)- is implicated as a mediator of aggressive behavior in all glioblastoma (GBM) subclasses. We are interested in elucidating molecular mechanisms that explain the relative mutual exclusivity of EGFR amplification and NFKBIA deletion in GBMs. Bioinformatics analysis of TCGA GBM data showed that NFKBIA hemizygous deletions were significantly depleted in samples with EGFR amplification (one-tailed p value of Fisher Exact test, P = 5.97e-4). Moreover, we showed by immunohistochemistry that IKBα was more highly expressed in EGFR-amplified than non-amplified GBMs. We use Ingenuity Pathway Analysis (IPA) to identify gene sets common to both EGFR amplification and NFKBIA hemizygous deletion to identity shared pathways that might explain mutual exclusivity and identified TNF, p53, PI3K, and NF-κB proliferation and apoptosis signaling pathways. We next genetically modeled glioma cell lines and GBM neurosphere cultures by transient transfection/stable viral transduction to recapitulate EGFR/NFKBIA combinations. qPCR of DNA and mRNA for EGFR and NFKBIA verified genotypes. Among the top hits predicted by our in silico studies, we identified sparcl1 and hgpx4 by RT-qPCR and immunoblots as concordantly upregulated in the EGFRamp/NFKBIA+/+ and EGFRnon-amp/NFKBIA+/- cell lines/neurospheres. We also showed differential DNA binding of NF-κB (by electro-mobility shift assay); target gene expression (eg. bcl-2, Il-6); and expression of upstream regulators of NF-κB pathways (viz. pAKT (S436) and IKKβ (Y466)) in GBM neurospheres with distinct EGFR/NFKBIA status. Moreover in U87MG cells (NFKBIA+/−), transiently silencing and overexpressing NFKBIA in different EGFR backgrounds (non-amplified and amplified) led to activation of PARP-dependent but caspase-3-independent apoptotic pathways. Interestingly, in U87MG cells and HPV E6/E7 transformed astrocytes, Annexin V/PI based FACS experiments indicated that NFKBIA overexpression suppressed necrosis. These data demonstrate a complex interplay of EGFR and IKBα/NF-κB in GBMs and identify shared pathways that might explain the relative mutual exclusivity of EGFR amplification and NFKBIA deletion.
Citation Format: Alok Mishra, Jun Kong, Daniel J. Brat. Signal transduction in EGFR-amplified and NFKBIA-deleted human gliomas. [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-029. doi:10.1158/1538-7445.AM2015-LB-029
Abstract LB-036: Neuronal activity-regulated secretion of neuroligin-3 promotes glioma growth
Authors: Venkatesh Humsa , Johung Tessa , Caretti Viola , Mallick Parag , Monje Michelle 
Published: August 2015

Abstract
Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). We demonstrate that active neurons similarly promote HGG proliferation and growth in vivo using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma orthotopic xenograft model. Activity-regulated mitogen(s) are secreted, as the conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures. The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen; soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feed-forward expression of NLGN3 in glioma cells, providing mechanistic insight into its surprising role as a mitogen. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.
Citation Format: Humsa Venkatesh, Tessa Johung, Viola Caretti, Parag Mallick, Michelle Monje. Neuronal activity-regulated secretion of neuroligin-3 promotes glioma growth. [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-036. doi:10.1158/1538-7445.AM2015-LB-036
Abstract LB-052: Kinase identification of proximal substrates (KIPS): A novel chemical genetics approach for kinase substrate identification
Authors: roffey jon , Turnbull Andrew , Dillon Christian , Boyd Susan , Riou Philippe , Linch Mark , Parker Peter , Kjaer Sven , McDonald Neil 
Published: August 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
Abstract LB-110: Expression of multiple androgen receptor splice variants in late stage prostate cancer
Authors: Ghazoui Zara , Jones Emma , Veldman-Jones Margaret , Jacobs Vivien N. , Smith Neil R. , Johnstone Michele , Barrett J. Carl , Harrington Elizabeth A. , Elvin Paul 
Published: August 2015

Abstract
The androgen receptor (AR) remains a key driver of disease progression even with the advent of new therapeutic agents such as abiraterone (A) and enzalutamide (E). Relapse after treatment with A or E has been associated with the emergence of tumour cells expressing AR splice variants, and at least one mutation in AR has been associated with resistance to E. We have investigated the expression of AR splice variants in late stage prostate cancers using Nanostring (nCounter®) to quantify the levels of AR transcripts and by IHC using antibodies targeting the N- and C-terminal AR domains. We also examined the expression of putative AR regulated genes found to be expressed in prostate cancer reported in publically available expression data.
Formalin fixed paraffin embedded tissue from 38 commercially sourced (TriStar Technology Group; Asterand; Avaden Biosciences) late stage prostate cancers including 10 castrate resistant prostate cancers (CRPC), were confirmed by pathology review. Total mRNA was isolated from a single 5μm section and gene expression from nCounter® analysis was expressed as normalised Log2 values. Immunohistochemical analysis of AR expression was determined by a pathologist using a H score.
Our analysis of AR splice variant expression, relative to a Nanostring detection threshold based on housekeeping genes, has shown the presence of more than one constitutively active AR splice variant in individual tumours. ARV7 was detected in 4/10 CRPC and always found together with ARV1, AR45, and the constitutively active ARV12. All of the CRPC that were negative for ARV7 expressed AR45 and ARV12. Unsupervised clustering of 507 putative AR regulated genes revealed three molecular subgroups among the 38 prostate tumours. One of these subgroups was characterised by the presence of 12/14 AR splice variants including ARV7. Of the other two subgroups, one contained AR45, the other ARV12. Pathway analysis of genes that were expressed to a higher level (&gt;1.5 Log2 fold) in the ARV7 positive compared to ARV7 negative tumours were predominantly associated with cell cycle and proliferation functions.
Our data suggests complexity in the molecular landscape of prostate cancer associated with AR splice variants, and that multiple AR splice variants may be of importance to identify patients likely to relapse on treatment with emerging therapy.
Citation Format: Zara Ghazoui, Emma Jones, Margaret Veldman-Jones, Vivien N. Jacobs, Neil R. Smith, Michele Johnstone, J. Carl Barrett, Elizabeth A. Harrington, Paul Elvin. Expression of multiple androgen receptor splice variants in late stage prostate 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-110. doi:10.1158/1538-7445.AM2015-LB-110
Abstract LB-121: Identification of Carboxylesterase-2 as a determinant of response to irinotecan and neoadjuvant FOLFIRINOX therapy in pancreatic ductal adenocarcinoma
Authors: Capello Michela , Lee Minhee , Wang Hong , Babel Ingrid , Katz Matthew H. , Fleming Jason B. , Maitra Anirban , Wang Huamin , Tian Weihua , Taguchi Ayumu , Hanash Samir M. 
Published: August 2015

Abstract
Background: Serine hydrolases (SHs) are among the largest classes of enzymes in human and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the pro-drug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. Methods: CES2 expression in PDAC and paired non-tumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. Results: Significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared to paired non-tumor tissue (P &lt; .0001), with 48/118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in PDAC cell lines was inversely correlated with irinotecan IC50 values (P = .021), while no molecule involved in irinotecan metabolism yielded a significant correlation between its expression and sensitivity to the drug. Remarkably, we recently found that high CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (P = .024). Conclusion: Our findings suggest that CES2 expression and activity, by mediating the intra-tumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.
Citation Format: Michela Capello, Minhee Lee, Hong Wang, Ingrid Babel, Matthew H. Katz, Jason B. Fleming, Anirban Maitra, Huamin Wang, Weihua Tian, Ayumu Taguchi, Samir M. Hanash. Identification of Carboxylesterase-2 as a determinant of response to irinotecan and neoadjuvant FOLFIRINOX therapy in pancreatic ductal adenocarcinoma. [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-121. doi:10.1158/1538-7445.AM2015-LB-121
Abstract LB-126: Declining T levels provide increased opportunity for mutagenesis in prostate stem cells
Authors: Zhou Ye , Jones Jeremy 
Published: August 2015

Abstract
Because both normal prostate development and the growth of prostate cancers depend on androgen-mediated activation of androgen receptor (AR) signaling, it is reasonable to hypothesize that androgens and AR signaling play a role in prostate tumor initiation as well; however, little is known about androgens and AR in this process. We hypothesize that the decline in androgen production that occurs naturally with age contributes directly to tumorigenesis. Previously, we showed that low serum testosterone (T) causes changes in the expression of genes in the androgen/AR signaling axis which allows the prostate tissue to sustain functional androgen levels in rodents. These changes may contribute to prostate tumorigenesis. There is ongoing debate concerning the cell of origin for prostate cancer, but most evidence would suggest that it can arise from stem cells or cells with stem-like features. Here, we used a murine model to manipulate serum androgen levels to assess the changes in prostate stem-like cells in response to low serum T and to investigate the potential mechanisms by which androgens and AR contribute to prostate tumorigenesis. Using flow cytometry, we observed that chronic exposure to low T causes a consistent expansion of prostate stem-like cell populations, including Lin-/CD133+/CD117+ cells (from 0.23% to 0.33%), Lin-/CD49fHigh/Trop2+ cells (from 6.47% to 8.42%) and intermediate CK5+/CK8+ cells (from 0.43% to 1.26%). Using an in vitro sphere forming assay, we found that stem-like cells isolated from low T treated animals had an increased ability to form spheres, suggesting that low T increases self-renewal capacity. We are currently testing the ability of low T to increase self-renewal capacity in rodent models. Using qPCR, we found that low T causes changes in the expression of genes in the androgen/AR signaling pathway as well as in the oxidative stress response in stem-like cells. We are currently using RNA-seq to understand on a global scale the changes that chronic low T exposure causes in these stem-like cells. Our studies suggest that chronic exposure to low T, as is the case in older men, could provide a greater opportunity for damage to cells that can become cancer initiating cells.
Citation Format: Ye Zhou, Jeremy Jones. Declining T levels provide increased opportunity for mutagenesis in prostate stem 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-126. doi:10.1158/1538-7445.AM2015-LB-126