bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-277: Four noval activating and resistance mutations of EGFR drug response targets were discovered in northern Chinese patients
Authors: Tian Geng 
Published: July 2017

Abstract
Background and Objective: Lung cancer is the most rapidly developed cancer in terms ofmorbidity and fatality rate. The presence of EGFR mutations is a useful tool to determine NSCLC patients' prognosis. But there are differences in Eastern Asian and European and American. The aim of this study is to discoveryand validate the new EGFR drug targets in Northern Chinese patients with non-small cell lung cancer (NSCLC) via bioinformatics analysis, molecular biology experiments and clinical outcomes, and raise new possibilities for designing personalized treatments for patients carrying specific mutations.
Methods: In this study, a new computational method and drug model was firstly established by referring to the HotSpot3D[1], which was applied to process mutagenesis data and identify new drug targets. We subsequently applied the computationaltool to more than 500 tumors of NSCLC patients in North China.The captured target DNAs were analyzed by next-generation sequencing using a nine gene lung cancer panel to find somatic variations. We then validated our predictions in cell-line-based experimental combining the results of the clinical follow-up.
Results: We used a new computational tool to analyze more than 500 tumors data of NSCLC patients in North China, discovering several rarely reported druggable mutations, including EGFR mutations (p.Val742Ile, p.Ile789Met, p.Asn842His) with erlotinib, gefitinib, lapatinib and EGFR mutations (p.Ser811Cys) with afatinib. Furthermore, we performed an experiment examining the sensitivity of the EGFR proteins with these variants to the target drugs mentioned above. We found that EGFR with the p.Ile789Metvariant was sensitive to gefitinib, consistent with a previous report [1]. In parallel, of the 500NSCLC patients, 200 were treated with the above targetdrugs, and clinical outcomes of treated patients were collected. The results were consistent with the cell-line-based experiments. Verification of other EGFR variants is still in progress.
Conclusion: In this study, severalnew EGFR druggable mutations were for the first time found and validated in NorthernChinese patients with non-small cell lung cancer (NSCLC). Our results will provide better treatment options for patients carryingthese specific mutations. [1] Niu B, Scott A D, Sengupta S, et al. Protein-structure-guided discovery of functional mutations across 19 cancer types[J]. Nature Genetics, 2016, 48(8).
Citation Format: Geng Tian. Four noval activating and resistance mutations of EGFR drug response targets were discovered in northern Chinese patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-277. doi:10.1158/1538-7445.AM2017-LB-277
Abstract LB-278: Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component
Authors: Avigdor Bracha E. , Beierl Katie , Gocke Christopher D. , Zabransky Daniel J. , Cravero Karen , Kyker-Snowmana Kelly , Button Berry , Chu David , Croessmann Sarah , Cochran Rory L. , Connolly Roisin M. , Park Ben H. , Cimino-Mathews Ashley , Wheelan Sarah J. 
Published: July 2017

Abstract
Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma. Metaplastic breast carcinoma is a rare but aggressive cancer with a heterogenous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or in situ mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer, or one histology as a clonal outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in eight patients and created a pipeline to identify somatic variants and predict their functional impact in these samples, without having matched normal tissue. We then determined the genetic relationships between the histologically distinct compartments. In each case, the tumor components have nearly identical landscapes of somatic variation, implying that the differing histologies do not derive from genetic clonal divergence, suggesting that epigenetic or noncoding changes mediate the metaplastic phenotype. This indicates that alternative therapeutic approaches, including epigenetic therapies, may render metaplastic breast cancers susceptible to current and future therapies.
Citation Format: Bracha E. Avigdor, Katie Beierl, Christopher D. Gocke, Daniel J. Zabransky, Karen Cravero, Kelly Kyker-Snowmana, Berry Button, David Chu, Sarah Croessmann, Rory L. Cochran, Roisin M. Connolly, Ben H. Park, Ashley Cimino-Mathews, Sarah J. Wheelan. Whole exome sequencing of metaplastic breast carcinoma indicates monoclonality with associated ductal carcinoma component [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-278. doi:10.1158/1538-7445.AM2017-LB-278
Abstract LB-300: In vivo evaluation of the intravenous MDM2-p53 antagonist RO6839921 alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma
Authors: Chen Lindi , Pastorino Fabio , Berry Philip , Bonner Jennifer , Wood Katrina , Veal Gareth , Ponzoni Mirco , Lunec John , Newell David R. , Tweddle Deborah A. 
Published: July 2017

Abstract
Background. Neuroblastoma is a predominantly TP53 wt tumor which supports the use of MDM2-p53 antagonists as a novel therapy for neuroblastoma patients. This is the first study to evaluate the efficacy of RO6839921, an IV prodrug of RG7388, alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma.
Methods. Studies were conducted using a well-established orthotopic model of neuroblastoma, implanted with SHSY5Y-Luc (TP53 wt; non-MYCN amplified) and NB1691-Luc (TP53 wt; MYCN and MDM2 amplified) cells, and randomized into control, intravenous RO6839921, oral temozolomide or RO6839921 and temozolomide in combination. Tumor growth was monitored using bioluminescence imaging. Active RG7388 in plasma and tumor samples were detected using liquid chromatography-mass spectrometry, and p53 pathway activation assessed by MIC-1 ELISA assays, Western analysis and/or immunohistochemistry for p53, p21 and cleaved caspase 3.
Results. Pharmacokinetic and pharmacodynamic analysis of RO6839921 observed peak plasma levels of active RG7388 at 1h posttreatment with maximal activation of the p53 pathway observed 3-6h posttreatment. RO6839921 had a favorable pharmacodynamic profile consistent with intermittent dosing. Assessment of anti-tumor efficacy demonstrated that RO6839921 was as effective as temozolomide and that RO6839921 in combination with temozolomide led to significantly greater tumor growth inhibition and survival than either agent given alone. RO6839921 alone and in combination with temozolomide was well tolerated.
Conclusions. These preclinical studies support the evaluation of combining RO6839921 with temozolomide in early phase clinical trials of neuroblastoma patients with wt TP53.
Citation Format: Lindi Chen, Fabio Pastorino, Philip Berry, Jennifer Bonner, Katrina Wood, Gareth Veal, Mirco Ponzoni, John Lunec, David R. Newell, Deborah A. Tweddle. In vivo evaluation of the intravenous MDM2-p53 antagonist RO6839921 alone and in combination with temozolomide in TP53 wild-type orthotopic models of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-300. doi:10.1158/1538-7445.AM2017-LB-300
Abstract LB-307: Dissecting mutual exclusiveness of oncogenic mutations in melanoma
Authors: Kumar Raj , Njauw Ching-Ni-Jenny , Ji Zhenyu , Rajadurai Anpuchchelvi , Tsao Hensin 
Published: July 2017

Abstract
Mutual exclusiveness of oncogenes is a general phenomenon in cancer. Specifically in melanoma BRAF and NRAS mutations do not co-exist except a few (0.7%) cases. Here, we are looking for critical exclusive common target(s) of BRAF and NRAS mutations meant for synthetic lethality in melanoma therapy. To specifically evaluate BRAF and NRAS mutation dependent gene regulation in melanoma, mRNA microarray gene expression analysis was performed in melanoma cell lines where growth suppressive and non-suppressive properties depend on mutual targets of BRAFV600E and NRASQ61R/K mutation. We identified the tumor suppressor gene SPRY4 as a novel transcriptional target of second oncogenes BRAFV600E or NRASQ61R/K responsible for suppressive growth phenotype in various melanoma cell lines. Sprouty4 (SPRY4) acts as a feedback suppressor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. It has a role in the regulation of cell growth, motility and progression of various cancer types’ breast cancer, osteosarcoma, endometrial adenocarcinoma, myeloid leukemia including melanoma. Remote inducible expression of either BRAFV600E or NRASQ61R/K enhances the expression of SPRY4 at mRNA and protein level only in poor growth cell lines such as NRASQ61R (Tet-On BRAFV600E: SKmel119, WM1361 and BRAFV600E (Tet-On NRASQ61R: Gmel and MGH-CH-1) but not in NRASQ61R (Tet-On BRAFV600E: SKmel-63), BRAFV600E (Tet-On NRASVQ61R: A375) mutation. In addition, we observed that BRAFV600E expression exhibit constitutive activation of stress pathway signaling that is presumed to induce secondary senescence, as it does in nevi or normal cells. SPRY4 modify second oncogene induced changes such as inhibition of SPRY4 rescues cell growth impaired by BRAF or NRAS mutation expression. Hence, second oncogene enhances SPRY4 expression in part through stress pathway as confirmed by phospho kinase array. These findings suggest that in SPRY4/MAPK/Stress pathway, SPRY4 as a common target of BRAF and NRAS mutations affecting melanoma growth.
Citation Format: Raj Kumar, Ching-Ni-Jenny Njauw, Zhenyu Ji, Anpuchchelvi Rajadurai, Hensin Tsao. Dissecting mutual exclusiveness of oncogenic mutations in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-307. doi:10.1158/1538-7445.AM2017-LB-307
Abstract LB-311: Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor
Authors: Rice James M. , Rogers Michael S. , Zetter Bruce R. 
Published: July 2017

Abstract
The protein-protein interaction (PPI) between the tumor suppressor antizyme (AZ) and its endogenous regulator antizyme inhibitor (AZIN) has recently been demonstrated to be important in several human cancers. AZIN siRNA treatment reduces AZIN expression and slows prostate cancer cell growth in vitro and in vivo but is not currently a viable therapeutic strategy. To further probe the AZ/AZIN PPI and to screen for potential small molecule inhibitors, we have developed a FRET assay (Z score &gt;0.7) utilizing the Clover (donor) and mRuby2 (acceptor) fluorescent proteins linked to AZIN and AZ, respectively. An alanine mutant screen of 43 amino acid positions in the AZIN protein revealed 2 hotspots that dramatically affect the affinity for the AZ protein, thereby identifying key regions for disruption by potential therapeutics. Furthermore, mutating the N327 and Y331 positions in ornithine decarboxylase (ODC) to equivalent residues in the homologous AZIN protein, increased the affinity of ODC for AZ, providing evidence for key residues that contribute to AZ/AZIN PPI. In addition, the S367G AZIN mutation, which is associated with an mRNA editing event in hepatocellular carcinoma, further increases the affinity of AZIN for AZ and supports a mechanism of AZ sequestration as an important driver in cancer cell growth. Taken together, this data expands our current understanding of the contribution of different amino acid residues to the AZ/AZIN binding interaction. The development of small molecule inhibitors to target these regions of the AZIN protein would rescue the tumor suppressive activity of AZ and present a novel therapeutic opportunity for the treatment of prostate cancer and hepatocellular carcinoma.
Note: This abstract was not presented at the meeting.
Citation Format: James M. Rice, Michael S. Rogers, Bruce R. Zetter. Characterization of the antizyme/antizyme inhibitor protein-protein interaction using a novel FRET sensor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-311. doi:10.1158/1538-7445.AM2017-LB-311
Abstract LB-312: Breast cancer targeting by theranostic gold nanorods
Authors: Jenkins Samir V. , Nima Zeid A. , Vang Kieng B. , Nedosekin Dmitry , Zharov Vladimir P. , Griffin Robert J. , Biris Alexandru S. , Dings Ruud P. 
Published: July 2017

Abstract
An ongoing need for new cancer therapeutics exists, especially ones that specifically home and target triple negative breast cancer (TNBC) tumors. Because TNBC does not express estrogen, progesterone, or Her2/Neu receptors, another target must be used for advanced drug delivery strategies. Here, we engineered a nanodrug delivery system consisting of silver-coated gold nanorods targeting EpCAM and loaded with doxorubicin. This novel nanodrug system, EpCAM-AuNR/Ag/Dox, was found to specifically target EpCAM-expressing tumor cells compared to low EpCAM-expressing tumors. Namely, the system had an inhibiting cell viability effective dose (ED50) of 3μM on 4T1 cells and an ED50 of 110μM for MDA-MD-231 cells. Flow cytometry indicated that 4T1 cells, on average, express two orders of magnitude more EpCAM than MDA-MD-231 cells, which correlates with our ED50 findings. Moreover, due to its thin silver coating, the AuNR/Ag allowed for detection by surface-enhanced Raman spectroscopy (SERS) and photoacoustics (PA). Analysis by both imaging detection techniques showed that the targeted nanodrug system was taken up by EpCAM-expressing cells and tumors at significantly higher rates than untargeted nanoparticles (p&lt;0.05). In conclusion, our novel approach establishes a plasmonically-active nanodrug therapeutic system for TNBC and, potentially, a delivery system with improved multimodal imaging capability for other clinically approved chemotherapeutics with dose-limiting toxicities, such as platinum-based or taxane-based therapies.
Citation Format: Samir V. Jenkins, Zeid A. Nima, Kieng B. Vang, Dmitry Nedosekin, Vladimir P. Zharov, Robert J. Griffin, Alexandru S. Biris, Ruud P. Dings. Breast cancer targeting by theranostic gold nanorods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-312. doi:10.1158/1538-7445.AM2017-LB-312
Abstract LB-324: Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness via targeting GRB7
Authors: Chen Kangmei , Ngan Hextan YS , Chan David W. 
Published: July 2017

Abstract
The human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. We and others have reported that GRB7 is frequently upregulated and associated with the progression of human cancers. Clinicopathological analysis has shown that the overexpressed GRB7 is correlated with high grade and metastatic ovarian cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. In this study, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers. We found that the protein level of GRB7 was much higher than its mRNA levels in a subset of ovarian cancer cell lines, indicating aberrant post-transcriptional alterations in GRB7. Using an in silico study, we identified miR-193a-3p and its isoform, miR-193b-3p, by specifically targeting the conserved site (GGCCAGT) at position 332-338 in the 3’ UTR (length: 387) of the human GRB7 gene. QPCR and western blot analyses revealed that only the expression levels of miR-193a-3p but not miR-193b-3p were inversely correlated in ovarian cancer cell lines accompanied with high levels of GRB7 protein levels. Further biochemical analyses using luciferase reporter assays in combination with mutational analyses identified miR-193a-3p specifically targeting GRB7 3’UTR, confirming miR-193a-3p, instead of its isoform miR-193b-3p, has a more important role in GRB7 post-transcriptional regulation in ovarian cancer cells. Constitutive expression or knockdown of miR-193a-3p could significantly alter GRB7 expression, as well as oncogenic capacities of ovarian cancer cells such as cell growth, cell migration and cell invasion. Importantly, we observed that there was a significant stepwise decrease of miR-193a-3p expression from low to high grade ovarian cancers, and was inversely correlated with GRB7 expressions. Intriguingly, treatment with the DNA methyl transferase inhibitor (5’-Aza-dc) could restore the expression of miR-193a-3p, suggesting the epigenetic inhibition of miR-193a-3p is clinically relevant. Importantly, such epigenetic alteration may be the clue leading to overexpression of GRB7 in ovarian cancer cells. Taken together, our findings suggest that epigenetically silencing of miR-193a-3p upregulates GRB7 and contribute to ovarian cancer aggressiveness in tumor progression.
Citation Format: Kangmei Chen, Hextan YS Ngan, David W. Chan. Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness via targeting GRB7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-324. doi:10.1158/1538-7445.AM2017-LB-324
Abstract LB-333: Lymphatic endothelium increases antioxidant capacity of triple-negative breast cancer cells and protects from cell death
Authors: Berisa Mirela , Podgrabinska Simona , Chipuk Jerry , Skobe Mihaela 
Published: July 2017

Abstract
Involvement of lymphatic system with cancer and the extent of lymph node metastases are directly correlated with the poor patient outcome. However, it is not understood whether the presence of lymphatic metastases is only indicative of an aggressive cancer or if the lymphatic vessel microenvironment directly contributes to the metastatic progression. We demonstrate that soluble factors produced by lymphatic endothelial cells (LECs) protect triple negative breast cancer cells from cell death in vitro. Co-culture with LECs or LEC-conditioned medium (LEC-CM) protected cancer cells from death induced by the loss of homotypic cell adhesion, nutrient deprivation, or loss of matrix attachment. High levels of reactive oxygen species (ROS) preceded cell death, and were significantly decreased in tumor cells upon treatment with LEC-CM. Furthermore, LEC-CM protected tumor cells from death induced by exogenous oxidative stress (H2O2), while treatment with the anti-oxidant N-acetyl-cysteine (NAC) recapitulated the cytoprotective effect of LEC-CM. RNA-Seq analysis revealed Nrf2 pathway as the most upregulated stress-pathway induced in tumor cells upon loss of adhesion. Nrf2 and other stress signaling pathways were significantly diminished in the presence of LEC-CM. Pharmacological inhibition of the pentose phosphate pathway (PPP) and the components of thioredoxin and glutathione scavanging systems increased ROS and cell death in LEC-CM indicating that the maintenance of redox homeostasis and cell viability by LEC-CM is dependent on the PPP pathway and in particular thioredoxin system. Furthermore, LEC-CM preserved integrity and function of mitochondria. These results demonstrate that soluble factors produced by lymphatic endothelium promote survival of triple-negative breast cancer cells under stress by regulating tumor cell redox homeostasis and promoting mitochondrial function.
Citation Format: Mirela Berisa, Simona Podgrabinska, Jerry Chipuk, Mihaela Skobe. Lymphatic endothelium increases antioxidant capacity of triple-negative breast cancer cells and protects from cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-333. doi:10.1158/1538-7445.AM2017-LB-333