bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1277: Neural crest-like gene FOXD1 plays a role in melanoma cell migration and invasion
Authors: Wu Huizi , Larribere Lionel , Weina Kasia , Knappe Nathalie , Gebhardt Christoffer , Umansky Viktor , Utikal Jochen 
Published: July 2016

Abstract
Melanoma is a highly aggressive skin cancer arising from transformed melanocytes. Despite tremendous efforts and considerable progress in clinical treatment, melanoma remains a deadly disease characterized by abundant treatment resistance due to high phenotype plasticity of melanoma cells. In order to evade therapy, melanoma cells can undergo phenotype switching from a differentiated state towards a dedifferentiated and more stem cell-like state. Recently, some melanoma cells with neural crest-like characteristics were shown to be able to sustain tumor growth and to give rise to distant metastases.
Here, we use the technique of directed differentiation of human induced pluripotent stem cells (hiPSCs) to characterize the human neural crest cell population in vitro and to identify potential genes that are reactivated during melanoma progression. We differentiated hiPSCs towards melanocytes via the neural crest stage. Expression analyses revealed an overexpression of the Forkhead Box D1 (FOXD1) transcription factor in neural crest cells and importantly, increased FOXD1 expression was also found in melanoma cells compared to normal human melanocytes. Interestingly, in invasive and less proliferative melanoma cells, FOXD1 expression was elevated compared to highly proliferative and less motile cells, indicating a potential role of this factor in motility acquisition. To gain deeper insight into the expression pattern of FOXD1 in clinical samples, a protein expression analysis using tissue microarrays was performed determining FOXD1 expression in melanocytic nevi, primary and metastatic melanoma samples. Surprisingly, in benign melanocytic nevi, FOXD1 was dominantly localized in the nucleus whereas a shift towards a cytoplasmic localization was observed in both, primary and metastatic melanomas. Loss of FOXD1 gene in melanoma cells also revealed the importance of this gene in melanoma cell migration and invasion. Further characterization of FOXD1 and its role in melanoma progression may help to understand the phenotypic plasticity of melanoma cells, which is required for overcoming resistance in anti-melanoma therapy.
In conclusion, FOXD1 is overexpressed and aberrantly localized in malignant melanoma cells compared to melanocytes. Our data indicate its function in melanoma migration and invasion. FOXD1 might be an interesting target in melanoma therapy.
Citation Format: Huizi Wu, Lionel Larribere, Kasia Weina, Nathalie Knappe, Christoffer Gebhardt, Viktor Umansky, Jochen Utikal. Neural crest-like gene FOXD1 plays a role in melanoma cell migration and invasion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1277.
Abstract 1298: CD40L-CD40 signaling on B-cell lymphoma response to BTK inhibitors
Authors: Sun Zhijian , Luo Lusong 
Published: July 2016

Abstract
The aberrant activation of B cells receptor (BCR) signaling plays an essential role in the pathogenesis of B-cell lymphomas. Targeting BCR signaling by inhibiting Bruton's tyrosine kinase (BTK) has been shown to be a successful strategy in treating B-cell lymphomas including mantle-cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Ibrutinib, an oral, covalent BTK inhibitor achieved high overall response rate (ORR) and prolonged duration of responses in CLL and MCL patients. In contrast, ibrutinib was reported to have much lower response rate in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and the responses in DLBCL was restricted to the activated B-cell (ABC) subtype. These differences highlight the need to understand the bypass signaling/pathway to BTK inhibition. In this study, we identified CD40L-CD40 pathway as one of the potential bypass pathways to BTK inhibitory therapy. We showed that CD40 was consistently expressed in mature B cells, whilst CD40L expression levels were heterogenic in tissue microarray (TMA) with 150 lymphoma samples. In these samples, circa 57% of lymphoma tissues have medium or strong level of CD40L expression in TMA, indicating the existence of CD40L-CD40 signaling in human lymphoma tissues. Consistent with the response rate of ibrutinib in patients, in 68 non-GCB type of DLBCL, in which aberrant activation of NF-kB pathway is important for the pathogenesis, about 60% samples showed CD40L expression. Co-culture of Rec-1 or TMD8 cells with HEK293/CD40L attenuated the anti-proliferation activity of ibrutinib in vitro. This observation was also confirmed with recombinant soluble CD40L protein. Detailed mechanistic analysis revealed that CD40L-CD40 signaling activated the NF-κB and MAPK pathway and offset the inhibition of ibrutinib. Additionally, activating NF-κB pathway with PKC agonist abolished the cell killing effects of ibrutinib. These data suggest CD40L may be used as a potential biomarker for studying clinical responses to BTK inhibitors. Additionally, our results support combination strategies of BTK inhibitors with agents blocking CD40 or downstream NF-κB and MAPK pathway in patient population where CD40L-CD40 pathway is activated.
Citation Format: Zhijian Sun, Lusong Luo. CD40L-CD40 signaling on B-cell lymphoma response to BTK inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1298.
Abstract 1326: 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside a novel c-Myc inhibitor induces GNMT expression and apoptosis in hepatocellular carcinoma
Authors: Kant Rajni , Yen Chia Hung , Lu Chung Kuang , Tung Chien Yi , Chen Yi-Ming 
Published: July 2016

Abstract
1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside (PGG) possesses potent anticancer activities. We identified PGG as GNMT inducer by using GNMT based drug screening platform. In this study we aimed to find the mechanism of action of PGG in hepatocellular carcinoma (HCC). We used microarray analysis to identify the differently expressed genes induced by PGG. Microarray experiment showed that c-Myc was involved in all detected pathways in enrichment analysis. PGG suppressed c-Myc mRNA and protein expression in Huh7 and Hep G2 cells. Knocked-down of c-Myc resulted in significant induction of GNMT promoter activity and endogenous GNMT mRNA expression. Furthermore, overexpression of c-Myc significantly inhibited GNMT promoter activity and endogenous GNMT protein expression. Moreover, PGG not only inhibited c-Myc mRNA expression but also induced degradation of c-Myc protein in Huh7 cells. Finally we found that PGG induces apoptosis in Huh7 cells. Taken together, PGG is a novel c-Myc inhibitor and induces GNMT through c- Myc modulation in HCC. Our results also suggest that PGG may potentially be a good drug candidate for HCC and c-Myc overexpressing cancers.
Citation Format: Rajni Kant, Chia Hung Yen, Chung Kuang Lu, Chien Yi Tung, Yi-Ming Chen. 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside a novel c-Myc inhibitor induces GNMT expression and apoptosis in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1326.
Abstract 1329: Intravenous delivery of Erlotinib-loaded PLA-PEG nanoparticles for treatment of GB
Authors: Hartman Lauren K. , Dhruv Harshil D. , Householder Kyle T. , Roth Jeffrey E. , Schorzman Allison N. , Zamboni William , Sirianni Rachel , Berens Michael E. 
Published: July 2016

Abstract
Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) gene represent common genetic signature abnormalities (&gt;50%) in primary glioblastomas (GBs) that arise de novo. Although activated EGFR signaling represents the most common genetic abnormality in GB, targeted therapeutics against EGFR, such as Erlotinib and Gefitinib, have found very limited clinical success mainly because of restricted access to the tumor cells behind the blood brain barrier. Nanoparticles, such as those composed of poly(lactic acid)-poly(glycolic acid) (PLA-PEG), may be capable of overcoming delivery barriers to expand the armamentarium of drugs useful against GB. PLA-PEG is one of only two polymer NP formulations in phase II clinical trial for intravenous administration (NCT01812746). In this study, we tested the ability of Erlotinib-loaded PLA-PEG nanoparticles to inhibit the EGFR signaling pathway in short-term cultures of GB patient derived xenograft (PDX) models. We also tested the ability of systemically administered PLA-PEG nanoparticles to deliver Erlotinib payload to intracranial GB PDX cells by pharmacokinetic (PK) analysis. Potency of Erlotinib-loaded PLA-PEG was determined in four PDX models (GBM6, GBM12, GBM39, and GBM59) with known EGFR and PTEN status using immunoblot analysis and CellTiterGlo® assay. Our results demonstrate that Erlotinib PLA-PEG inhibits EGFR signaling in all PDX models tested with potency equal to free Erlotininb (EC50 range 4.9 - 16.8 μM). Pharmacokinetic measurements were done in plasma and brain tissue samples (tumor-bearing hemisphere and contralateral hemisphere were analyzed separately) collected from intracranial GBM12 tumor bearing mice at 5 min, 1 hr, 6hr, and 24 hr after intravenous (IV) dose of free Erlotinib at 7.5 mg/Kg and Erlotininb PLA-PEG at 13.125 mg/Kg. PLA-PEG-mediated brain penetration (AUCplasm:AUCBrain) of Erlotinib is ∼7.5%. Using orthotopic PDX implants, perivascular/intratumoral penetration by PLA-PEG is being measured. Additional improvements in PLA-PEG to heighten uptake into brain, as well as tumor-specific targeting and enriched payload density will foster improved clinical utility of EGFR targeted therapies against GB. Supported by a grant from the Ben & Catherine Ivy Foundation.
Citation Format: Lauren K. Hartman, Harshil D. Dhruv, Kyle T. Householder, Jeffrey E. Roth, Allison N. Schorzman, William Zamboni, Rachel Sirianni, Michael E. Berens. Intravenous delivery of Erlotinib-loaded PLA-PEG nanoparticles for treatment of GB. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1329.
Abstract 1337: Exploration of 2-aryl fused thiophene analogs as selective inhibitors of MEK5
Authors: Flaherty Patrick T. , Shah Dhruv , Gupta Mohit , Wright Thomas , Cavanaugh Jane E. , Burow Matthew E. 
Published: July 2016

Abstract
In several cancers intermediate enzymes in the MAPK cascades are up-regulated and may represent adaptive changes giving these cancers a competitive metabolic edge over normal cells. Additionally these alterations may induce resistance to previously useful chemotherapeutic agents. The enzyme MEK5, a component of the MEK5/ERK5 cascade, is up-regulated in several cancer types including triple negative breast cancer and prostrate cancers. Our group has previously described the synthesis and testing of anthranillic acid derived compounds and their ring constrained analogs. To explore chemical functional group tolerance and preference on the central arene ring by MEK5, a series of fused-thiophene ring variations, obtainable by the Gewald reaction were prepared and tested. These compounds were examined at 10 μM with MDA-MB-231 cells treated with EGF to induce MEK1/2 and MEK5 phosphorylation. Western blot analysis using IR-tagged antibodies against pERK1/2, pERK5, ERK1/2, or ERK5 was used to determine total and relative inhibition of MEK-mediated phosphorylation of respective pERK products. Incubation with PD0325901 resulted in full suppression of both pERK1/2 and pERK5. For the variations explored, several novel compounds were identified that resulted in no inhibition in the formation of pERK1/2 and 70% inhibition of pERK5. This establishes a new structural class of selective Type III inhibitors of MEK5 that are more amenable to structural variation, facilitating additional structure activity relationship studies.
Citation Format: Patrick T. Flaherty, Dhruv Shah, Mohit Gupta, Thomas Wright, Jane E. Cavanaugh, Matthew E. Burow. Exploration of 2-aryl fused thiophene analogs as selective inhibitors of MEK5. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1337.
Abstract 1344: Novel targeting all-in-one nanoporphyrin platform against bladder cancer
Authors: Li Yuanpei , Lin Tzu-yin , Pan Chongxian , Lam Kit S. 
Published: July 2016

Abstract
We have developed an extremely versatile and highly innovative theranostic nanoporphyrin (NP) platform for the integration of a broad range of clinical relevant imaging and therapeutic functions, including magnetic resonance imaging (MRI), positron emission tomography, fluorescence optical tomography, photodynamic therapy, photothermal therapy and targeted drug delivery. NPs exhibit architecture-dependent fluorescence- and magnetic resonance- properties, which could significantly increase the sensitivity of optical imaging and MRI for tumor detection. We recently integrated the NP platform into our previously reported bladder cancer targeted nanoparticles that were coated with a bladder cancer-specific ligand named PLZ4, resulting in a novel bladder cancer targeting and multifunctional PLZ4-nanoporphyrin (PNP) platform. PNP selectively delivered photosensitizer and chemotherapy into bladder cancer cells 30-50 times more than to adjacent normal urothelial cells, compared to only 2-3 times with reported photosensitizer, 5-aminolevulinic acid (ALA). Photodynamic therapy with PNP generated reactive oxygen species was over 100 times more potent than 5-ALA in vitro. PNP-mediated intravesical photo-therapy completely eliminated orthotopic patient-derived bladder cancer xenografts (PDXs). Image-guided photodynamic and photothermal therapies synergized with targeted chemotherapy of doxorubicin and significantly prolonged overall survival of mice carrying PDXs. This uniquely engineered targeting PNP platform has tremendous potential to improve the management of bladder cancer in clinic.
Citation Format: Yuanpei Li, Tzu-yin Lin, Chongxian Pan, Kit S. Lam. Novel targeting all-in-one nanoporphyrin platform against bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1344.
Abstract 1358: Structure-based drug design of 3-site binding, high affinity inhibitors of S100B in malignant melanoma
Authors: Cavalier Michael C. , Wilder Paul T. , Luci Diane , Maloney David J. , Fang Lei , Ansari Mohd. Imran , MacKerell Alexander D. , Coop Andrew , Jadhav Ajit , Weber David J. 
Published: July 2016

Abstract
An especially predictive biomarker when used in combination with other diagnostic indicators, S100B is elevated in &gt;90% of malignant melanoma (MM) patients and its protein level correlates directly with poor survival (&lt;1 yr.) and relapse. For patients with low levels of S100B (5-10%), MM vaccines are uniquely effective. While this correlation is not fully understood, mechanistic studies show that S100B is capable of blocking p53 oligomerization, promoting p53 phosphorylation in its C-terminus, and contributing to p53 degradation in concert with hdm2. Correspondingly, lowering S100B levels via siRNA or via small molecule inhibitors restore p53 levels and its tumor suppressor activities including UV-activated apoptosis pathways found in normal melanocytes. Additionally, elevated S100B and overexpression of the receptor for advanced glycation end products (RAGE) confers a metastatic phenotype. Studies into how S100B affects tumor progression and metastasis are ongoing, novel S100B inhibitors (termed SBiXs) to ablate S100B-dependent effects in cancer are in development. Structure-activity relationship (SAR) studies are ongoing to improve the affinity and selectivity of SBiXs. These studies reveal that the binding surface of S100B can be divided into “hot spots” or “persistent sites” that contribute more energetically to the protein-protein interactions (PPI) than the surrounding protein surface. Described here are descriptions of SBiXs which bind these Sites (1, 2, and 3), details to the SAR studies involved in the chemical optimization of these ligands, and information into the tethering of these SBiXs into a single-molecule capable of binding all 3 sites simultaneously. Also provided is a discussion regarding how protein dynamics affect the on/off rates of SBiXs and the resulting apparent binding affinity. The results described here represent a Structure-based drug design approach to the development of PPI inhibitors nearing the threshold required for a useful therapeutic window.
Citation Format: Michael C. Cavalier, Paul T. Wilder, Diane Luci, David J. Maloney, Lei Fang, Mohd. Imran Ansari, Alexander D. MacKerell, Andrew Coop, Ajit Jadhav, David J. Weber. Structure-based drug design of 3-site binding, high affinity inhibitors of S100B in malignant melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1358.
Abstract 1386: Clinical research results for a NGS-based kit for targeted detection of clinically relevant gene rearrangements in lung tumor samples
Authors: Schageman Jeoffrey J. , Costa José Luis , Sheils Orla , Glassco John E. , Chi David , Sherlock Jon , Bishop John , Petraroli Rosella P. , Bramlett Kelli S. 
Published: July 2016

Abstract
In recent years, advances in next-generation sequencing (NGS) technologies have enabled faster and cheaper methods for uncovering the genetic basis of disease. For cancer, NGS based screening for known tumor subtypes may inform diagnosis and allow the clinician to tailor a specific therapeutic approach in the future. Here, we present the testing results of one such NGS based kit used to detect specific chromosomal translocations in retrospective non-small cell lung cancer (NSCLC) samples by targeting specific breakpoints in known fusion transcripts.
The included panel tested consists of a single primer pool containing amplicon designs to simultaneously screen for over 75 specific rearrangements involving the receptor tyrosine kinase (RTK) genes ALK, RET and ROS1 as well as NTRK1. The panel was compatible with formalin-fixed paraffin-embedded (FFPE) lung tumor research samples and achieved high-sensitivity down to 10 ng of RNA input. In addition, amplicon assays designed at the 5’ and 3’ ends the RTK genes provide non-specific evidence that a translocation exists in a sample by comparing expression imbalance between the two ends.
Testing was carried out at three external clinical research laboratories. In addition to positive and negative control samples, each site contributed FFPE lung tumor research samples for which ALK fusion status was known prior to NGS library preparation carried out using the Ion AmpliSeq™ workflow. For site-specific samples (n = 144, 16 samples per sequencing run), high concordance, sensitivity and specificity were measured at 97.2%, 90.5% and 98.4%, respectively.
Citation Format: Jeoffrey J. Schageman, José Luis Costa, Orla Sheils, John E. Glassco, David Chi, Jon Sherlock, John Bishop, Rosella P. Petraroli, Kelli S. Bramlett. Clinical research results for a NGS-based kit for targeted detection of clinically relevant gene rearrangements in lung tumor samples. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1386.
Abstract 142: Mutation and immune profiles in early-stage lung squamous cell carcinoma
Authors: Choi Murim , Kadara Humam , Zhang Jiexin , Parra Cuentas Edwin , Rodriguez Canales Jaime , Gaffney Stephen G. , Zhao Zi-Ming , Behrens Carmen , Fujimoto Junya , Chow Chi-Wan , Kalhor Neda , Moran Cesar , Rimm David , Swisher Stephen , Gibbons Don L. , Heymach John V. , Kaftan Edward , Townsend Jeffrey , Lynch Thomas J. , Schlessinger Joseph , Lee J. Jack , Lifton Richard , Herbst Roy S. , Wistuba Ignacio I. 
Published: July 2016

Abstract
PURPOSE: Lung squamous cell carcinoma (LUSC) accounts for 20-30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We sought to perform whole-exome sequencing (WES), comprehensive immune profiling and clinicopathological analysis of early-stage LUSCs to increase our understanding of the pathobiology of this malignancy.
METHODS: Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n = 108) were analyzed by WES. Immunohistochemistry and image analysis-based profiling of 10 immune markers was done on a subset of LUSCs (n = 91). Associations among mutations, immune markers and clinicopathological variables were statistically examined using ANOVA and Fisher tests. Cox proportional hazards regression models were used for statistical analysis of clinical outcome.
RESULTS: This early-stage LUSC cohort displayed an average of 209 exonic mutations per tumor. Fourteen genes exhibited significant enrichment for mutation: TP53, MLL2, PIK3CA, NFE2L2, CDH8, KEAP1, PTEN, ADCY8, PTPRT, CALCR, GRM8, FBXW7, RB1 and CDKN2A. Among mutated genes associated with poor recurrence-free survival, MLL2 mutations predicted poor prognosis in both TP53 mutant and wild type LUSCs. We also found that in treated patients, FBXW7 and KEAP1 mutations were associated with poor response to adjuvant therapy, particularly in TP53-mutant tumors. Analysis of mutations with immune markers revealed that ADCY8 and PIK3CA mutations were associated with markedly decreased tumoral PD-L1 expression, LUSCs with PIK3CA mutations exhibited elevated CD45ro levels and CDKN2A-mutant tumors displayed an up-regulated immune response.
CONCLUSION: Our findings pinpoint mutated genes that may impact clinical outcome as well as personalized strategies for targeted immunotherapies in early-stage LUSC.
Citation Format: Murim Choi, Humam Kadara, Jiexin Zhang, Edwin Parra Cuentas, Jaime Rodriguez Canales, Stephen G. Gaffney, Zi-Ming Zhao, Carmen Behrens, Junya Fujimoto, Chi-Wan Chow, Neda Kalhor, Cesar Moran, David Rimm, Stephen Swisher, Don L. Gibbons, John V. Heymach, Edward Kaftan, Jeffrey Townsend, Thomas J. Lynch, Joseph Schlessinger, J. Jack Lee, Richard Lifton, Roy S. Herbst, Ignacio I. Wistuba. Mutation and immune profiles in early-stage lung squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 142.