bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3708: microRNAs involved in BRAF inhibitor resistance
Authors: Koetz Lisa , Sokolova Elena , Brown Brian D. , Hernando Eva 
Published: May 2015

Abstract
BRAF inhibitors (BRAFi) have shown remarkable clinical activity in advanced metastatic melanomas with mutant BRAF(V600E). However, there is considerable variability in both the extent and the duration of patient responses, and acquired resistance invariably emerges. To date, a number of mechanisms underlying acquired resistance to BRAF inhibitors have been identified, most of which reactivate ERK signaling while simultaneously engaging parallel survival pathways. However, these mechanisms account for only a fraction of progressed melanoma and do not explain the large variability of initial response rates and time to progression of melanoma patients subjected to these therapies. We hypothesize that in addition to genetic events, non-genetic alterations such as microRNA changes are critical in mediating time to progression in melanoma tumors treated with BRAF inhibitors. In order to identify microRNAs involved in BRAF inhibitor resistance we performed a functional screen approach utilizing a novel lentiviral-based library of microRNA ‘decoys’. These constructs are better able to stably suppress endogenous microRNA activity than the hairpin RNAs traditionally used. This pooled parallel loss-of-microRNA function analysis in BRAF(V600E) mutant melanoma cells showed enrichment and loss of specific decoys after drug treatment, corresponding to microRNAs that may enhance or compromise the response, respectively. MicroRNA decoys that are positively or negatively selected during drug treatment are being validated using single decoy constructs for their ability to modulate BRAFi response. MicroRNA target genes will be determined by a combination of microarray analysis, in silico predictive algorithms, and 3′UTR-luciferase reporter assay. MicroRNAs and target genes are being validated on human samples from treated patients. Those potentially involved in processes/pathways known to influence drug resistance (i.e. survival genes) will be examined for their ability to mimic or counteract microRNA effects in BRAFi resistance when silenced or overexpressed, respectively. Identification of novel modulators of drug resistance provides the opportunity to design rational combinatorial approaches that will enhance and prolong the effect of these therapies, with the ultimate goal of achieving cures.
Citation Format: Lisa Koetz, Elena Sokolova, Brian D. Brown, Eva Hernando. microRNAs involved in BRAF inhibitor resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3708. doi:10.1158/1538-7445.AM2014-3708
Abstract 3710: The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to Vemurafenib in melanoma
Authors: Zhan Yao , Dahabieh Michael S. , Pettersson Filippa , Dobocan Monica C. , Boutchou Marie Noel M. , Kempen Leon Van , Rincon Sonia V. del , Miller Wilson H. 
Published: May 2015

Abstract
In eukaryotic cells, mRNA translation is restricted by the translation initiation step, in which eIF4E has been regarded as a master regulator. Overexpression of eIF4E has been found in different cancer types; however, whether eIF4E is involved in melanoma tumorigenesis and resistance to standard of care in melanoma remains unclear. We hypothesize that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the B-raf inhibitor, Vemurafenib. From our preliminary data, we show that eIF4E is overexpressed in a panel of malignant melanoma cell lines compared to immortalized melanocytes Mel ST. By genetically knocking down eIF4E via siRNA, we can significantly repress the proliferation of a subset of melanoma cell lines and decrease the level of the eIF4E downstream target Cyclin D1. In addition, the B-raf inhibitor Vemurafenib can drastically inhibit 4EBP-1 phosphorylation in BRAFV600E melanoma cell lines, and further cap binding analysis confirmed that Vemurafenib stabilizes the eIF4E - 4EBP-1 association in these cell lines.. In contrast, 4EBP-1 is highly phosphorylated in all Vemurafenib resistant cell lines, compared to the parental A375, even in the presence of Vemurafenib. Furthermore, cap binding assay show that, unlike their parental counterpart, four out of six resistant lines exhibit weak eIF4E - 4EBP-1 association even in the presence of Vemurafenib. This may imply that more free eIF4E is available for cap-dependent translation initiation in Vemu resistant lines compared to the parental A375. Besides, eIF4E activity contributes to the proliferation of some melanoma cell lines with acquired resistance to Vemurafenib, since siRNA-silencing eIF4E decreases their proliferation. In conclusion, our data show that eIF4E promotes proliferation of some melanoma cell lines and may be involved in maintaining the survival of some melanoma cell lines with acquired vemurafenib resistance. These data suggest that therapeutically targeting eIF4E may be a viable means of inhibiting melanoma cell proliferation and overcoming Vemurafenib resistance.
Citation Format: Yao Zhan, Michael S. Dahabieh, Filippa Pettersson, Monica C. Dobocan, Marie Noel M. Boutchou, Leon Van Kempen, Sonia V. del Rincon, Wilson H. Miller, Jr.. The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to Vemurafenib in melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3710. doi:10.1158/1538-7445.AM2014-3710
Abstract 3718: Adaptive drug escape of EML4-ALK lung cancer against targeted ALK inhibitor involving TGFβ2-mitochondrial priming
Authors: Yin Lihong , Zhang Wei , Shi Ivy , Feng Yan , Bagai Rakesh , Lindner Daniel , Ma Patrick C. 
Published: May 2015

Abstract
Lung cancer is the second most common malignancy with the highest cancer-mortality rate. EML4-ALK chromosomal translocation is now known to represent a highly actionable unique molecular target in approximately 5% of non-small cell lung cancer (NSCLC) patients. The ALK tyrosine kinase inhibitor (TKI) crizotinib induces remarkably high response rates in molecularly-selected NSCLC patients harboring EML4-ALK driven tumors, and is being used in first-line therapy. Nonetheless, responsive tumors ultimately develop acquired drug resistance. We have recently investigated non-mutational mechanisms of tumor resistant escape emerging under early TKI treatment time-window. Our recent studies in EGFR-mutant NSCLC in early adaptive drug escape against EGFR TKI identified an autocrine upregulation of TGFβ2 within these survivor cells. Here, we found that TGFβ2 was elevated significantly in the EML4-ALK-driven H3122 cells undergoing early adaptive drug escape against ALK TKI (TAE684) at treatment day 14. Interestingly, we found that the augmented TGFβ signaling was specific to TGFβ2, but not TGFβ1 or TGFβ3. We also found correlative enhanced mitochondrial BCL-2/BCL-xL prosurvival signaling in the day 14 TKI surviving H3122 cells. The upregulated TGFβ2-BCL-2/BCL-xL prosurvival mitochondrial priming was further validated in H3122 xenografts by IHC. Exogenous TGFβ2 stimulation in vitro for 7 days induced a dose-dependent upregulated BCL-2 and BCL-xL expression. Inhibiting mitochondrial BCL-2/BCL-xL priming using dual BCL-2/BCL-xL inhibitor ABT-263 as BH3-mimetic led to significant reduction in early adaptive drug escape induced by ALK TKIs. Our study showed that EML4-ALK NSCLC could escape ALK TKI early in treatment through cell plasticity that involved TGFβ2-mitochondrial priming in an upregulated prosurvival state. We also found that the early adaptive drug-escaping cancer cells possessed inherently increased EMT-ness (upregulated vimentin, AXL, GAS6) and cancer stemness (upregulated OCT4, NANOG). These findings provide deeper insights into the process of drug resistance emergence and highlighted potential window-of-opportunities to therapeutically target early adaptive escape to eradicate targeted drug resistance and impact long term survival.
Citation Format: Lihong Yin, Wei Zhang, Ivy Shi, Yan Feng, Rakesh Bagai, Daniel Lindner, Patrick C. Ma. Adaptive drug escape of EML4-ALK lung cancer against targeted ALK inhibitor involving TGFβ2-mitochondrial priming. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3718. doi:10.1158/1538-7445.AM2014-3718
Abstract 3721: ALK inactivation induced acquired resistance to alectinib in lung cancer harboring EML4-ALK fusion gene
Authors: Isozaki Hideko , Ichihara Eiki , Yasugi Masayuki , Nobuaki Ochi , Hotta Katsuyuki , Takigawa Nagio , Sendo Toshiaki , Tanimoto Mitsune , Kiura Katsuyuki 
Published: May 2015

Abstract
Dramatic clinical responses to a first generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) crizotinib have been observed in patients with advanced non-small cell lung cancer (NSCLC) haboring ALK fusion gene. Alectinib (CH5424802) (Chugai Pharmaceutical Co., Ltd.) is a second generation ALK-TKI could partially overcome acquired resistance to crizotinib in vitro (Cancer Cell 19, 2011: 679-90), and showed promising result in phase I/II clinical trials with high response rate (93.5 %) and less toxicity than crizotinib. However, even this promising ALK-TKI, the problem of acquired resistance is inevitable.
To elucidate resistant mechanisms, we established an alectinib-resistant cell line H2228/CHR from H2228 that have echinoderm microtubule associated protein like 4 (EML4)-ALK fusion gene, by continuous exposure to this agent. ALK fusion gene disappeared in H2228/CHR, which was confirmed Western blotting, IHC, qRT-PCR and FISH. H2228/CHR cells presented higher phosphorylated levels of epidermal growth factor receptor (EGFR) than the parental H2228 cells and became more sensitive to EGFR-TKI erlotinib.
Next, we established alectinib-resistant ABC-11/CHR cells from ABC-11, a cell line established from pleural effusion of EML4-ALK positive ALK-TKI naïve patient. In ABC-11/CHR cells, phosphorylated levels of ALK was markedly decreased and phosphorylated levels of MET was increased.In addition, autocrine of HGF was increased in ABC-11/CHR cells. ABC-11/CHR showed sensitivity to ALK/MET tyrosine kinase inhibitor, crizotinib in vitro and in vivo model.
In conclusion, inactivation of ALK signaling induced acquired resistance to alectinib in NSCLC harboring ALK fusion gene. Signaling switch from ALK to EGFR or MET was observed in the alectinib-resistant cells. We revealed to overcome such acquired resistance using erlotinib or crizotinib.
Citation Format: Hideko Isozaki, Eiki Ichihara, Masayuki Yasugi, Ochi Nobuaki, Katsuyuki Hotta, Nagio Takigawa, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura. ALK inactivation induced acquired resistance to alectinib in lung cancer harboring EML4-ALK fusion gene. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3721. doi:10.1158/1538-7445.AM2014-3721
Abstract 3729: An individualized approach to bladder cancer treatment using patient-derived cell lines to predict response to chemotherapeutic agents
Authors: Barlow LaMont , Chua Chee Wai , Lei Ming , DeCastro G. Joel , Badani Ketan , Benson Mitchell , McKiernan James , Shen Michael 
Published: May 2015

Abstract
Introduction: Chemotherapy (both intravesical and systemic) can reduce the risk of recurrence and progression in various stages of bladder cancer. However, recurrence after treatment failure is associated with an increased risk of progression. There are currently no established methods for predicting patient-specific responses to treatment prior to drug selection. In our studies, we have developed a novel protocol for efficient establishment of cell lines from primary human bladder tumors, which enables in vitro drug sensitivity assays using chemotherapeutic agents.
Methods: Using an Institutional Review Board-approved tissue acquisition protocol, informed consent was obtained prior to specimen acquisition for all samples. Specimens were obtained during standard transurethral resection of papillary bladder tumors. Following generation of a single-cell suspension, epithelial cells were isolated using immunomagnetic cell separation and used for establishment of adherent cell cultures using a novel protocol. We performed immunohistochemistry on parental tissue as well as cultured cells to confirm that the urothelial cancer phenotype was maintained during serial passaging. For sensitivity assays, cultured cells were passaged and treated with chemotherapeutic agents, followed by assessment of cell viability using MTT assays.
Results: To date, seven specimens from patients with papillary urothelial carcinoma have been obtained, resulting in the establishment of six independent adherent cell lines. All established lines have been serially passaged (as high as P10) without significant decline in growth rate, and maintained expression of CK7, uroplakin III, p53, and Ki67 in patterns similar to parental tissue. Cells from line #7 were treated with mitomycin C, docetaxel, gemcitabine, and rapamycin at three different equivalent concentrations, resulting in a unique sensitivity profile that was reproduced in a replicate experiment performed at a subsequent passage.
Conclusions: We have established a novel protocol for culture and rapid expansion of primary cells from human bladder tumors for assays of drug response. Ultimately, we envision that this approach will provide a basis for the design of patient-specific therapeutic regimens for bladder cancer.
Citation Format: LaMont Barlow, Chee Wai Chua, Ming Lei, G. Joel DeCastro, Ketan Badani, Mitchell Benson, James McKiernan, Michael Shen. An individualized approach to bladder cancer treatment using patient-derived cell lines to predict response to chemotherapeutic agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3729. doi:10.1158/1538-7445.AM2014-3729
Abstract 3733: SilenciX®, novel stable knock-down cellular models to screen new molecular targets through the synthetic lethality approach
Authors: Mennesson Eric , Renault Anne-Marie , Fixe Isabelle , GRILLON Catherine , Kiéda Claudine , Normand Nadia 
Published: May 2015

Abstract
PARP inhibitors are promising therapeutic drugs for cancers harboring BRCA1 and BRCA2 mutations. PARP is involved in the Base Excision Repair (BER) DNA repair pathway. Tumors with BRCA mutations are deficient in Homologous Recombination (HR), another DNA repair pathway. To maintain DNA integrity and prevent cell death, at least one one of the BER or HE pathways must be functional, while the other may be inhibited or silenced (eg. mutation, drug).
In drug discovery, Synthethic Lethality (SL) used a cancer mutation and a drug in combination to cause the tumor cell's death. SL is thus a promising approach to find new druggable targets by controlling the HR and BER DNA repair pathways in order to selectively kill mutated cancer cells. However, the main technical hurdle in SL approaches is to easily identify cancer-specific molecular interaction in various cancer types, while using robust and validated experimental cellular models.
In this presentation we demonstrate how the SilenciX® technology meets SL experimental requirements. BRCA1 and BRCA2 Silencix® cells were treated with PARP1 inhibitors (Olaparib, Veliparib, Rucaparib) and with Gemcitabine.
All inhibitors except Gemcitabine were synthetic lethal in BRCA1 SilenciX® cell lines.
To mimic the cancer micro-environement, the model was tested under hypoxic conditions.
We conclude that SilenciX® cell lines are ingenious gene-specific Knock Down engineered cell lines using a new pEBV derived plasmid, avoiding integration and off-target effects, suitable for a broad range of synthetic lethality studies.
Citation Format: Eric Mennesson, Anne-Marie Renault, Isabelle Fixe, Catherine GRILLON, Claudine Kiéda, Nadia Normand. SilenciX®, novel stable knock-down cellular models to screen new molecular targets through the synthetic lethality approach. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3733. doi:10.1158/1538-7445.AM2014-3733
Abstract 3735: Monitoring the level of the universal nucleotide AMP in diverse enzymatic reactions using bioluminescent homogenous assay platform
Authors: Goueli Said A. , Hsiao Kevin , Zegzouti Hicham , Mondal Subhanjan 
Published: May 2015

Abstract
Adenine nucleotides are major determinants of the energy status of the cell and thus any modulation of their cellular concentration has significant consequences to cellular metabolism, cellular growth and cell death. Many biochemical reactions that generate AMP as a reaction product are pivotal players in a variety of signaling pathways and thus are considered validated drug targets. These include enzymes involved in protein ubiquitination (Ubiquitin ligases), protein synthesis (aminoacyl tRNA synthetases), second messenger signaling (cAMP-phosphodiesterases), and DNA synthesis and repair (prokaryotic and eukaryotic DNA ligases). Therefore, an assay that monitors the activity of these enzymes is desirable in the search for selective modulators and the development of novel therapeutics. As AMP is a common product of these enzymatic reactions, the development of an assay that monitors AMP in a homogenous and sensitive fashion will have significant impact in these diverse areas of research. In addition, enzyme reactions that generate products which can be converted to AMP can be also monitored using this assay. We demonstrate the utility of this assay platform in monitoring the activity of cAMP-PDE, aminoacyl tRNA synthetases, ubiquitin ligases, DNA ligases. Furthermore, enzyme reactions such as methyltransferases that produce product (SAH) which can be converted to AMP can be monitored using this assay platform
Citation Format: Said A. Goueli, Kevin Hsiao, Hicham Zegzouti, Subhanjan Mondal. Monitoring the level of the universal nucleotide AMP in diverse enzymatic reactions using bioluminescent homogenous assay platform. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3735. doi:10.1158/1538-7445.AM2014-3735
Abstract 3742: Detection of EGFR, HER2, HER3 and HER4 homodimerization and heterodimerization using EFC-based cellular assays
Authors: Lamerdin Jane , Saharia Abhishek , Lin-Jones Jennifer , Nguyen Mimi , Fabionar Hyna , Gunturi Sangeetha , Srivastava Abha , Wehrman Tom 
Published: May 2015

Abstract
Ligand-induced receptor dimerization is the first functional step in receptor signaling, representing the most proximal, functional read-out for receptor activation. Here we present a novel application of the Enzyme Fragment Complementation system to monitor receptor-receptor interactions at the surface of intact cells, applicable to diverse receptor types such as RTKs, Interleukin receptors, BMP receptors and cytokine receptors, amongst others. For the purpose of this poster, we will focus on the HER family of receptors. It is well understood that the HER family proteins can dimerize with the other members of its family leading to a complicated oncogenic signaling cascade. Surprisingly, existing cellular assays have been unable to faithfully monitor these interactions proximally in a drug discovery setting. We present EFC-based cellular assays that monitor EGFR homodimerization, EGFR-ErbB2 and ErbB2-ErbB3 heterodimerization events at the receptor. The high signal to noise ratio, serum tolerance and reproducibility make these assays ideal for a diverse range of applications for the identification and development of therapeutic small molecules and biologics, including screening, functional characterization, QC lot release assays and neutralizing antibody studies.
Citation Format: Jane Lamerdin, Abhishek Saharia, Jennifer Lin-Jones, Mimi Nguyen, Hyna Fabionar, Sangeetha Gunturi, Abha Srivastava, Tom Wehrman. Detection of EGFR, HER2, HER3 and HER4 homodimerization and heterodimerization using EFC-based cellular assays. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3742. doi:10.1158/1538-7445.AM2014-3742
Abstract 3750: Targeting PD-L1 sensitizes head and neck squamous cell carcinoma to cisplatin
Authors: Qiao Peter , Lajud Shayanne A. , Nagda Danish A. , Tanaka Nobuaki , Civantos Alyssa , O'Malley Bert W. , Li Daqing 
Published: May 2015

Abstract
Platinum-based chemotherapy agents such as Cisplatin (CDDP) are commonly used as first-line treatment for several types of human cancers including ovarian, lung, testicular, and head and neck squamous cell carcinomas (HNSCC). Unfortunately, CDDP monotherapy is often ineffective due to inherent or acquired tumor resistance to therapy, also known as chemoresistance. This contributes to a need for the administration of larger, more toxic doses, as well as failure of chemotherapy and tumor recurrence. Despite the clinical significance of chemoresistance, the mechanisms driving this phenomenon are not completely understood.
Programmed cell death ligand 1 (PD-L1), a membrane-bound glycoprotein responsible for modulating the immunological response through the induction of T-Cell anergy and apoptosis, has been shown to be overexpressed in many cancers, including HNSCC. While PD-L1 overexpression has been directly related to the immunoevasion of cancer cells allowing for tumor progression, recent reports suggest that PD-L1 also plays an important role in the tumor response to doxorubicin-based chemotherapy independent of its immune function. The present study investigates the role of PD-L1 in response to CDDP in HNSCC.
In vitro experiments were performed using four well-characterized human HNSCC cell lines. Quantitative polymerase chain reaction (qPCR) and western blot were conducted to determine the baseline and post-CDDP-treatment PD-L1 gene expression. The results demonstrated that PD-L1 mRNA transcription and protein expression are upregulated in response to CDDP, suggesting that PD-L1 is involved in the chemoresponse. Conversely, knockdown of PD-L1 using siRNA resulted in chemosensitization of HNSCC cells to CDDP. Together, these findings implicate PD-L1 in the CDDP-chemoresponse in HNSCC.
In conclusion, we propose a role for PD-L1 that is distinct from the classic immunoevasion pathway. Our findings demonstrate that disruption of this protein leads to increased sensitivity of HNSCC cells to CDDP, suggesting a potential combination therapeutic strategy for patients with CDDP-resistant HNSCC.
Citation Format: Peter Qiao, Shayanne A. Lajud, Danish A. Nagda, Nobuaki Tanaka, Alyssa Civantos, Bert W. O'Malley, Daqing Li. Targeting PD-L1 sensitizes head and neck squamous cell carcinoma to cisplatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3750. doi:10.1158/1538-7445.AM2014-3750