bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2043: Entinostat in combination with Cladribine synergistically induces apoptosis in multiple myeloma cells
Authors: Wang Bolun , Lyu Hui , Liu Bolin 
Published: July 2017

Abstract
Cladribine (2-CDA) is a well-known purine nucleoside analog against lymphoproliferative disorders. Entinostat, a selective class I histone deacetylase (HDAC) inhibitor, exerts anti-tumor activity in various cancers, including multiple myeloma (MM). We sought to determine whether cladribine and entinostat may exhibit synergistic anti-proliferative/anti-survival effects on MM cells. Here we showed that, in cell growth MTS assays, either cladribine or entinostat alone inhibited cell proliferation in a dose-dependent manner. The combinations of cladribine and entinostat significantly induced growth inhibition in MM cells tested. The combination index (CI) curves showed a synergistic effect between cladribine and entinostat. An apoptotic-ELISA and western blot analyses of caspase-3 and PARP revealed that entinostat in combination with cladribine exhibited a much more potent activity than either agent alone to promote the MM cells undergoing apoptosis in a dose and time-dependent manner. Collectively, our data suggest that combinations of entinostat and cladribine possess synergistic anti-proliferative/anti-survival activity in MM cells. Regimens consisting of entinostat and cladribine may represent novel therapeutic strategies against MM.
Citation Format: Bolun Wang, Hui Lyu, Bolin Liu. Entinostat in combination with Cladribine synergistically induces apoptosis in multiple myeloma cells [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 2043. doi:10.1158/1538-7445.AM2017-2043
Abstract 2045: Exploring the potential of cellular thermal shift assay (CETSA) to study drug resistance during cancer therapy
Authors: Sreekumar Lekshmy Kunjamma Usha , Lim Yan Ting , Veerappan Saranya , Nordlund Par 
Published: July 2017

Abstract
The aim of this project is to understand the various mechanisms contributing to drug resistance development in cancer therapy.
The efficacy of therapeutics is dependent on a drug binding to its target. We have developed a method that allows for the first time to directly evaluate drug binding to target proteins in cells and tissue samples the cellular thermal shift assay (CETSA) (Martinez Molina et al. Science, 341:84). CETSA is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. By monitoring the drug occupancy in the target protein, CETSA can be used to study processes of drug transport and metabolism in cancer cells. We have used CETSA to study the acquired drug resistance of, antifolate and fluropyrimidine drugs in pairs of parental and resistant cell lines. CETSA shifts and isothermal dose response fingerprint (ITDRF) were used to study the relative drug target engagement in these cells. Quantitative mass spectrometry was used to monitor differences in protein expression levels across the cell lines.
Based on the CETSA measurements, resistant cells clearly showed a higher drug dose threshold as compared to the parent cell lines, typically requiring 8-50 times higher dose to establish similar target engagement. Several potential mechanism for drug resistant emerged - we, for example, observed up-regulation of thymidylate synthase and down regulation of reduced folate carrier (RFC) protein associated with antifolate transport, in some resistant cell lines.
The data supports that CETSA is a potential valuable tool to dissect various mechanisms those contribute to resistant development in cancer cells.
Citation Format: Lekshmy Kunjamma Usha Sreekumar, Yan Ting Lim, Saranya Veerappan, Par Nordlund. Exploring the potential of cellular thermal shift assay (CETSA) to study drug resistance during cancer therapy [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 2045. doi:10.1158/1538-7445.AM2017-2045
Abstract 2047: The muscarinic receptor antagonist, benztropine, blocks the expansion of a temozolomide resistant subpopulation of glioma cells
Authors: Bonnin Damian A. Almiron , Howard Joseph M. , Young Alison L. , Israel Mark A. , Havrda Matthew C. 
Published: July 2017

Abstract
Virtually all malignant gliomas become drug-resistant and recur after initial treatment, recurrent tumors are fatal within two-years, and no therapies exist that cure gliomas. The recognition that subpopulations of primitive cells with an oligodendrocyte precursor-like (OPC-like) phenotype capable of resisting standard therapy and contributing to recurrence, frames the question of whether adjuvant therapies designed to modify or eliminate OPC-like cells could slow the progression of glioma. Agents that force the differentiation of treatment-resistant OPC-like glioma cells, a phenomenon that requires cessation of proliferation, are compelling candidates for targeting OPC-like GSCs. Recently, it was observed that OPC proliferation was driven by activation of the M1, M3 and M4 muscarinic receptors. In another report, a large-scale drug screen designed to seek drugs to induce OPC differentiation in the context of multiple sclerosis identified a muscarinic receptor antagonist, benztropine (a.k.a. Cogentin), as a promoter of OPC differentiation and cell cycle exit. We have conducted studies in glioma cell lines supporting a role for benztropine in suppressing the development of drug-resistance to the standard glioma chemo-therapeutic temozolomide (TMZ). Upon treatment with TMZ, we identified the emergence of an OPC-like subpopulation of glioma cells identifiable by the co-expression of CD44, CD15 and PDGFRa. Treatment with pre-inhibitory doses of benztropine significantly reduced the TMZ IC50 in all glioma lines examined in association with blocking emergence of the CD44/CD15/PDGFR-positive subpopulation. Ongoing studies are designed to determine the tumor initiating potential of the CD44/CD15/PDGFR-positive subpopulation and whether benztropine will suppress the development of TMZ resistance in animal models of glioma.
Citation Format: Damian A. Almiron Bonnin, Joseph M. Howard, Alison L. Young, Mark A. Israel, Matthew C. Havrda. The muscarinic receptor antagonist, benztropine, blocks the expansion of a temozolomide resistant subpopulation of glioma cells [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 2047. doi:10.1158/1538-7445.AM2017-2047
Abstract 2051: LSTRA cell line as a model for large granular lymphocytic leukemia in drug screening
Authors: Chueh Fu-Shin , Chueh Fu-Yu , Yu Chao-Lan 
Published: July 2017

Abstract
Large granular lymphocytic (LGL) leukemia is a rare form of leukemia that is caused by the increase in cytotoxic T-lymphocytes or natural killer (NK) cells. A subcategory of T-LGL leukemia that co-expresses T and NK cell surface markers is very aggressive and has a very poor prognosis. Current treatment of aggressive T-LGL is based on non-specific immunosuppressive therapy. Lack of model cell lines contributes to slow progress in designing targeted therapy and clinical trials. Our recent studies demonstrate that the mouse T-leukemic cell line LSTRA reproduces some important characteristics of aggressive T-LGL leukemia. This is the first report of a cell line model mimicking the deadly human leukemia and has great potentials for drug screening in treating T-LGL leukemia.
Bortezomib is one of the drugs that show promising results in treating LGL leukemia patients in clinical trials. Bortezomib is the first FDA-approved reversible proteasome inhibitor in treating multiple myeloma and mantle cell lymphoma patients. One of the major concerns in using single-agent bortezomib is that patients develop resistance during the course of treatment and cancers relapse. Therefore, it is important to develop novel strategies in overcoming LGL leukemic cells’ resistance to bortezomib and its derivatives.
In our current study, we showed that bortezomib inhibited cell proliferation and induced apoptosis in LSTRA leukemic cells. Partial reversion after 48-72 hr of bortezomib treatment suggested development of resistance to bortezomib. We further established bortezomib-resistant LSTRA cells that tolerated significantly higher levels of bortezomib. Both carfilzomib (FDA-approved second generation irreversible proteasome inhibitor) and MLN 4924 (proteasome pathway upstream inhibitor) failed to overcome bortezomib resistance. Only luteolin, a common flavonoid found in plants, can effectively overcome bortezomib resistance.
Metabolic reprogramming has been linked to drug resistance in cancer cells. Indeed, We found that bortezomib-resistant LSTRA cells had smaller cell size as well as reduced rate of glucose uptake, lactate secretion, and mitochondrial respiration. These results suggest that reduced mitochondrial activity may be an important molecular marker for LSTRA cell’s resistance to bortezomib. All together, we identified luteolin as a potential small molecule in overcoming LGL leukemia’s resistance to proteasome inhibitor therapy. Altered mitochondrial activity and cell metabolism in bortezomib-resistant cells provide additional targets in developing novel combined chemotherapy for cancer patients.
Citation Format: Fu-Shin Chueh, Fu-Yu Chueh, Chao-Lan Yu. LSTRA cell line as a model for large granular lymphocytic leukemia in drug screening [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 2051. doi:10.1158/1538-7445.AM2017-2051
Abstract 2059: Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition
Authors: Cheon Ji Hyun , Park Yu Jin , Son Ji Yeon , Yoon Sung Pil , Kim Hyung Sik 
Published: July 2017

Abstract
1
Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition
Ji Hyun Cheon1, Yu Jin Park, Ji Yeon Son, Sung Pil Yoon, and Hyung Sik Kim
Lab of molecular of toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
A high expression of P-glycoprotein (P-gp) is consistently observed in multidrug resistance (MDR) cancer cells. The purpose of our study was to identify conditions that would increase the sensitivity of P-gp-overexpressing drug-resistant KBV20C cancer cell line. We used commercially available epigenetic library, which includes 128 compounds. Using cellular viability test, we identified that XL019 highly sensitized KBV20C-resistant cells to vincristine treatment. However, XL019-induced sensitization was not observed in vincristine-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Using FACS analysis, western-blot, and annexin V staining, we identified that XL109 sensitized vincristine-treated KBV20C cells via apoptosis and G2 arrest. Furthermore, sensitization potency of XL109 in combination with vincristine was measured in KBV20C cells when comparing with P-gp inhibitor verapamil or another Jak2 inhibitor CEP-33779. We further investigated the mechanisms of XL109 against sensitization of vincristine-treated KBV20C cells. The sensitization mechanism of XL109 was mainly depends on the inhibition of P-gp. In addition, ATPase activity was also conducted to identify as potential role of XL019 in P-gp inhibition. In the docking modeling, XL019 and CEP-33779 showed high binding affinity docking score against ABCB1 receptor protein by -10.590 and -9.104, respectively. Collectively, inhibition of P-gp by XL109 can increase the vincristine-sensitivity in MDR cancer cells through increased apoptosis and G2 arrest. Our findings indicate that Jak2 inhibitor may be a promising target in the treatment of patients resistant to anti-mitotic drug.
Note: This abstract was not presented at the meeting.
Citation Format: Ji Hyun Cheon, Yu Jin Park, Ji Yeon Son, Sung Pil Yoon, Hyung Sik Kim. Co-treatment of XL019, a selective Jak2 inhibitor, highly sensitizes drug-resistant cancer cells by increasing P-gp inhibition [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 2059. doi:10.1158/1538-7445.AM2017-2059
Abstract 2062: Inhibition of STAT3 overcomes gemcitabine resistance in pancreatic cancer cells
Authors: Chen Chi-Wei , Wu Ruiqin , Meng Yunxiao , Zhu Wenge 
Published: July 2017

Abstract
Gemcitabine is used as the first line treatment of pancreatic ductal adenocarcinoma (PDAC), however, either innate or acquired resistance to gemcitabine limit its therapeutic efficacy. In this study, several DNA damage agents including DNA repair inhibitors, and kinase inhibitors were examined for suppression of cell growth of gemcitabine resistant cells. The results show that most of these compounds are cross-resistant to gemcitabine-resistant pancreatic cells. By using STRING protein network database, we found that STAT3 signaling pathway plays a connectional role to link targeted proteins we tested. Interestingly, gemcitabine-resistant pancreatic cells have higher level of phosphor-STAT3 (pSTAT3) and are more sensitive to STAT3 inhibitor, S3I-201. Furthermore, combined S3I-201 with gemcitabine synergically suppresses the growth of both cell lines in vitro. We also confirmed the therapeutic efficacy of combined treatments using xenografted model. Taken together, inhibition of STAT3 overcomes gemcitabine resistance in pancreatic cancer cells. This study may provide us with a new approach to treat pancreatic cancer as well as gemcitabine resistance of pancreatic cancer.
Citation Format: Chi-Wei Chen, Ruiqin Wu, Yunxiao Meng, Wenge Zhu. Inhibition of STAT3 overcomes gemcitabine resistance in pancreatic cancer cells [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 2062. doi:10.1158/1538-7445.AM2017-2062
Abstract 2063: The farnesyltransferase inhibitor tipifarnib causes dramatic tumor regression and increases survival in murine HrasG12V driven aggressive thyroid cancers: Consequent adaptive and acquired resistance mechanisms inform combination treatments with improved responses
Authors: Untch Brian R. , Anjos Vanessa Dos , Garcia-Rendueles Maria ER , Knauf Jeff A. , Ho Alan L. , Fagin James A. 
Published: July 2017

Abstract
Of the three RAS oncoproteins, only HRAS is delocalized and functionally inactivated by farnesyltransferase inhibition (FTI), an approach that has yet to be exploited clinically. We treated a murine model of poorly differentiated and anaplastic thyroid cancer (Tpo-cre/HrasG12V/p53flox/flox; Hras;p53) with the FTI tipifarnib, and observed sustained tumor regression and increased survival; however, tumors eventually recurred. Following HRAS delocalization by tipifarnib in vitro, ERK phosphorylation was only inhibited transiently in HRAS-mutant cell lines, which was associated with increased GTP loading of wild-type RAS proteins in the setting of RTK ligand stimulation. This adaptive reactivation of RAS-MAPK signaling was abrogated by selective RTK (i.e. EGFR, FGFR) inhibitors, or by MEK inhibitors. Importantly, tipifarnib combined with the MEK inhibitor AZD6244 led to improved responses in Hras;p53 mouse tumors, whereas combination with the EGFR/FGFR inhibitors erlotinib and ponatinib did not, suggesting heterogeneity of upstream inputs. In order to identify acquired resistance mechanisms, tumor-bearing Hras;p53 mice were treated with tipifarnib until resistance developed (6 months). Whole exome sequencing of resistant tumors identified a truncating NF1 mutation and an activating mutation in GNAS at high allelic frequency. Upon NF1 knockdown in the human HRAS- mutant cell line C643, tipifarnib failed to inhibit pERK in vitro and caused resistance to tipifarnib in xenografts. By contrast, activating GNAS mutations transduced into Hras;p53 mouse tumor cell lines produced tipifarnib-resistant xenografts that activated the GNAS-cAMP-CREB pathway and demonstrated signs of redifferentiation. These data show that pharmacological targeting of RAS in a genetically accurate, mouse model of a RAS-driven virulent cancer leads to objective major responses and improved survival. We identified adaptive and acquired resistance mechanisms, and show that combined treatment with selective MEK inhibitors are beneficial. These data should also inform a currently enrolling clinical trial of tipifarnib for HRAS-mutant malignancies.
Citation Format: Brian R. Untch, Vanessa Dos Anjos, Maria ER Garcia-Rendueles, Jeff A. Knauf, Alan L. Ho, James A. Fagin. The farnesyltransferase inhibitor tipifarnib causes dramatic tumor regression and increases survival in murine HrasG12V driven aggressive thyroid cancers: Consequent adaptive and acquired resistance mechanisms inform combination treatments with improved responses [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 2063. doi:10.1158/1538-7445.AM2017-2063
Abstract 2065: Targeting the crosstalk between MET and Notch signaling in Rhabdomyosarcoma
Authors: Rota Rossella , Cossetti Cristina , Pomella Silvia , Gualtieri Alberto , Carcarino Elena , Ponzetto Carola , Taulli Riccardo , Miele Lucio , Locatelli Franco 
Published: July 2017

Abstract
Rhabdomyosarcoma (RMS) in a pediatric soft tissue sarcoma expressing myogenic markers. RMS includes two histological subtypes, embryonal and alveolar, which differ clinically and molecularly. The majority of alveolar RMS expresses fusion oncoproteins such as PAX3/7-FOXO1. Fusion positive (FP) RMS are at high risk showing a dismal prognosis while fusion negative (FN) ones have a better outcome. The MET protooncogene is a target gene of PAX3-FOXO1 and is overexpressed in FP RMS. However, it is upregulated/overactivated in FN RMS as well. It concurs to disease pathogenesis and is a potential target of therapy. We have shown that MET is down-regulated by the myomiR cluster miR-1/206 that promotes myogenic-like differentiation and inhibits proliferation of RMS cells. Notch signaling is also deregulated in RMS and inhibition of either Notch1 in FN or Notch3 in both subtypes leads to tumor growth blockade. Some preliminary data from our lab indicate that the expression of miR-1/206 is induced in Notch3-silenced RMS cells. Therefore, we sought to investigate the crosstalk between MET and Notch signaling in RMS.
We detected a down-regulation of MET transcript and protein in Notch3 knocked down RMS cells. In turn, MET silencing reduced Notch1 and Notch3 activation together with the levels of Notch ligands, JAG1 and DLL1. In line with this, forced expression of an activated form of MET (Tpr) resulted in Notch1 over-activation and up-regulation in FN RMS cells. Notably, a FN cell line treated for long time (more than 6 months) with growing doses of EMD, a clinically relevant MET inhibitor, showed resistance to treatment, over-activation of MET, i.e., hyperphosphorylation, and Notch1 signaling hyperactivation. These preliminary results suggest that MET and Notch signaling could crosstalk in RMS and that their co-targeting could be used to overcome drug resistance to single agent therapy. To this end, combination treatments of MET inhibitors with clinically relevant gamma-secretase inhibitors are in course.
The work is supported by Associazione Italiana Ricerca sul Cancro project IG15312 to RR.
Citation Format: Rossella Rota, Cristina Cossetti, Silvia Pomella, Alberto Gualtieri, Elena Carcarino, Carola Ponzetto, Riccardo Taulli, Lucio Miele, Franco Locatelli. Targeting the crosstalk between MET and Notch signaling in Rhabdomyosarcoma [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 2065. doi:10.1158/1538-7445.AM2017-2065
Abstract 2070: HMGB1 governs p53 to autophagic degradation via its nucleus-to-cytoplasm transport
Authors: He Qiaojun , Luo Peihua , Yang Xiaochun , Weng Qinjie , Ding Ling , Yang Bo 
Published: July 2017

Abstract
P53 is under exquisitely fine regulation and acts as a transcription factor that regulates the expression of thousands of genes that control apoptosis, necroptosis, ferrotosis, cell cycle arrest, senescence, metabolism and fertility. Regulation of p53 turnover is essential not only for the response to chemotherapeutic drugs or radiation in cancer cell but also to keep p53 activity under control in a normal cell. Moreover, .p53 is found to be overactivated in various diseases including idiopathic pulmonary fibrosis (IPF), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Promoting hyperactivated-p53 degradation can combat these diseases. However, the strategies that based on known proteasome-dependent degradation only can stabilize the expression level of p53 such as nutlins (inhibit the interaction between mdm2 and tumor suppressor p53). Autophagy-lysosomal degradation is the other pathway for controlling cellular protein stability. More and more researches have established that numerous proteins can be degraded through both proteasome and autophagy-lysosome pathways. However, very little is known to date about p53 turnover through autophagy-lysosome pathway. Here we discover that the activation of p53 autophagic degradation during an oral small molecule receptor tyrosine kinase inhibitor sunitinib in p53 wt cancer cells and normal cells. Mechanistically, the nucleus-to-cytoplasm shift is essential for the autophagic degradation of p53 induced by sunitinib, however, does not require p53 nuclear export signals. Indeed, p53 degradation is achieved by the nucleus-to-cytoplasm transport of its nuclear binding target HMGB1, shifting the distribution of p53 from the nucleus to the cytoplasm. Then cytoplasmic p53 directly interacts with the autophagy cargo receptor p62 to promote degradation. Importantly, inhibition of HMGB1 sensitizes cancer cell to sunitinib. Taken together, our study identified an alternative p53 protein turnover mechanism induced by sunitinib, thus not only elucidating the underlying mechanisms that limit sunitinib efficacy in cancer therapy but also opening an avenue for expanding the clinical indications of sunitinib.
Note: This abstract was not presented at the meeting.
Citation Format: Qiaojun He, Peihua Luo, Xiaochun Yang, Qinjie Weng, Ling Ding, Bo Yang. HMGB1 governs p53 to autophagic degradation via its nucleus-to-cytoplasm transport [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 2070. doi:10.1158/1538-7445.AM2017-2070