bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1166: Identification of a novel quinoxaline-isoselenourea targeting STAT3 pathway as a potential melanoma therapeutic
Authors: Alcolea Verónica , Karelia Deepkamal , Pandey Manoj K. , Plano Daniel , Singh Parvesh , Irby Rosalyn B. , Palop Juan , Amin Shantu , Sanmartín Carmen , Sharma Arun K. 
Published: July 2017

Abstract
The prognosis for patients with metastatic melanoma remains very poor. Constitutive STAT3 activation has been correlated to larger tumor size, metastasis, acquired resistance against vemurafenib (PLX-4032), and poor patient survival suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno-/isothio-urea derivatives (compounds 1/3) were studied in a panel of five melanoma cell lines, including B-RAFV600E mutant and wild type (WT) cells. Compound 1 (IC50 range 0.8-3.8 µM) showed lower IC50 values than 3 (IC50 range 8.1-38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 range 0.4-&gt;50 µM), especially at shorter treatment time (24 h). These effects are long-lasting since melanoma cells did not recover their proliferative potential after 14 days of the treatment. In addition, we confirmed that compound 1 induces cell death by apoptosis using Live and Dead, Annexin V and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduces protein levels of STAT3 and its phosphorylation, as well as decreases the expression of STAT3 regulated genes involved in survival and metastasis such as survivin and c-myc. Compound 1 also upregulates the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of 1 with SH2 domain of STAT3 suggesting its activity through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of STAT3 pathway to non-specifically target both B-RAF mutant and WT melanoma cells with much better cytotoxicity than the current therapy PLX-4032.
Citation Format: Verónica Alcolea, Deepkamal Karelia, Manoj K. Pandey, Daniel Plano, Parvesh Singh, Rosalyn B. Irby, Juan Palop, Shantu Amin, Carmen Sanmartín, Arun K. Sharma. Identification of a novel quinoxaline-isoselenourea targeting STAT3 pathway as a potential melanoma therapeutic [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 1166. doi:10.1158/1538-7445.AM2017-1166
Abstract 1169: mtTERT promoter as a target for treatment of glioblastoma
Authors: Bollam Saumya R. , Dhruv Harshil D. , Kang Hyun-Jin , Peng Sen , Gokhale Vijay , Hurley Laurence , Berens Michael 
Published: July 2017

Abstract
Approximately 86% of GBM tumors exhibit mutation at -124 or -146 bases upstream of the ATG start site in the transcription activating promoter region of Human telomerase reverse transcriptase (hTERT). Mutation in the promoter region of hTERT impairs repression, leading to overexpression of hTERT; inappropriate hTERT is associated with oncogenesis, tumor maintenance, and resistance to apoptosis. We surveyed long-term glioma cell lines and glioma PDX models for mt-hTERT; mRNA and protein expression of hTERT were assessed by qPCR and western blot. The -124 and -146 mutations are located in the major 5-12 G-quadruplex and result in misfolding of the silencer element and consequent over-expression of hTERT. Using a diverse small molecule library, we identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, TG-4260, which binds to the 26 mer base-pair heteroduplex loop, which is the nucleation site for cooperative folding of the major 5-12 G-quadruplex. The chaperone effect of TG-4260 corrects DNA hTERT G-quadruplex misfolding resulting from the somatic mutations and restores the silencer function of the G-quadruplex thereby reducing hTERT activity. TG-4260 directly decreases the transcription activity of the WT and the −124, −124/125, −138/139, and −146 mutants to a similar extent and suppresses the downstream gene BCL2, which activates caspase-3 and produces cell-cycle arrest, leading to cell death. Finally, TG-4260 significantly inhibits telomerase and shortens telomere length after five days of treatment and induces a senescence-like phenotype. This is the first example of the use of a pharmacoperone molecule to correct the misfolding of a DNA G-quadruplex element resulting from mutations in an early folding intermediate. Finally, we screened GBM cell models against a novel small molecule inhibitor that interferes with mutated hTERT promoter and demonstrated that TG-4260 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes.
Citation Format: Saumya R. Bollam, Harshil D. Dhruv, Hyun-Jin Kang, Sen Peng, Vijay Gokhale, Laurence Hurley, Michael Berens. mtTERT promoter as a target for treatment of glioblastoma [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 1169. doi:10.1158/1538-7445.AM2017-1169
Abstract 1174: CT179 degrades the olig2 transcription factor in glioblastoma stem-like cells and prolongs survival
Authors: Alton Gordon R. , Beaton Graham , Knowles Susan , Stein Gregory , Kesari Santosh 
Published: July 2017

Abstract
Olig2 is a bHLH transcription factor that has been shown to be a key driver of glioblastoma (GBM) tumorigenesis. Olig2 is expressed in human tumor-derived glioma stem-like cells. A growing body of evidence suggests that glioma stem-like cells (GSCs) are more representative of their parent tumors when cultured under defined serum-free conditions with the mitogens epidermal growth factor (EGF) and fibroblast growth factor (FGF). Furthermore, recent research has indicated that human Proneural GSCs grown in vitro in PDGF are more tumorigenic in vivo. We have designed and synthesized a potent inhibitor of Olig2 that possesses all the necessary properties for clinical development as an important new GBM therapeutic. CT179 dose dependently causes the degradation of Olig2 in multiple GBM cell lines and this correlates to G2/M arrest and increased apoptosis. CT179 also induces the loss of expression of EGFR and PDGFR in human GSCs. CT179 achieves high concentrations in the CNS with a long duration of pharmacologic action. Furthermore, CT179 significantly extends survival of mice implanted orthotopically with patient-derived human tumor GSCs. Immunohistochemistry demonstrates a marked reduction of Olig2 positive cells in the tumor bearing animals. Together, these results indicate that CT179 has significant promise as a new therapeutic for the treatment of human GBM.
Citation Format: Gordon R. Alton, Graham Beaton, Susan Knowles, Gregory Stein, Santosh Kesari. CT179 degrades the olig2 transcription factor in glioblastoma stem-like cells and prolongs survival [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 1174. doi:10.1158/1538-7445.AM2017-1174
Abstract 1177: Targeting NEDD8 to uncover an exceptional responder molecular subtype in glioblastoma
Authors: Hartman Lauren K. , Finlay Darren , Pan Peiwen , Kim Seungchan , Speyer Gil , Kiefer Jeff , Dhruv Harshil , Vuori Kristiina , Berens Michael 
Published: July 2017

Abstract
Neddylation is a post-translational mechanism that marks proteins for degradation through activity of NEDD8 Activating Enzyme (NAE). NAE blocks cullin-RING ligases from initiating proteosomal degradation of select substrates including cell cycle regulators and apoptosis modulators. MLN4924, or Pevonedistat, targets NAE and inhibits Neddylation and induces apoptosis in sensitive cells. We have discovered, in a cohort of glioblastoma PDX models, an exceptional responder to MLN4924 (GBM102). Most pertinently the effects we observe are in a PDX cultured as 3D neurospheres that more closely resemble the true tumor architecture, heterogeneity, and “stem-like” phenotype characteristic of tumor growth. We have leveraged RNAseq expression data from Cancer Cell Line Encyclopedia (CCLE) and Pevonedistat response data from The Cancer Therapeutics Response Portal (CTRP) to apply a network-based analysis to identify pathways enriched with differential dependencies between cell lines sensitive and non-sensitive to MLN4924. The analysis also identifies potential mediating genes that appear to play critical roles in such differential dependency networks. Identified differential networks and mediators provide insight for cellular mechanisms underlying drug response. Additionally, we also investigated the efficacy of MLN4924 against orthotopic glioma PDX models (GBM102 and GBM116) in vivo to validate our findings in vitro. Thus genomic characterization of patient samples may lead to the identification of a molecular signature which is associated with a subset of GBMs vulnerable to MLN4924. As the treatment options for GBM are extremely limited, this may highlight a novel alternative opportunity to treat a select fraction of patients with this aggressive disease.
Citation Format: Lauren K. Hartman, Darren Finlay, Peiwen Pan, Seungchan Kim, Gil Speyer, Jeff Kiefer, Harshil Dhruv, Kristiina Vuori, Michael Berens. Targeting NEDD8 to uncover an exceptional responder molecular subtype in glioblastoma [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 1177. doi:10.1158/1538-7445.AM2017-1177
Abstract 1181: Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™
Authors: Gavory Gerald , O'Dowd Colin , Rozycka Ewelina , Dossang Anthony , Henderson Ashling , Hughes Caroline , Miel Hugues , Barker Oliver , Costa Joana , Hewitt Peter , McFarland Mary , Proctor Lauren , Harrison Tim 
Published: July 2017

Abstract
Over the past decade, protein ubiquitination has emerged as an important post-translational modification with regulatory functions in all important cellular processes. Deubiquitinating enzymes (DUBs) including ubiquitin specific proteases (USPs) are cysteine proteases that catalyse the de-ubiquitination of protein substrates including tumor suppressors and oncogenes, hence regulating their levels and/or function. As a result of their increasing implications in the etiology of numerous pathological conditions including cancer, DUBs are emerging as an attractive and promising target class for the development of 1st in class medicines with high therapeutic impact. However, despite 15 years of intense research DUBs have proved largely refractory to drug discovery efforts.
Herein, we further describe the application of Ubi-Plex™, our drug discovery platform for the identification and optimisation of DUB inhibitors. In particular, we will highlight the versatility and robustness of Ubi-Plex™ by describing the outcome of our focussed library screening, hit identification, hit validation and elaboration activities on USP19.
A series of novel, highly potent (e.g. IC50 &lt; 10 nM) and reversible USP19 inhibitors have been identified. Further profiling has also demonstrated excellent selectivity against a large panel of DUBs and other non-related enzymes (e.g. kinases, proteases). These inhibitors are cell-permeable and exhibit potent target engagement in cells with EC50 values &lt; 30 nM. Finally, we will describe our progress towards the development of lead molecules with drug-like properties with the aim to rapidly establish in vivo proof-of-concept studies.
In summary, this work further exemplifies the tractability of the DUB target family and reports the discovery and detailed profiling of the first highly potent and selective inhibitors of USP19. These molecules may provide opportunities for the development of new anticancer therapeutics as well as for the treatment of muscle wasting disorders including cachexia.
Citation Format: Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Anthony Dossang, Ashling Henderson, Caroline Hughes, Hugues Miel, Oliver Barker, Joana Costa, Peter Hewitt, Mary McFarland, Lauren Proctor, Tim Harrison. Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex™ [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 1181. doi:10.1158/1538-7445.AM2017-1181
Abstract 1189: Enhanced YAP expression leads to EGFR TKI resistance in lung adenocarcinomas
Authors: Lee Ting-Fang , Tseng Yu-Chi , Wu Cheng-Wen 
Published: July 2017

Abstract
Epidermal growth factor receptor (EGFR) mutation is prevalently expressed in lung adenocarcinoma cases and acts as one of the major driving oncogenes. EGFR tyrosine kinase inhibitors (TKIs) have been used in patients with EGFR-mutant as an effective targeted therapy in lung adenocarcinoma, but drug resistance and tumor recurrence inevitably occurs. Recently, Yes-associate protein (YAP) has been reported to promote multiple cancer cell properties, such as promoting cell proliferation, EMT and drug resistance. This study investigated the roles of YAP in TKI-resistant lung adenocarcinoma. In TKI-sensitive cells, enhanced YAP expression leads to TKI resistant. Also, upregulated YAP expression and activation were detected in long term TKI-induced resistant cells. With reduced YAP expression using shRNA or YAP inhibitors, TKI-resistant cells become TKI-sensitive. Moreover, combined EGFR TKI and an YAP inhibitor statin, prolonged survival among lung cancer patients analyzed by Taiwan National Health Insurance Research database. These observations revealed the importance of YAP in promoting TKI-resistance and combined YAP inhibition can be a potential therapy delaying the occurrence of TKI-resistance in lung adenocarcinoma.
Citation Format: Ting-Fang Lee, Yu-Chi Tseng, Cheng-Wen Wu. Enhanced YAP expression leads to EGFR TKI resistance in lung adenocarcinomas [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 1189. doi:10.1158/1538-7445.AM2017-1189
Abstract 1192: Regorafenib (Stivarga®) reverses BCRP-mediated multidrug resistance in vitro and in vivo
Authors: Zhang Yun-Kai , Wang Yi-Jun , Zhang Guan-Nan , Zhang Wen-Ji , Wei Meng-Ning , Shi Zhi , Chen Zhe-Sheng 
Published: July 2017

Abstract
Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in various kinds of cancers, such as breast, colon, lung and ovarian cancers. Regorafenib, an oral multi-kinase inhibitor, was found to have inhibitory effects on BCRP-mediated MDR both in vitro and in vivo. Regorafenib significantly sensitized BCRP-overexpressing cancerous cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Our mechanism studies revealed that regorafenib inhibited the ATP-driven efflux function of BCRP. Our induced-fit docking and molecular dynamics simulations suggested the existence of strong and stable interactions between regorafenib and BCRP protein. Animal study revealed that the combination of regorafenib and topotecan resulted in great inhibitory effects on the growth of S1-M1-80 xenograft tumors. Regorafenib significantly increased the intratumoral concentration of topotecan but had no significant effects on topotecan plasma concentration. In conclusion, our study indicated that regorafenib could be useful in combating multidrug resistance in cancer treatments.
Citation Format: Yun-Kai Zhang, Yi-Jun Wang, Guan-Nan Zhang, Wen-Ji Zhang, Meng-Ning Wei, Zhi Shi, Zhe-Sheng Chen. Regorafenib (Stivarga®) reverses BCRP-mediated multidrug resistance in vitro and in vivo [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 1192. doi:10.1158/1538-7445.AM2017-1192
Abstract 1204: Enhanced efficacy of selumetinib by pretreatment of 5-FU in preclinical Ras/Raf-mutant colorectal cancer models
Authors: Jang Hye Yeon , Lee Haeng Jung , Nam Yeo Jin , Kim Won Dong , Bae Yong Ju , Jung Jin Hwang , Lee Seung Jin , Moon Dae Hyuk 
Published: July 2017

Abstract
Optimal strategy for the application of MEK inhibitor as combination therapy has not been established in Ras/Raf-mutant colorectal cancer (CRC). As we preliminary observed that 5-FU-induced pharmacodynamic changes were restored by ERK inhibition, we hypothesized that post-treatment of MEK inhibitor would enhance antitumor activity of 5-FU. Treatment of 5-FU for 2 days followed by selumetinib for another 2 days (FS schedule) exhibited synergism for cell viability, whereas reverse or concomitant combination showed antagonism or inconsistent response, respectively, in 8 kinds of CRC cell lines including BRAFV600E colo205, BRAFV600E RKO, or KRASG13D HCT8 cells. Combination as FS schedule persistently down-regulated the phosphorylation of ERK and pS6 throughout treatment period, whereas selumininib alone or reverse combination transiently decreased within 24 hr. The cells treated as FS schedule exhibited higher apoptosis and lower capacity of anchorage-independent cell growth than the cells under single or reverse combination. Microarray analysis revealed the distinct groups of genes underlying different efficacy by schedule-dependent treatment. Tumor growth in mice administered 5-FU at 10 mg/kg/day for colo205 and at 30 mg/kg/day for HCT8 for 7 days followed by selumetinib at 10 mg/kg/day for colo205 and 25 mg/kg/day for HCT8 for another 7 days was significantly retarded than that in mice treated with single agents. But the combination in reverse sequence induced comparable tumor growth to single agents. Decreased expression of Ki67 was observed in tumors from mice treated as FS scheduling. Our results suggest that the schedule-dependent combination of 5-FU and selumetinib may be benefit in patients having CRC with hyper-activation of Ras/RAF pathway.
Citation Format: Hye Yeon Jang, Haeng Jung Lee, Yeo Jin Nam, Won Dong Kim, Yong Ju Bae, Jin Hwang Jung, Seung Jin Lee, Dae Hyuk Moon. Enhanced efficacy of selumetinib by pretreatment of 5-FU in preclinical Ras/Raf-mutant colorectal cancer models [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 1204. doi:10.1158/1538-7445.AM2017-1204
Abstract 1210: Hederagenin overcomes the cisplatin resistance of head and neck cancer by targeting the antioxidant defense mechanisms
Authors: Shin Daiha , Kim Eun Hye , Jang Hyejin , Lee Jaewang , Kim Ji Won , Lee Jae Ryung , Kwon Minsu , Baek Seungho , Roh Jong-Lyel 
Published: July 2017

Abstract
Background: Cisplatin is a first-line chemotherapeutic agent for head and neck cancer (HNC). Acquired resistance to cisplatin is the most common reason for the failure of cisplatin chemotherapy. Hederagenin is extracted from the leaves of Cyclocarya paliurus, also known as sweet tea, which is one of the most popular teas utilized in traditional Chinese medicine. There is accumulating evidence it exhibited significant cytotoxicity against several types of cancers, however, which has been rarely tested in HNC cells. Herein, we examined the potential utility of hederagenin for overcoming cisplatin resistance in HNC cells and further clarified its molecular mechanisms of action.
Methods: Parental and cisplatin-resistant HNC cells, and Nrf2 or SLC7A11 gene overexpressed HNC cell lines and other human HNC cells were used. The cells were used to examine the effects of hederagenin treatment in HNC cell lines by measuring cell viability, cell cycle, cell death, reactive oxygen species (ROS) production, glutathione level, mitochondrial membrane potential (ΔΨm), and protein expression. The anti-tumor effect of hederagenin in mouse tumor xenograft models was also tested.
Results: Hederagenin induced cell death in both cisplatin-sensitive and -resistant HNC cells. Hederagenin treatment resulted in effective death of cisplatin-resistant HNC cells in a form of apoptotic cell death with the ΔΨm change. Hederagenin inhibited Nrf2 and SLC7A11 resulting in an increased ROS accumulation in HNC cells, of which effects were reversed by the pretreatment of antioxidant trolox. In addition, hederagenin caused the apoptosis effectively induced by targeting the antioxidant defense mechanisms in HNC cells. Subsequently, hederagenin activated signaling pathways of cell death involving caspase-3, PUMA, and PARP in the cells. The growth inhibitory effects of hedragenin were also confirmed in the tumor xenograft model implanted with cisplatin-resistant HNC cells.
Conclusions: Our data suggests that hederagenin can overcome the resistance of cisplatin in resistant HNC cells via targeting antioxidant systems.
Citation Format: Daiha Shin, Eun Hye Kim, Hyejin Jang, Jaewang Lee, Ji Won Kim, Jae Ryung Lee, Minsu Kwon, Seungho Baek, Jong-Lyel Roh. Hederagenin overcomes the cisplatin resistance of head and neck cancer by targeting the antioxidant defense mechanisms [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 1210. doi:10.1158/1538-7445.AM2017-1210
Abstract 1215: Apigenin overcomes drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer
Authors: Seo Hye-Sook , Ku Jin Mo , Hong Se Hyang , Choi Hyeong Sim , Woo Jong-Kyu , Jang Bo-Hyoung , Shin Yong Cheol , Ko Seong-Gyu 
Published: July 2017

Abstract
Drug resistance in chemotherapy is a major obstacle for successful treatment of cancer. Drug resistance is caused by various reasons including the overexpression of P-glycoprotein (P-gp, MDR1). Development of new useful compound which overcomes drug resistance is urgent. Apigenin, a dietary flavonoid, is reported as an anti-cancer drug in vivo and in vitro. In the present study, we investigated whether apigenin is able to reverse drug resistance using adriamycin-resistant breast cancer cells (MCF-7/ADR) and xenograft mouse model. As a result, apigenin significantly decreased cell growth and colony formation in MCF-7/ADR and its parental MCF-7 cells. This growth inhibition was related with accumulation of subG0/G1 apoptotic population and increase of apoptosis cell number. Apigenin reduced the mRNA expressions of multi-drug resistance 1 (MDR1) and multi-drug resistance associated proteins (MRPs) in MCF-7/ADR cells. Apigenin also down-regulated the expression of P-gp. Apigenin reversed drug efflux from MCF-7/ADR cells resulting in Rho123 accumulation. Inhibition of drug resistance by apigenin is related with suppression of STAT3 signaling pathway. Apigenin decreased STAT-3 activation (p-STAT3) and its nuclear translocation, and inhibited the secretion of VEGF and MMP-9 which are STAT3 target genes. STAT3 inhibitor, JAK inhibitor I and HIF-1α inhibitor decreased cell growth in MCF-7 and MCF-7/ADR cells. In conclusion, apigenin overcomes drug resistance, and this study advances human health.
Note: This abstract was not presented at the meeting.
Citation Format: Hye-Sook Seo, Jin Mo Ku, Se Hyang Hong, Hyeong Sim Choi, Jong-Kyu Woo, Bo-Hyoung Jang, Yong Cheol Shin, Seong-Gyu Ko. Apigenin overcomes drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer [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 1215. doi:10.1158/1538-7445.AM2017-1215