bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4351: Identification of molecular signature associated with the castration-resistant prostate cancer (CRPC) development by next-generation sequencing (NGS)-based transcriptomic profiling
Authors: Kim Seon-Kyu , Kim Jeong-Hwan , Jeong Pildu , Kim Wun-Jae , Kim Yong Sung , Yun Seok-Joong , Kim Seon-Young 
Published: August 2015

Abstract
Backgrounds:
Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer produced by disease progression following surgical or pharmaceutical castration. The development process of CRPC becoming castrate resistant is unclear. The objective of this study is to identify a gene set and putative signaling pathway for mediating the development of CRPC.
Methods:
RNA-seq data was generated using 54 prostate samples [primary prostate cancer (PCa), CRPC, and benign prostatic hyperplasia (BPH)], among which 8 were paired samples of PCa and CRPC obtained from 4 patients. Diverse statistical methods, including a generalized linear model likelihood ratio test, were applied to identify the signature associated with CRPC development. The interconnectivity between genes in the signature was verified by Ingenuity Pathway Analysis TM. We also confirmed a relevance of the signature with experimental assays using prostate cancer cell lines.
Results:
Unsupervised hierarchical cluster analysis of RNA-seq data revealed a clear gene expression pattern of tumorigenesis in PCa with heterogeneous molecular characteristics of CRPC. Comparing paired cancer samples, 309 genes were differentially expressed between PCa and CRPC samples. We also tested unpaired sample groups (PCa vs. CRPC) and found that 182 genes had significantly differences of expression (a generalized linear model likelihood ratio test, P &lt; 0.001, a 2-fold or greater relative difference). When comparing two gene sets, a total of 15 genes was common in both paired and unpaired CRPC groups. Among them, AR and SPINK1 were significantly increased in the CRPC than in the PCa groups. Gene network analyses and experimental assays of AR and SPINK1 revealed that CRPC development could be mediated by SPINK1-AR pathway.
Conclusion:
The molecular signature defined by activation of SPINK1-AR may be a genetic determinant of progression from PCa to CRPC.
Note: This abstract was not presented at the meeting.
Citation Format: Seon-Kyu Kim, Jeong-Hwan Kim, Pildu Jeong, Wun-Jae Kim, Yong Sung Kim, Seok-Joong Yun, Seon-Young Kim. Identification of molecular signature associated with the castration-resistant prostate cancer (CRPC) development by next-generation sequencing (NGS)-based transcriptomic profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4351. doi:10.1158/1538-7445.AM2015-4351
Abstract 4358: Targeting connexin 43 with α-connexin carboxyl-terminal (ACT1) peptide in breast cancer
Authors: Grek Christina , Rhett Joshua Matthew , Abt Melissa , Bruce Jaclynn , Ghatnekar Gautam , Yeh Elizabeth S. 
Published: August 2015

Abstract
Expression and functional studies have identified connexins (Cxs), a family of gap junction proteins, as potential tumor suppressors. Studies suggest that connexin 43 (Cx43) has a role in breast cancer cell proliferation, differentiation, and migration. Although pan-gap junction drugs are available, the lack of specificity of these agents increases the opportunity for off target effects. Consequently, a therapeutic agent that specifically modulates Cx43 would be beneficial and has not been tested in breast cancer. In this study, we now test a Cx43 specific agent, called α-connexin carboxyl-terminal (ACT1), in breast cancer. Our studies demonstrate that modulation of Cx43 activity in breast cancer can be effectively achieved with the agent ACT1 to sustain Cx43-mediated gap junctional activity resulting in impaired malignant progression. Furthermore, using ER+ and HER2+ breast cancer cell models, we show that ACT1 treatment enhances the activity of lapatinib and tamoxifen.
Citation Format: Christina Grek, Joshua Matthew Rhett, Melissa Abt, Jaclynn Bruce, Gautam Ghatnekar, Elizabeth S. Yeh. Targeting connexin 43 with α-connexin carboxyl-terminal (ACT1) peptide in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4358. doi:10.1158/1538-7445.AM2015-4358
Abstract 4362: Screening of investigational antimalarials for anticancer activity in high risk N-MYC amplified neuroblastoma (NB)
Authors: Coulter Don W. , Vennerstrom Jonathan , Sharp John G. , Dong Yuxiang , Wang Xiaofang , McIntyre Erin , McGuire Tim 
Published: August 2015

Abstract
Introduction: NB is a pediatric tumor of neural crest origin. Patients who have N-MYC amplified metastatic tumors have poor outcomes. The importance of autophagy in protecting NB cells from chemotherapy has been postulated. In the following study we screened bisquinoline (BQ) and ozonide (OZ) antimalarials (potential autophagy inhibitors) in a highly N-MYC amplified NB cell line (BE-2) and a moderately amplified N-MYC NB cell line (IMR-32). A combination of monolayer cell culture and neurospheres were used to screen activity.
Methods: Using a 96 well MMT based assay and 16 hour treatment with compounds dissolved in DMSO, cytotoxicity was calculated as a percent decline in absorbance compared to DMSO controls. 32 BQ and 13 OZ antimalarials were tested. All compounds were tested at a concentration of 1 mcg/ml; an achievable concentration in patients. Selected compounds that were cytotoxic in monolayer culture will be tested in neurosphere culture and then in a mouse xenograft model alone and combined with chemotherapy.
Results: The bisquinolone antimalarials were consistently active in both BE-2 and IMR cell culture. Among the bisquinolones, Q1-9, Q2-5, Q2-61, and Q3-75 had the greatest cytotoxicity. There was no clear structure-activity-relationship for this small bisquinoline library. Among the ozonides, OZ465, OZ513, and OZ521 were the most active. From these data, we could infer that the presence of a weak base functional group was required, but was insufficient for cytotoxicity. Initial studies in BE-2 and IMR neurosphere culture using an LDH assay for cytotoxicity suggests similar activity. Monolayer results are shown in the Table below:
SymbolDrug ClassBE-2*IMR-32*Q1-9BQ38.535.8Q2-5BQ29.844.4Q2-61BQ40.731.4Q3-75BQ40.619.3OZ465OZ3820.6OZ513OZ73.627.7OZ521OZ4415.9
*Percent decline in absorbance compared to DMSO control
Conclusion: The above data indicates that two classes of antimalarials had moderate cytotoxicity in both 96-well monolayer assays as well as in a neurosphere assay (data not shown). The results suggest cytotoxic activity in high and moderately amplified N-MYC NB in both monolayers and neurospheres.
Note: This abstract was not presented at the meeting.
Citation Format: Don W. Coulter, Jonathan Vennerstrom, John G. Sharp, Yuxiang Dong, Xiaofang Wang, Erin McIntyre, Tim McGuire. Screening of investigational antimalarials for anticancer activity in high risk N-MYC amplified neuroblastoma (NB). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4362. doi:10.1158/1538-7445.AM2015-4362
Abstract 4421: GPER-mediated activation of the cAMP response element-binding protein (CREB) and subsequent IGFBP-1 expression is altered during the development of tamoxifen resistance
Authors: Vaziri-Gohar Ali , Houston Kevin D. 
Published: August 2015

Abstract
Tamoxifen is a commonly prescribed anti-estrogen treatment for breast cancer patients; this selective estrogen receptor modulator functions as an ERα-antagonist in breast tissue and inhibits cell proliferation and survival of breast cancer cells. More recently, the active metabolite of tamoxifen, 4-OHT (Tam), has been shown to activate the G protein-coupled estrogen receptor (GPER). Previous studies from our laboratory identified a novel, GPER-dependent mechanism of Tam action in breast cancer cells that requires the extracellular accumulation of the insulin-like growth factor binding protein-1 (IGFBP-1). The molecular mechanisms of Tam-induced IGFBP-1 production mediated by GPER have not been determined. GPER activation has been shown to stimulate cAMP production and PKA activation in several cell types. We hypothesized the cAMP response element-binding protein (CREB) activation is required for Tam-induced IGFBP-1 production in breast caner cells. To determine if CREB activation may be involved in IGFBP-1 transcription, CREB phosphorylation (S133) status and nuclear accumulation were determined in MCF-7 cells after Tam treatment. The phosphorylation and nuclear accumulation of CREB were observed in Tam-treated MCF-7 cells suggesting that CREB activation may be required for Tam-induced IGFBP-1 transcription. Increased CREB phosphorylation and IGFBP-1 transcription were inhibited by pretreatment with the PKA inhibitor H-89 supporting a role for CREB in Tam-induced IGFBP-1 expression. H-89 pretreatment also significantly decreased the previously reported inhibition of IGF-1-stimulated signaling by Tam treatment in breast cancer cells. We have previously reported that Tam-induced IGFBP-1 expression is dysregulated in Tam-resistant MCF-7 cells (MCF-7TamR). To determine if aberrant CREB signaling results in the observed dysregulation, similar experiments were performed in MCF-7TamR cells. Our results show that CREB phosphorylation and nuclear accumulation are decreased in Tam-resistant cells compared to Tam-sensitive cells. Taken together, these results suggest that activation of GPER results in CREB-dependent IGFBP-1 production and subsequent inhibition of IGF-1-stimulated signaling in breast cancer cells treated with Tam. Furthermore, dysregulation of GPER-mediated CREB activation may be involved in the development of Tam resistance in breast cancer.
Citation Format: Ali Vaziri-Gohar, Kevin D. Houston. GPER-mediated activation of the cAMP response element-binding protein (CREB) and subsequent IGFBP-1 expression is altered during the development of tamoxifen resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4421. doi:10.1158/1538-7445.AM2015-4421
Abstract 4422: TTT-28, a newly synthesized thiazole-valine peptide, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1 transporter
Authors: Wang Yi-Jun , Anreddy Nagaraju , Patel Bhargav A. , Chufan Eduardo E. , Singh Satyakam , Zhang Guan-Nan , Zhang Yun-Kai , Barbuti Anna Maria , Ambudkar Suresh V. , Talele Tanaji T. , Chen Zhe-Sheng 
Published: August 2015

Abstract
Cancer cells often exhibit either intrinsic or acquired resistance to chemotherapy through a phenomenon known as multidrug resistance (MDR). Different mechanisms contribute to the development of MDR, preeminent among them being the accelerated drug efflux mediated by overexpression of ATP-binding cassette (ABC) transporters. Currently, it has been found that some small molecule tyrosine kinase inhibitors (TKIs), such as motesanib, linsitinib, masitinib and nilotinib, were able to modulate the activity of ABC transporters. Thus, the aim of this study was to determine whether TTT-28, a newly synthesized thiazole-valine peptide, could reverse ABCB1-mediated MDR. The results showed that TTT-28 significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to its substrate anticancer drugs. Using calcein-AM efflux assay, we identified TTT-28 (IC50 = 1.0 μM) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitterion. TTT-28 significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. Furthermore, TTT-28 inhibited the photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin with IC50 = 0.75 μM and stimulated the basal ATP hydrolysis of ABCB1 in a concentration-dependent manner (EC50 ATPase = 0.027 μM). Consistent with these findings, biochemical and docking studies showed site-1 to be the preferable binding site for TTT-28 within the drug-binding pocket of human ABCB1. Therefore, we report that TTT-28 antagonizes MDR by inhibiting the efflux activity of the ABCB1 transporter. These findings reveal high clinical values for the co-administration of TTT-28 and ABCB1 substrate chemotherapeutic drugs in cancer patients that overexpress ABCB1 and stimulate further research on circumventing the ABCB1-mediated MDR in cancers.
Citation Format: Yi-Jun Wang, Nagaraju Anreddy, Bhargav A. Patel, Eduardo E. Chufan, Satyakam Singh, Guan-Nan Zhang, Yun-Kai Zhang, Anna Maria Barbuti, Suresh V. Ambudkar, Tanaji T. Talele, Zhe-Sheng Chen. TTT-28, a newly synthesized thiazole-valine peptide, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1 transporter. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4422. doi:10.1158/1538-7445.AM2015-4422
Abstract 4424: Molecular diagnostics of drug resistant multiple myeloma cases using targeted next generation sequencing
Authors: Ikeda Hiroshi , Sasaki Yasushi , Igarashi Tetsuyuki , Aoki Yuka , Hayashi Toshiaki , Ishida Tadao , Tokino Takashi , Sinomura Yasuhisa 
Published: August 2015

Abstract
In multiple myeloma (MM), there are two distinct genetic subtypes based on copy number alterations and translocations. About half of all MM cases are a hyperdiploid type, which is characterized by multiple trisomies of chromosomes 3, 5, 7, 9 11, 15, 19 and 21 and a lower prevalence of primary translocations involving the immunoglobulin heavy chain (IgH) locus at 14q32. The remaining cases are the non-hyperdiploid type, and chromosomes 8, 13, 14, and 16 are frequently lost. Non-hyperdiploid myeloma is strongly association with translocations of IgH alleles with various partner chromosomes, such as t(11;14)(q13;q32), t(4;14)(p16.3; q32), t(14;16)(q32;q23), t(6;14)(p21;q32) or t(14;20) (q32;q11). The copy number alterations in other chromosome regions such as 1q, 6q, 8p, and 16q occur in both subtypes. Overall, non-hyperdiploid MM is associated with worse survival than hyperdiploid MM. In this study, we sequenced all exons of 409 cancer-related genes in matched tumor and normal DNA from 5 non-hyperdiploid MM patients using a next-generation semiconductor sequencing protocol. DNA was extracted from magnetic bead-enriched bone marrow CD138 positive tumor cells from the patients and CD138 negative cells were used as matched normal cells. We detected both point mutations and copy number variations (CNVs). One individual with refractory MM (IgG λ type, ISS stage II) displayed 8 non-synonymous somatic mutations in addition to numbers of CNVs including CCND1 and RB1. We observed 2 point mutations and 3 CNVs, affecting NF-kB pathway genes: IKBKB, CYLD, IKBKE, CD79B and SYK. Although the basis of NF-kB pathway activation is only partially understood, our findings greatly expand the mechanisms by which NF-kB may be activated in this patient. We also detected several gene alterations, which may be associated with poor prognosis and poor response to chemotherapy in patients with refractory MM. Although its value should be further confirmed in larger samples, the targeted next generation sequencing is a valuable tool for high-throughput genetic testing in clinical research.
Citation Format: Hiroshi Ikeda, Yasushi Sasaki, Tetsuyuki Igarashi, Yuka Aoki, Toshiaki Hayashi, Tadao Ishida, Takashi Tokino, Yasuhisa Sinomura. Molecular diagnostics of drug resistant multiple myeloma cases using targeted next generation sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4424. doi:10.1158/1538-7445.AM2015-4424
Abstract 4449: A novel Porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations
Authors: Ke Zhiyuan , Madan Babita , Lim Shermaine Q.y. , Wang Sifang , Alam Jenefer , Ho Soo Yei , Jeyaraj Duraiswamy Athisayamani , Ghosh Kakaly , Chew Yun Shan , Ding Li Jun , Monoharan Vithya , Pendharkar Vishal , Ong Esther , Hill Jeffrey , Sangthongpitag Kanda , Keller Thomas , Lee May Ann , Virshup David M. 
Published: August 2015

Abstract
Various mutations in the Wnt pathway contribute to aberrant activation of Wnt signaling, which is implicated in multiple cancers. Besides the mutation of Adenomatous polyposis coli (APC) or beta-catenin which causes the continuous activation of Wnt signaling by stabilizing beta-catenin, there are mutations of other genes such as RNF43 that regulate Wnt signaling at the level of the ligand or cell surface receptor. Inhibition of the secretion of all human Wnts by blocking their palmitoleoylation by the O-acyltransferase, Porcupine (PORCN), could be an alternative therapeutic approach. Here we have developed a compound with a novel pharmacophore that can inhibit PORCN activity and hence Wnt signaling in nanomolar concentration. In vivo efficacy study demonstrated that the compound is highly efficacious in preventing tumor growth in genetic modification model MMTV-WNT1 mouse. We have identified a subset of pancreatic cancer, cholangiocarcinoma and mucinous ovarian cancer cell lines that are sensitive to the compound. Most of these cell lines harbor mutations in RNF43. Xenograft tumor models derived from the cancer cell lines were found to be sensitive to the compound. Our results demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors in a subset of cancers with mutation in RNF43 is a feasible and nontoxic strategy to overcome the problem of redundancy of Wnts, thereby, providing new option for therapy in diseases with up regulated Wnt expression.
Citation Format: Zhiyuan Ke, Babita Madan, Shermaine Q.y. Lim, Sifang Wang, Jenefer Alam, Soo Yei Ho, Duraiswamy Athisayamani Jeyaraj, Kakaly Ghosh, Yun Shan Chew, Li Jun Ding, Vithya Monoharan, Vishal Pendharkar, Esther Ong, Jeffrey Hill, Kanda Sangthongpitag, Thomas Keller, May Ann Lee, David M. Virshup. A novel Porcupine inhibitor is effective in the treatment of cancers with RNF43 mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4449. doi:10.1158/1538-7445.AM2015-4449
Abstract 4487: Design, synthesis, and biological activity of N-phenyl ureidobenzenesulfonates (PUB-SOs) as new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms
Authors: Fortin Sébastien , Moussa Hanane , Gagné-Boulet Mathieu , Lacroix Jacques , Côté Marie-France , Velic Denis , Pauty Joris , Masson Jean-Yves 
Published: August 2015

Abstract
Our research group has developed a new family of promising anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs). PUB-SOs are based on a genuinely new molecular scaffold and pharmacophore constituted by two key aromatic moieties linked by a sulfonate bridge. PUB-SOs block the cell cycle progression in the S-phase and cause DNA double-strand breaks as confirmed by the phosphorylation of H2AX. In addition, PUB-SOs exemplified by prototypical PUB-SO referred to as SFOM-0046 activate selectively ATR-Chk1 pathway in all cell lines studied while it does not activate the ATM-Chk2 pathway. Using immunofluorescence, cell cycle analysis and cell survival assays, we showed that the combination of the Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) and SFOM-0046 provide a proof-of concept that the cytotoxicity of PUB-SOs can be synergized by relevant anticancer drugs. Accordingly, we hypothesized that PUB-SOs inhibit proteins or enzymes involved in critical DNA repair/replication mechanisms.
In such a context, we designed a new structure-activity relationship study to assess the effects of the nature and position of different substituents on the aromatic ring B. More than 50 new PUB-SO derivatives were prepared so far and they exhibit antiproliferative activity on the low micromolar range on HT-1080 fibrosarcoma, HT-29 colon carcinoma, M21 skin melanoma and MCF7 breast carcinoma. They block also the cell cycle progression in the S-phase. These results show that substituents on ring B can be modulated to optimize both the antiproliferative and as well as biopharmaceutical properties.
In conclusion, PUB-SOs are easily synthesized, purified and pharmacomodulated, and they are therefore promising new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms through a genuinely innovative molecular scaffold and pharmacophore.
Citation Format: Sébastien Fortin, Hanane Moussa, Mathieu Gagné-Boulet, Jacques Lacroix, Marie-France Côté, Denis Velic, Joris Pauty, Jean-Yves Masson. Design, synthesis, and biological activity of N-phenyl ureidobenzenesulfonates (PUB-SOs) as new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4487. doi:10.1158/1538-7445.AM2015-4487