bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3864: Development of high-specific and sensitive reporter assays for the detection of Wnt/β-catenin signaling activity
Authors: Yamaguchi Kiyoshi , Zhu Chi , Ohsugi Tomoyuki , Saku Akari , Ikenoue Tsuneo , Furukawa Yoichi 
Published: August 2018

Abstract
The Wnt/β-catenin signaling pathway is involved in development, tissue homeostasis, and regeneration. Since aberrant activation of this pathway plays a crucial role in human carcinogenesis, inhibition of this pathway has been shown to be a promising therapeutic strategy for cancers with de-regulated Wnt signaling. Although cell-based assays using synthetic TCF/LEF reporters (also known as TOPFLASH) have contributed to the discovery of small molecules that modulate Wnt signaling pathway, these assays often raise a problem of the specificity in the screening. In this study, we aimed to develop a specific reporter for the detection of Wnt signaling activity. We performed integrated transcriptome analysis and found that expression of histidine ammonia-lyase gene (HAL) is negatively regulated by β-catenin/TCF. In addition to TOPFLASH, we leveraged a promoter region of HAL as another transcriptional readout of Wnt signaling. Subsequently, HepG2 cells stably expressing both optimized HAL promoter reporter and TOPFLASH reporter were established. Since inhibition of the β-catenin/TCF transcriptional activity decreased TOPFLASH activity and simultaneously increased HAL reporter activity, we termed this assay as a bidirectional reporter assay. To verify the effectiveness of this assay, we compared the number of hits in the screening of a test library using the bidirectional assay with that using the conventional TOPFLASH/FOPFLASH assay. Among the 361 compounds in the library, the bidirectional reporter assay identified 9 hits, while the TOPFLASH/FOPFLASH assay did 79 hits. Four compounds were overlapped between these assays, suggesting that the bidirectional assay decreased false positives compared with the conventional assay. The concept of bidirectional assay might be useful for the screening of compounds that regulate other transcriptional factors and/or disease-associated signaling pathways.
Citation Format: Kiyoshi Yamaguchi, Chi Zhu, Tomoyuki Ohsugi, Akari Saku, Tsuneo Ikenoue, Yoichi Furukawa. Development of high-specific and sensitive reporter assays for the detection of Wnt/β-catenin signaling activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3864.
Abstract 3867: Activating ESR1 mutations detection by single ddPCR assay
Authors: Bidard Francois-Clement , Jeannot Emmanuelle , Cabel Luc , Epaillard Nicolas , Ayachy Radouane El , Noret Aurelien , Vincent-Salomon Anne , Pierga Jean-Yves , Bieche Ivan , Proudhon Charlotte , Stern Marc-Henri 
Published: August 2018

Abstract
Background: In metastatic breast cancer, most mutations of ESR1 (which encodes the estrogen receptor alpha ERα) occur in exon 5 (E380Q) and/or 8 (L536, Y537, D538). These mutations are responsible for acquired resistance to hormone deprivation but can be targeted by selective estrogen receptor degraders (SERD) such as fulvestrant. Circulating tumor DNA (ctDNA) allows a non-invasive assessment of ESR1 mutations, but implementing its routine use requires a sensitive, specific and fast technique, at a moderate cost.
Methods: We designed a ddPCR assay scanning for all mutations targeting the 536-538 amino acid residues of ERα with a unique pair of probes and multiplexed it with other probes targeting E380Q. Sensitivity and specificity were assessed in vitro; this multiple hotspot scanning (MHS) ddPCR was used to detect ESR1 mutants in cohorts of patients with hormone deprivation-resistant metastatic breast cancer.
Results: All the above-mentioned mutations were detected in a single MHS ddPCR assay with a high specificity and with a limit of detection of ~0.1% in mutant allele frequency, allowing ESR1 mutant detection in circulating tumor DNA. A perfect concordance with targeted next generation sequencing was observed in the first 31 clinical plasma samples tested. This technique also detected ESR1 polyclonal mutations.
Conclusion: This technique allows for a sensitive, large scale and repeated screening of ESR1 mutants with a single ddPCR assay. The clinical utility of ESR1 mutation detection by this technique is now investigated in the randomized phase 3 PADA-1 trial (sponsors: Unicancer/Gineco), in which patients with rising levels of circulating ESR1 mutants during aromatase inhibitor / palbociclib therapy are eventually switched to fulvestrant / palbociclib (NCT03079011).
ESR1 mutants detectable in a single ddPCR assayAA changesMutant frequency (as per Toy et al, Cancer Discov 2017).E380Q19%L536H4%L536P2%L536R1%Y537S11%Y537C6%Y537N5%Y537D1%D538G32%D538-L539ins1%total % of mutations covered~82% (Many of the 18% remaining mutations occur outside exon 5 & 8 and have no proven functional impact)
Citation Format: Francois-Clement Bidard, Emmanuelle Jeannot, Luc Cabel, Nicolas Epaillard, Radouane El Ayachy, Aurelien Noret, Anne Vincent-Salomon, Jean-Yves Pierga, Ivan Bieche, Charlotte Proudhon, Marc-Henri Stern. Activating ESR1 mutations detection by single ddPCR assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3867.
Abstract 3876: Development and in vitro evaluation of cell membrane lipid-extracted nanoliposomes for lung cancer treatment
Authors: King Jasmine , Bhatt Aarohi , Goodrich Drew , Preteroti Thomas , Alharbi Hanan , Campbell Robert 
Published: August 2018

Abstract
Background: Every year more deaths are attributed to lung cancer compared to colon, prostate, and breast cancers combined. Lung cancer is typically diagnosed at late stages, and has demonstrated poor treatment outcomes due to acquired drug resistance. Unfortunately, as one method is introduced to overcome drug resistance a new mechanism can arise. In an effort to overcome drug resistance lipid extracts (LE) were derived from target cells, and the ingredients were used to develop nanoliposomes that would selectively target a desired cell population compared to controls. The early studies were designed to demonstrate the use of CLENs (cellular membrane lipid-extracted nanoliposomes) for the targeting of lung cancer. Experimental Procedures: CLENs were initially prepared using various ratios of LE/DOPC/Chol/PEG by thin film evaporation. Particle size and zeta potential values were determined for all preparations of CLENs (with and without drug). CLENs were evaluated for selectivity for target compared to control cells. Cytotoxicity studies were performed on various doxorubicin hydrochloride-loaded CLENs using a cell model of lung cancer (ChagGo-K-1). For cellular uptake studies ChaGo-K-1 cells were seeded at 10,000 cells/mL in a 48-well plate and allowed to incubate for 24 hours prior to cell studies. A fluorescence microplate reader was used to determine fluorescence intensity values for the two studies. Results: ChaGo-K-1 CLENs demonstrated an average particle size of 206+/-2 nm and zeta-potential of -21+/-3 mV, illustrating favorable characteristics for drug delivery and interstitial drug targeting. The cellular uptake studies suggested that ChaGo-K-1 CLENs were selective for ChaGo-K-1 cells in vitro, when compared to all other control varieties of CLENs. Drug-loaded ChaGo-K-1 CLENs displayed significant cytotoxicity against ChaGo-K-1 cells compared to control cells. Fluorescence microscopy revealed association of ChagGo-K-1 CLENs with target cells. Conclusions: Based on promising early finding CLENs may represent a relatively tumor specific drug delivery system that can be used to overcome drug resistance, improve efficacy, and to limit off-target drug effects. Preclinical studies will investigate whether the relative selectivity and cytotoxicity observed against lung cancer cells in vitro translates to favorable tumor uptake and efficacy in vivo.
Citation Format: Jasmine King, Aarohi Bhatt, Drew Goodrich, Thomas Preteroti, Hanan Alharbi, Robert Campbell. Development and in vitro evaluation of cell membrane lipid-extracted nanoliposomes for lung cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3876.
Abstract 3887: Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity
Authors: Udagawa Chihiro , Nakamura Hiromi , Ohnishi Hiroshi , Tamura Kenji , Shimoi Tatsunori , Yoshida Masayuki , Yoshida Teruhiko , Okamura Hiroshi , Totoki Yasushi , Shibata Tatsuhiro , Zembutsu Hitoshi 
Published: August 2018

Abstract
Although trastuzumab-induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify a genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed whole exome sequencing of germline DNA samples from 9 patients with trastuzumab-induced cardiotoxicity, and conducted a case-control association study of 2,258 genetic variants between 9 cases (with trastuzumab-induced cardiotoxicity) and general Japanese population controls registered in Human Genetic Variation Database (HGVD). To further validate the result of the screening study, we carried out a replication study of 10 variants showing Pmin &lt; 0.001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab-induced cardiotoxicity). In the replication study, we observed that three variants had effect in the same direction as in the screening study (SNV1 in exon 2 of HERADR1, SNV2 in exon 2 of HERADR2 and SNV3 in exon 44 of HERADR3). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab-induced cardiotoxicity (SNV3 in HERADR3, combined-Pmin = 0.00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for the patients with HER2 positive cancer.
Citation Format: Chihiro Udagawa, Hiromi Nakamura, Hiroshi Ohnishi, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Hiroshi Okamura, Yasushi Totoki, Tatsuhiro Shibata, Hitoshi Zembutsu. Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3887.
Abstract 390: Genome-wide CRISPR screens in brain tumor initiating cells (BTICs) identify potent sensitizers and resistors of conventional chemoradiotherapy
Authors: Chokshi Chirayu , Tieu David , Brown Kevin , Venugopal Chitra , Vora Parvez , Chan Katherine , Tong Amy , Qazi Maleeha , Singh Mohini , Savage Neil , Habsid Andrea , Moffat Jason , Singh Sheila 
Published: August 2018

Abstract
Glioblastoma (GBM) is a highly aggressive and most common form of malignant primary brain tumors in adults (WHO grade IV). Despite surgical and therapeutic interventions, including chemotherapy with the alkylating agent Temozolomide (TMZ) and cranial irradiation, GBM relapse is inevitable with a median survival of &lt;15 months. Extensive intratumoral heterogeneity in GBM is believed to be the leading cause of therapy resistance and disease relapse, suggesting that therapy acts as a bottleneck for tumor evolution. Recently, the advent of CRISPR-Cas9 technology has led to the development of genome-wide libraries of sgRNAs capable of introducing insertion-deletion (indels) within exonic regions of genes, leading to a frameshift mutation two-thirds of the time. Here, we present the first genome-wide CRISPR-Cas9 knockout screen in patient-derived GBM BTICs aimed to discover synthetic lethal sensitizers of conventional chemoradiotherapy. Briefly, we performed genome-wide CRISPR-Cas9 screens in treatment-naïve GBM BTICs subjected to in vitro chemotherapy with TMZ and irradiation. By comparing sgRNA dynamics at each doubling period, we were able to identify potent sensitizer genes exclusive to combined chemoradiotherapy, and not TMZ or irradiation alone. Candidate sensitizer genes were validated in an arrayed format to evaluate impact on GBM BTIC self renewal, proliferation, and sensitivity to TMZ and radiation. We aim to further validate these sensitizers of conventional chemoradiotherapy by performing a focused CRISPR-Cas9 genetic screen in our patient-derived xenograft model of treatment-refractory GBM. Ultimately, adjuvants targeting sensitizer genes could greatly enhance the impact of conventional chemoradiotherapy in GBM patients, leading to an increase in patient survival.
Citation Format: Chirayu Chokshi, David Tieu, Kevin Brown, Chitra Venugopal, Parvez Vora, Katherine Chan, Amy Tong, Maleeha Qazi, Mohini Singh, Neil Savage, Andrea Habsid, Jason Moffat, Sheila Singh. Genome-wide CRISPR screens in brain tumor initiating cells (BTICs) identify potent sensitizers and resistors of conventional chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 390.
Abstract 3928: Sertraline in melanoma treatment: TCTP as a therapeutic target
Authors: Boia-Ferreira Marianna , Basílio Alana , Baldissera Antonielle B. , Matsubara Fernando H. , Appel Marcia H. , Costa Cleber R. da , Chaim Olga M. , Gremski Luiza H. , Veiga Silvio S. , Senff-Ribeiro Andrea 
Published: August 2018

Abstract
Background: Sertraline (an SSRI antidepressant) binds directly to TCTP protein and decreases its intracellular levels. TCTP (Translationally Controlled Tumor Protein) is an antiapoptotic protein highly conserved through phylogeny. TCTP overexpression was detected in several tumor types. Silencing TCTP was shown to induce tumor reversion, a process overriding at the molecular level the malignant process. There is a reciprocal repression between TCTP and P53.
Methods: We evaluated the role of TCTP in melanoma using sertraline and siRNA. Cell viability, migration and clonogenicity were assessed in human and murine melanoma cell in vitro. Sertraline was evaluated in vivo in a murine melanoma model and compared to dacarbazine, a major a chemotherapeutic agent used in melanoma treatment. Long-term effect of sertraline was evaluated keeping cells on regular culture for 5 days after a 72h-treatment and then assessing proliferation, clonogenicity and in vivo growth.
Results: (i) In human melanoma cell lines, sertraline treatment and decrease of TCTP levels (by siRNA) are related to the inhibition of clonogenicity and migration; (ii) TCTP levels are related to melanoma malignancy and invasiveness (in B16F10/F1 murine model); (iii) knockdown of TCTP triggers decrease of proliferation and migration on murine melanoma cells; (iv) sertraline decreases TCTP mRNA levels in B16F10 cells and results in inhibition of clonogenicity; (v) sertraline presents remarkable in vivo antitumoral effects in B16F10/C57BL6 model, greater than dacarbazine, the main chemotherapeutic agent used for melanoma; (vi) sertraline treatment is capable of a long-term effect on melanoma cells, suggesting that the drug can trigger tumor reversion, a reprogram of tumor cells to a less malignant phenotype. Our data could pave the way for new approaches in the treatment of melanoma, a pathology whose prognostic is poor in late stages, and the efficiency of the current available chemotherapeutic treatment is very low.
Conclusion: Altogether, these results indicate that sertraline could be effective against melanoma and TCTP can be a target for melanoma treatment, opening up new therapies for melanoma treatment.
Citation Format: Marianna Boia-Ferreira, Alana Basílio, Antonielle B. Baldissera, Fernando H. Matsubara, Marcia H. Appel, Cleber R. da Costa, Olga M. Chaim, Luiza H. Gremski, Silvio S. Veiga, Andrea Senff-Ribeiro. Sertraline in melanoma treatment: TCTP as a therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3928.
Abstract 3949: p53-restoring small molecule CB001 suppresses tumor growth and metastasis
Authors: Zhang Shengliang , Zhou Lanlan , Wagner Jessica , Dicker David T. , El-Deiry Wafik S. 
Published: August 2018

Abstract
The uncontrolled growth and metastasis of tumor cells leads to morbidity and mortality in patients with cancer. The tumor suppressor p53, as a guardian of genome integrity, plays an important role in suppressing tumor growth and metastasis. However, loss of p53 pathway signaling frequently occurs in advanced tumors. Dysfunction of the p53 pathway is due to either p53 gene mutation or inactivation of p53. Mutations not only result in loss of wild-type p53 function, but also endow mutant p53 with a gain-of function, which further confers tumor aggressiveness and metastasis. Restoring p53 pathway signaling is an attractive strategy for suppressing tumor growth and metastasis in cancer therapy. Small-molecule CB001 restores p53 pathway signaling in p53-deficient colorectal cancer cells. We examined p53 pathway signaling based on the p53-responsive bioluminescence and the protein level of p53 targets. CB001 restores p53 pathway signaling in a p53-dependent and -independent manner in cancer cells. CB001 restores p53 pathway signaling via p73 in mutant p53-expressing cancer cells, and activates the p53 pathway in wild-type p53-expressing cancer cells. Correlated with restoration of p53 pathway signaling, CB001 induces cell death in cancer cells, but not in normal cells. Neither phosphorylation of H2AX in cancer cells nor DNA intercalation was observed upon CB001 treatment at the tested doses, suggesting little or no genotoxicity of CB001 in human colorectal cancer cells. Furthermore, both cell scratch assay and Boyden chamber assay reveal that CB-001 inhibits cancer cell migration. We further demonstrate that CB001 induces cell death and inhibits cell migration via p73 in p53-mutant colorectal cancer cells. These results taken together
suggest that CB001 is a promising lead for drug development with a strong capability to suppress tumor growth and metastasis through restoring p53 pathway in cancer cells.
Citation Format: Shengliang Zhang, Lanlan Zhou, Jessica Wagner, David T. Dicker, Wafik S. El-Deiry. p53-restoring small molecule CB001 suppresses tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3949.
Abstract 3953: The role of USF1 in the regulation of lipogenesis and breast cancer tumor progression
Authors: Lewis Jessica , Mahmud Iqbal , Liao Daiqing 
Published: August 2018

Abstract
Breast cancer accounts for nearly one-quarter of all cancer diagnoses and is the principal cause of cancer-related mortality in women worldwide. Triple negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer commonly resistant to therapeutics that have been successful in increasing survival in patients with ER+, PR+ and HER2+ breast cancer subtypes. As such, identifying factors that contribute to poor patient outcomes and mediate the growth and survival of TNBC cells remain important areas of investigation. USF1 (upstream stimulatory factor 1), a gene linked to drive lipogenesis and cellular proliferation, is over-expressed in human malignancies, yet its contribution to cancer remains unclear. In analyzing large number of genomic datasets including The Cancer Genome Atlas (TCGA), we found that USF1 expression is significantly higher in TNBC tumor samples and cell lines. Also, USF1 gene expression positively correlates with key lipogenic enzymes. Significantly, we found that high expression of USF1 in breast cancer correlates with decreased patient survival. We found that USF1 shRNA expression resulted in cell death in breast cancer cell lines. We therefore hypothesize that USF1 drives de novo lipogenesis to promote breast tumorigenesis. Further studies are underway to determine the mechanisms by which USF1 promotes de novo lipogenesis, tumorigenesis and metastatic progression. Our studies will shed lights on the roles of USF1 in breast cancer tumor biology and undercover potential novel anticancer drug targets. (Supported by McKnight Foundation, Bankhead-Coley Cancer Research Program and James and Esther King Biomedical Research Program, Florida Department of Health.)
Citation Format: Jessica Lewis, Iqbal Mahmud, Daiqing Liao. The role of USF1 in the regulation of lipogenesis and breast cancer tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3953.
Abstract 3955: PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer
Authors: LI Xinran , Mak Victor CY , Zhou Yuan , Lu Yiling , Cheung Annie NY , Mills Gordon B , Cheung Lydia WT 
Published: August 2018

Abstract
The phosphoinositide 3-kinase (PI3K) regulatory subunit p85α is one of the critical gatekeepers of PI3K pathway activation through stabilizing and inhibiting the catalytic subunit p110. p85α is encoded by PIK3R1, which is frequently mutated or deleted in multiple cancer types including ovarian cancer, providing justification of exploring the approaches to target the aberrations. In this study, we observed a spectrum of oncogenic phenotypes in ovarian cancer cells upon knockdown of PIK3R1 in vitro and in vivo, indicating the functional significance of PIK3R1 loss in ovarian cancer. Strikingly, PIK3R1 loss not only led to AKT activation (canonical signaling of PI3K), but also unexpectedly JAK2/STAT3 signaling activation (non-canonical signaling of PI3K). PIK3R1 loss induced translocation of STAT3 into the nucleus, where gene transcription was promoted and thereby the malignant properties. Using in vitro 3D culture spheroid assay, we found that PIK3R1 loss sensitized ovarian cancer cells to AKT inhibitors and JAK2/STAT3 inhibitors. More importantly, the combination of AKT and STAT3 inhibitors resulted in synergistic loss of cell viability. The demonstrated signaling alterations and the associated therapeutic susceptibility downstream of PIK3R1 loss may open new avenue for the treatment of PIK3R1 loss-bearing cancer. [This study was supported by Research Grants Council of the Hong Kong SAR, China, Project No. 27103616]
Citation Format: Xinran LI, Victor CY Mak, Yuan Zhou, Yiling Lu, Annie NY Cheung, Gordon B Mills, Lydia WT Cheung. PIK3R1 loss activates AKT and STAT3 signaling in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3955.