bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2945: Arsenic trioxide sensitizes glioma stem cells to brain penetrant PI3K and mTOR inhibitor GDC-0084
Authors: Dong Jianwen , Martinez-Ledesma Emmanuel , Nguyen Nghi , Carrillo Caroline , Piao Yuji , Henry Verlene , Park Soon Young , Tiao Ningyi , Stephan Clifford , Verhaak Roel , Sulman Erik , Balasubramaniyan Veerakumar , Groot John F. de 
Published: August 2018

Abstract
Glioblastoma is the most aggressive primary malignant brain tumor with few effective therapies. The current study evaluated arsenic trioxide (As2O3, ATO), a small-molecular agent that inhibits tumor growth via promoting promyelocytic leukemia protein (PML) degradation, in combination with multiple PI3K/mTOR inhibitors using high-throughput screening (HTS) to validate if ATO reverses glioblastoma resistance to PI3K/mTOR-targeted therapy. Quantitative single-agent and 2-drug combinations (5 drug doses, maximal concentration of 1 uM of each agent) were evaluated in 20 patient-derived glioma stem-like cells (GSCs). ATO was applied as an “anchor” drug and several mTOR and EGFR inhibitors as “probe” drugs to explore potential combination efficacy. Data from single-agent screening demonstrated that brain penetrant PI3K/mTOR inhibitor GDC-0084 potently inhibited cell viability with an IC50 ranging from 0.12μM to 5.78μM under normoxic conditions. Under hypoxic conditions, 10 of the 16 GSC cell lines remained sensitive, indicating less efficacy of GDC-0084 in the setting of a hypoxic microenvironment. Evaluation of drug combinations identified ATO and GDC-0084 as the most effective combination in vitro. ATO was synergistic with GDC-0084 in several GSCs resistant to GDC-0084 monotherapy. GSC sensitivity to GDC-0084 as single agent and in combination correlated with apoptosis, angiogenesis and PI3K/Akt pathways using gene set enrichment analyses (GSEA). In vitro combination treatment significantly inhibited PML, p-S6, p-AKT and p-mTOR expressions compared to single agent. In an orthotopic mouse model of glioma, targeting PI3K/mTOR with GDC-0084 prolonged the median survival to 81 days compared to 69 days in the control group. The efficacy of combining ATO and GDC-0084 in an orthotopic GSC mouse model is ongoing. Our studies confirm prior work demonstrating the efficacy of combining GDC-0084 with ATO, which now requires clinical validation.
Citation Format: Jianwen Dong, Emmanuel Martinez-Ledesma, Nghi Nguyen, Caroline Carrillo, Yuji Piao, Verlene Henry, Soon Young Park, Ningyi Tiao, Clifford Stephan, Roel Verhaak, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Arsenic trioxide sensitizes glioma stem cells to brain penetrant PI3K and mTOR inhibitor GDC-0084 [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 2945.
Abstract 2948: Synergistic effect of combining Akt inhibitor SC66 with anticancer drugs cisplatin and paclitaxel in chemoresistant ovarian cancer cells
Authors: Wu Yi-Hui , Chou Cheng-Yang 
Published: August 2018

Abstract
Background and aims Akt plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether Akt inhibition by SC66 is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with chemotherapy drugs.
Methods Using eight human ovarian cancer cell lines, we determined the effect of SC66 by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, western blot, and apoptosis assays. We evaluated the association between phospho-Akt/mTOR, COL11A1 and SC66 sensitivity. We also determined the effect of SC66 on tumor growth using mice inoculated with human ovarian cancer cells.
Results Cell sensitivity to SC66 was inversely correlated with the expressions of phosphorylation of Akt and COL11A1, and cisplatin resistance. SC66 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase. SC66 also attenuated the expression of TWIST1 and Mcl-1, important factors in invasiveness and anti-apoptosis. SC66 sensitizes chemo-resistant cells to cisplatin and paclitaxel treatment, and enhanced apoptosis in the chemo-resistant cells. In addition, SC66 inhibited COL11A1 expression via decreasing the binding activity of c/EBPβ and NF-YA to the COL11A1 promoter, which was associated with chemoresistance and cell invasiveness respectively. In vivo, treatment with SC66 enhanced the therapeutic efficacy of cisplatin and paclitaxel in mouse xenograft.
Conclusions These results indicate the SC66 could have therapeutic efficacy in human ovarian cancers.
Citation Format: Yi-Hui Wu, Cheng-Yang Chou. Synergistic effect of combining Akt inhibitor SC66 with anticancer drugs cisplatin and paclitaxel in chemoresistant ovarian cancer cells [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 2948.
Abstract 2988: Loss of Rbm38 cooperates with mutant p53 to promote lymphomagenesis through downregulation of Pten
Authors: Zhang Jin , yang Heejung , Zhang Yanhong , Chen Mingyi , Chen Xinbin 
Published: August 2018

Abstract
The tumor suppressor TP53 is the most commonly mutated gene in human cancers and mutant p53 has a gain of function by promoting tumor progression, metastasis, and resistance to anticancer therapy. Interestingly, the RNA binding protein Rbm38, a critical regulator of mutant p53 translation, is frequently lost in tumors with mutant p53. To determine the role of the Rbm38-mutant p53 axis in tumorigenesis, we showed that loss of Rbm38 significantly alters the cancer susceptibility of mutant p53 knockin mice by shortening the lifespan, altering the tumor incidence, and promoting T-cell lymphomagenesis. To understand how Rbm38 deficiency promotes mutant p53 gain of function, we showed that loss of Rbm38 not only enhances mutant p53 expression but also decreases expression of tumor suppressor Pten, a critical regulator of T-cell development. Furthermore, we showed that Rbm38 is required for Pten expression by stabilizing Pten mRNA through an AU-rich element in its 3'UTR. Thus, we have uncovered a novel mechanism by which Pten is regulated by Rbm38 via mRNA stability. Our data also suggest that Rbm38 controls T-cell lymphomagenesis by concomitantly modulating mutant p53 and Pten, which may be explored as a therapeutic strategy for the treatment of T-cell malignancies.
Citation Format: Jin Zhang, Heejung yang, Yanhong Zhang, Mingyi Chen, Xinbin Chen. Loss of Rbm38 cooperates with mutant p53 to promote lymphomagenesis through downregulation of Pten [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 2988.
Abstract 2997: Epigenomic signatures of acquired platinum resistance in high grade serous ovarian cancer
Authors: Fang Fang , Cardenas Horacio , Jiang Guanglong , Perkins Susan M. , Zhang Chi , Keer Harold , Liu Yunlong , Matei Daniela , Nephew Kenneth 
Published: August 2018

Abstract
Epithelial ovarian cancer (OC) is the most lethal gynecologic malignancy. The majority of advanced stage patients develop uniformly fatal resistance to standard platinum-based treatments. Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in OC. The goal of the current study was to identify methylation changes associated with the development of acquired resistance to platinum-based chemotherapy. We hypothesized that OC tumors harboring an aberrant DNA methylome could be reversed by DNMTi and re-sensitized to platinum treatment. To achieve our objective, we generated and compared tumor DNA methylation profiles from patients with recurrent platinum-resistant OC treated on a clinical trial with a DNA methyl transferase inhibitor, guadecitabine, before (n=65) and after (n=19) treatment (NCT01696032), and patients with primary (platinum-naïve) OC (n=20). Human ovarian surface epithelial cells (HOSE) were used as controls (n=5). We examined methylation levels across the genome using the Infinium Human Methylation 450 Bead Chip (Illumina). By comparing the methylome of platinum naive and platinum resistant ovarian tumors, normalized to HOSE, we identified 444 CpG island-containing gene promoters that became hypermethylated in resistant tumors. Of those, 45 gene promoters were hypermethylated at an FDR&lt;0.05 and 19 genes at an FDR&lt;0.05 and Δβ&gt;0.1. Among those significantly hypermethylated genes, acquired promoter CpG island methylation of Ras Association Domain Family 1A (RASSF1A; a tumor suppressor gene in multiple cancer types) was observed. Of the 444 hypermethylated promoters in tumor resistant samples, 93 CpG islands became hypomethylated after guadecitabine treatment, suggesting that these promoters may be associated with reversal of resistance. Of those were the IFNA8 promoter, a gene known to be associated with anti-tumor effects in ovarian and other solid malignancies, and DEFB124, which is involved in the innate immune response. Pathways associated with immune reactivation were highly enriched by guadecitabine treatment, including IL-12 signaling and production of macrophages and MAPK and apoptosis signaling. Together, these results support that aberrant DNA methylation affecting gene networks associate with immune response plays a role in platinum resistant development and could be a therapeutic target.
Citation Format: Fang Fang, Horacio Cardenas, Guanglong Jiang, Susan M. Perkins, Chi Zhang, Harold Keer, Yunlong Liu, Daniela Matei, Kenneth Nephew. Epigenomic signatures of acquired platinum resistance in high grade serous 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 2997.
Abstract 3003: Loss of heterozygosity of essential genes represents a novel class of cancer vulnerabilities
Authors: Nichols Caitlin A. , Paolella Brenton R. , Gibson William J. , Brown Meredith S. , Urbanski Laura M. , Kosmicki Jack A. , Busanovich John P. , Berger Ashton C. , Gao Galen F. , Cherniack Andrew D. , Beroukhim Rameen 
Published: August 2018

Abstract
Despite progress in precision cancer drug discovery, few highly selective therapies exist in the clinic, creating the need for additional therapeutic targets. We have shown that copy number alterations (CNAs) in essential genes represent novel non-driver gene vulnerabilities in cancer. Here we interrogate loss of heterozygosity (LOH) of single nucleotide polymorphisms (SNPs) located in essential genes as a novel class of candidate therapeutic targets. We hypothesized that monoallelic inactivation of the single allele retained in tumors can selectively kill cancer cells, while somatic cells, which retain both alleles, will tolerate allele-specific knockout. We identified a list of over 1000 common missense SNPs in at least 1500 essential genes that undergo LOH in cancer and performed proof-of-concept allele-specific gene inactivation in two essential genes (PRIM1 and EXOSC8) using CRISPR-Cas9. We assessed the fidelity of allele-specific gene disruption and its cellular effects on gene expression, cell growth, and cell death in LOH and non-LOH genetic contexts. We determined that allele-specific knockout of PRIM1 and EXOSC8 selectively targets cells harboring only the single targeted allele of that gene. In cells retaining only the sensitive allele, we observed decreased target gene expression and cell viability that did not occur in cells retaining the resistant allele. We conclude that allele-selective inactivation of essential genes in regions of LOH (such as PRIM1 and EXOSC8) represents a novel candidate therapeutic strategy in cancer. The corresponding class of novel non-driver cancer vulnerabilities may provide a rich source of targets for future precision therapeutic development using gene editing, RNAi, or small-molecule approaches.
Citation Format: Caitlin A. Nichols, Brenton R. Paolella, William J. Gibson, Meredith S. Brown, Laura M. Urbanski, Jack A. Kosmicki, John P. Busanovich, Ashton C. Berger, Galen F. Gao, Andrew D. Cherniack, Rameen Beroukhim. Loss of heterozygosity of essential genes represents a novel class of cancer vulnerabilities [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 3003.
Abstract 3044: Label-free detection and identification of cancer-associated vesicles in human breast cancer
Authors: You Sixian , Sun Yi , Tu Haohua , Barkalifa Ronit , Chaney Eric J. , Marjanovic Marina , Higham Anna M. , Luckey Natasha N. , Cradock Kimberly A. , Liu Z. George , Boppart Stephen A. 
Published: August 2018

Abstract
Detection and identification of cancer-associated vesicles in their native tissue environment is essential to understand vesicle-mediated communication in cancer progression and potentially facilitate the treatment and management of cancer. Here we develop a label-free optical imaging method that can reliably detect cancer-associated vesicles in vitro, in vivo and in untreated human tissue ex vivo. Preliminary analysis conducted on fresh human breast tissue obtained from healthy and cancer subjects showed that a significant portion of vesicles from the cancer subjects have unique optical signatures in comparison with those from healthy subjects. Additionally, the spatial distribution of these vesicles with unique optical signatures in the tumor micro- and macro-environment appeared correlated with the staging of human breast cancer. These results suggest the potential capability of this methodology to identify and characterize the tumor associated vesicles in the authentic tumor microenvironment, which could open new windows in the explorations of their diagnostic values and physiological roles in cancer progression.
Citation Format: Sixian You, Yi Sun, Haohua Tu, Ronit Barkalifa, Eric J. Chaney, Marina Marjanovic, Anna M. Higham, Natasha N. Luckey, Kimberly A. Cradock, Z. George Liu, Stephen A. Boppart. Label-free detection and identification of cancer-associated vesicles in human breast 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 3044.
Abstract 3069: DSP-0692, a novel and selective stearoyl-CoA desaturase (SCD) inhibitor targeting cancer stem cells
Authors: Sugaru Eiji , Furuta Yudai , Fukunaga Yuichi , Umehara Hiroki , Otsubo Tsuguteru , Watanabe Manabu , Hasegawa Futoshi , Tojo Shingo , Hashizume Miki , Ban Hitoshi 
Published: August 2018

Abstract
In recent years evidence has accumulated in support of the cancer stem cells (CSCs) model in cancer chemotherapy resistance, highlighting the urgency and necessity of identifying CSC-specific targets for new cancer therapeutics.
SCD, a key enzyme for lipid metabolism, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. In particular, recent studies have implicated SCD involved also in the maintenance of CSCs.
Here, the identification and the functional characterization of DSP-0692, a novel and selective SCD inhibitor, is reported, using various pharmacological approaches to address the mechanism of SCD inhibition in cancer cells and its efficacy in preclinical tumor models. In these preclinical models, DSP-0692 inhibited human SCD activity with low nanomolar IC50 values. SCD expression was induced in tumor cells cultured in sphere conditions, which were resistant to conventional agents within therapeutic concentration. DSP-0692 showed strong growth inhibition when tumor cells were cultured in sphere conditions, but had little impact on cells cultured under normal two-dimensional conditions. In addition, DSP-0692 inhibited the CSC-related signaling pathway and decreased CSC markers expression in tumor cells as well as in tumor tissues. Treatment of DSP-0692 as single agent suppressed tumor growth in multiple models. Furthermore, this efficacy was enhanced in combination with conventional chemotherapies in those tumor models. Of note, SCD protein expression in tumor tissues was useful as a predictive marker for the susceptibility to DSP-0692 treatment.
Taken together, these data suggest that inhibition of fatty acid desaturation by DSP-0692 could be a new therapeutic strategy in SCD-positive cancer, with potential to overcome resistance to standard chemotherapies.
Citation Format: Eiji Sugaru, Yudai Furuta, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Futoshi Hasegawa, Shingo Tojo, Miki Hashizume, Hitoshi Ban. DSP-0692, a novel and selective stearoyl-CoA desaturase (SCD) inhibitor targeting cancer stem cells [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 3069.
Abstract 3070: Cancer stem cells in field cancerization of oral squamous cell carcinoma
Authors: Mohanta Simple , DR Ravindra , Kekatpure Vikram , Hedne Naveen , Pillai Vijay , Chauhan Shubhra , BS Naveen , Ramakrishnan Athira , Jacob Bichu , Surendra Vishak , Mohanty Leeky , Muralidharan Anjana , Suresh Amritha , Kuriakose Moni Abraham 
Published: August 2018

Abstract
Introduction: Field cancerization, the occurrence of transformed cells in the area adjacent to the tumor, has been attributed to the probable reasons of local recurrence of oral squamous cell carcinoma. Cancer stem cells (CSCs) have properties of tumor initiation, migration, and metastasis. The objective of the study was to evaluate their role in field cancerization.
Experimental Procedure: A panel of CSCs and its related markers was established from literature and validated in i) samples from surgical margins, ii) samples from 1 cm and 2 cm distance from margin around the tumor and in additional sides. First-phase validation was done in retrospective surgical margins of tumor (N=23) by qPCR and immunohistochemistry. The best marker subset from qPCR to predict recurrence was identified by ROC curve and logistic regression analysis and validated by immunohistochemistry. The final validation is being carried out in prospective samples from tumor-adjacent normal area as mentioned above. The marker profiles were correlated with the histology of the samples and the clinical outcome of the patients on follow-up.
Summary of Data: Out of 18 markers selected from literature CD44, CD147, SOX2, Snail, ATR, CyclinD1, MMP9 were selected from gene expression of first-phase validation. Among these SOX2, ATR, Cyclin D1, CD44 and CD147 were selected from IHC of first phase for second-phase validation in prospective samples (n=10) collected from 27 patients, which were clinically normal with varied grades of dysplasia; these samples were evaluated by the selected markers from the first set of validation. The correlation of markers expression with disease outcome of patients and with other clinical parameters is currently ongoing.
Conclusion: Our results suggest that CSCs have role in field cancerization and might be predictive of tumor recurrence/reinitiation and/or development of second primary tumor.
Citation Format: Simple Mohanta, Ravindra DR, Vikram Kekatpure, Naveen Hedne, Vijay Pillai, Shubhra Chauhan, Naveen BS, Athira Ramakrishnan, Bichu Jacob, Vishak Surendra, Leeky Mohanty, Anjana Muralidharan, Amritha Suresh, Moni Abraham Kuriakose. Cancer stem cells in field cancerization of oral squamous cell carcinoma [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 3070.
Abstract 3073: Low copy number of mtDNA is associated with cancer stemness in ESCC
Authors: Hara Takeo , Masuike Yasunori , Tanaka Koji , Makino Tomoki , Yamasaki Makoto , Miyazaki Yasuhiro , Takahashi Tsuyoshi , Kurokawa Yukinori , Eguchi Hidetoshi , Nakajima Kiyokazu , Mori Masaki , Doki Yuichiro 
Published: August 2018

Abstract
Alterations of mitochondrial DNA (mtDNA) copy numbers in various human cancers have been studied. However, those of esophageal squamous cell carcinoma (ESCC) is still unclear. In the present study, we investigated the correlation of mtDNA copy number with clinicopathologic features, prognosis and malignant potential of ESCC. MtDNA copy numbers of resected specimen from 80 patients treated with radical esophagectomy were measured by quantitative real-time PCR analyses. Human ESCC cells, TE8 and TE11, were cultured and depletion of mtDNA content was induced by knockdown of mitochondrial transcription factor A expression or treatment with ethidium bromide. The mRNA expression, proliferation, invasion and cell cycle were investigated. The results showed that mtDNA copy number of cancerous parts was 56.0 (37.4-234.5) % of non-cancerous parts and significantly lower (p&lt;0.05). Low mtDNA copy number in resected cancerous tissues was significantly correlated with pathological depth of tumor invasion and pathological stage (p&lt;0.05). The patients with lower mtDNA copy number had significantly poorer 5-year overall and recurrence-free survival than higher group (p&lt;0.01). MtDNA depleted TE8 and TE11 cells proliferated more slowly than control cells under normoxia, but proliferated at almost the same rate even under hypoxic condition. In mtDNA depleted cells, the mRNA expression of cd44 were increased, and the sphere formation abilities were enhanced and the cell cycle arrest at G0/G1 phase was induced. In conclusion, low copy number of mtDNA is associated with cancer stemness in ESCC. MtDNA copy number may be a novel therapeutic target for esophageal squamous cell carcinoma.
Citation Format: Takeo Hara, Yasunori Masuike, Koji Tanaka, Tomoki Makino, Makoto Yamasaki, Yasuhiro Miyazaki, Tsuyoshi Takahashi, Yukinori Kurokawa, Hidetoshi Eguchi, Kiyokazu Nakajima, Masaki Mori, Yuichiro Doki. Low copy number of mtDNA is associated with cancer stemness in ESCC [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 3073.