bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5886: Translational reprogramming of breast cancer and its role in tamoxifen resistance
Authors: Bakogianni Sofia , Geter Phillip , Ernlund Amanda , Arju Rezina , Gadi Abhilash , Schneider Robert J. 
Published: August 2018

Abstract
Breast cancer is the most commonly diagnosed malignancy among women in the U.S. and the second leading cause of cancer-related deaths in women. The estrogen receptor-positive (ER+) breast cancer subtype comprises the majority (70-80%) of breast cancer cases and the majority of late recurrences. Anti-estrogen therapy with tamoxifen remains a cornerstone of adjuvant therapy for ER+ breast cancers in the premenopausal setting, but resistance is inevitable for a third of patients, leading to metastatic disease, which is responsible for the majority of breast cancer deaths. Our work demonstrates that tamoxifen resistance in ER+ breast cancer involves selective mRNA translation mediated by hyperactivation of mTOR and MNK1, two kinases that play major roles in mRNA translation. The hyperactivation of mTOR and MNK1 converges on eukaryotic translation initiation factor 4E (eIF4E) to increase its availability and mRNA selectivity. Using tamoxifen-sensitive and -resistant ER+ cells, we conducted genome-wide transcriptomic and translatomic analyses +/- silencing of eIF4E. We identified key genes responsible for tamoxifen resistance, whose mRNAs are selectively translationally upregulated with increased levels of eIF4E. RUNX2 is a key mRNA that is selectively translationally upregulated, which we show provides resistance by opposing estrogenic signaling and possibly phenotypically reprogramming the cell. Silencing of RUNX2 strongly resensitizes the cells to tamoxifen. We also show that RUNX2 impairs cellular proliferation and cell survival of previously drug-resistant cells in the presence of tamoxifen. Silencing of key translationally upregulated mRNAs, such as RUNX2, can partially restore endocrine therapy sensitivity. Using a tamoxifen-resistant ER+ PDX model, and patient-derived sensitive and resistant tumor tissues (no recurrence or recurrence within 5 years), we validated the hyperactivation of mTOR and MNK1, the overexpression of eIF4E, and selective mRNA translation in tamoxifen resistance. We hypothesize that selection for increased expression of RUNX2 and other selectively translated mRNAs promotes a more “basal-like,” estrogen-independent phenotype. We aim to determine how tamoxifen resistance translationally reprograms breast cancer cells to a different breast cancer phenotype (e.g., cancer stem cell-like, basal-like, luminal with disrupted ER signaling).
Citation Format: Sofia Bakogianni, Phillip Geter, Amanda Ernlund, Rezina Arju, Abhilash Gadi, Robert J. Schneider. Translational reprogramming of breast cancer and its role in tamoxifen resistance [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 5886.
Abstract 5890: Aurora-A potentiates chemoresistance via regulating the microRNA biogenesis pathway
Authors: Lin Li Jyuan 
Published: August 2018

Abstract
Chemotherapy has a good success rate in colorectal cancer; however, recurrence of colorectal cancer is still frequent due to the development of drug resistance. MicroRNA (miRNA) is a type of non-coding RNA with a size of around 19-22 nucleotides and plays an important role in regulating many biological functions, the onset of diseases, as well as drug response. It was reported that Dicer, one of the key enzymes of the miRNA biogenesis pathway, may be involved in the chemoresistance through regulating the expression of miRNAs. Aurora-A, a cell cycle-regulated kinase, plays a vital role in cancer development and chemoresistance. According to the TCGA database, the expression levels of Dicer and Aurora-A are both increased in colorectal cancer. Here, we demonstrated that overexpressed Aurora-A can regulate the chemodrug response by influencing the miRNA biogenesis pathway via Dicer in colorectal cancer. Our results showed that the protein level, but not the mRNA expression, of Dicer was decreased upon 5-FU or oxaliplatin treatment in drug sensitive cells; whereas, the expression level of Dicer was increased in oxaliplatin resistant cell lines. Knockdown expression of Dicer in oxaliplatin resistant cell lines could reverse the resistance of oxaliplatin. The expression levels of several potential miRNAs changed upon chemodrugs treatment. Interestingly, we found that overexpressed Aurora-A could increase the expression of Dicer and potentiate drug resistance in colorectal cancer cells. In contrast, knockdown expression of Aurora-A decreased Dicer protein expression and led to enhanced drug sensitivity. Taken together, our results suggested that Aurora-A and Dicer can collaborate to regulate drug response through influencing the miRNA biogenesis pathway in colorectal cancer. The further mechanism of Dicer and Aurora-A in chemoresistance is currently under our investigation.
Citation Format: Li Jyuan Lin. Aurora-A potentiates chemoresistance via regulating the microRNA biogenesis pathway [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 5890.
Abstract 5895: Targeting RhoA-regulated gene transcription in drug-resistant melanoma
Authors: Misek Sean A. , Gallo Kathleen A. , Neubig Richard R. 
Published: August 2018

Abstract
Much of the recent focus of melanoma targeted therapy has been on the ERK pathway, which is aberrantly activated in approximately 90% of melanoma tumors. Over half of these express BRAFV600E. Current targeted therapies such as Vemurafenib (BRAFV600E inhibitor), or a combination therapy of BRAF + MEK inhibitors show profound initial effects in a majority of BRAFV600E expressing tumors. However, these responses are often short-lived and resistance typically develops within months. The goal of this work is to identify pharmacologically targetable resistance mechanisms so that effective combination therapies can be developed.
Preliminary bioinformatics analysis suggests that the RhoA subfamily of Rho GTPases is activated in BRAFi-resistant cancer cell lines and BRAFi/MEKi-resistant human melanoma tumors. Thus, we hypothesize that RhoA promotes BRAFi resistance, so simultaneously targeting RhoA and BRAF may reverse drug resistance. Using cell line models of acquired BRAFi-resistance we demonstrated that the RhoA pathway is activated in a subset of resistant cell lines. The cell lines with increased RhoA activation have increased sensitivity to multiple ROCK inhibitors.
In addition to regulating the cytoskeleton, RhoA can also regulate gene transcription through activation of multiple transcriptional co-activators, including MRTF and YAP. MRTF and YAP regulated gene transcription through their role as transcriptional co-activators and their interaction with chromatin remodeling complexes. MRTF and YAP are both activated in BRAFi-resistant cell lines. Indirectly targeting MRTF with CCG-222740 or YAP with the YES1 inhibitor Dasatinib effectively kills BRAFi-resistant melanoma cells.
Sox10 was previously identified as a gene which promotes BRAFi resistance. Expression of Sox10 is downregulated, and Sox9 is upregulated, 100-1000-fold exclusively in the resistant cell lines which have RhoA activation. Further, a Sox10 gene signature is inversely correlated with a RhoA/C signature in the TCGA dataset and melanoma scRNA-seq data. Sox10 loss is a major drug resistance melanoma in melanoma. These data suggest that targeting RhoA-regulated gene transcription may be an effective mechanism to target Sox9High/Sox10Low cells, and ultimately prevent or reverse drug resistance.
Taken together these data suggest that MRTF and YAP promote Vemurafenib resistance in Sox9High/Sox10Low melanoma cells.
Citation Format: Sean A. Misek, Kathleen A. Gallo, Richard R. Neubig. Targeting RhoA-regulated gene transcription in drug-resistant melanoma [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 5895.
Abstract 5898: A systems approach for determining the mechanism of resistance to tumor treating fields in glioblastoma
Authors: Chen Dongjiang , Le Son , Thomas Nagheme , Tran David D. 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy. Recently, Tumor Treating Fields (TTFields) was approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules' assembly, leading to disrupted chromosomal segregation and cell death. However, the majority of GBM are not sensitive to TTFields and most of TTFields responders eventually develop resistance. However the mechanism of resistance remains largely unexplored. Understanding how cancer cells gain the ability to circumvent the biophysical forces of TTFields and their downstream effects will provide new opportunities to improve therapeutic efficacy of this novel anti-cancer treatment modality. To accomplish these objectives, we have developed several human GBM cell lines that demonstrated relative resistance to the cytotoxic effects of TTFields compared to the parental cells. Importantly TTFields-induced chromosomal instability such as the formation of micronuclei was unchanged in resistant cells compared to their sensitive counterparts, suggesting that resistance to TTFields may be conferred by a selective loss of deleterious downstream reactions to the biophysical damages. To systematically identify the mechanism of resistance, we have recently developed two innovative computational platforms, GeneRep and nSCORE and experimentally validated them in several published datasets. The tandem platforms complemented each other and allowed us to 1) interrogate large-scale gene expression profiles of pairs of TTFields resistant cells vs. sensitive counterparts to extract candidate resistance-specific gene regulatory networks, and 2) functionally rank specific core factors responsible for resistance, respectively. Once identified, biological confirmation of these factors using cell lines, mouse models and samples of patient's derived TTFields sensitive and resistant GBM. Our long-term goal is to develop targeted therapy to prevent tumor's resistance to TTFields therapy.
Citation Format: Dongjiang Chen, Son Le, Nagheme Thomas, David D. Tran. A systems approach for determining the mechanism of resistance to tumor treating fields in glioblastoma [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 5898.
Abstract 5899: Genome-wide CRISPR-Cas9 screening identifies genetic vulnerabilities and potential therapeutic targets in castration resistant prostate cancer
Authors: Haldrup Jakob , Schmidt Linnéa , Pedersen Jakob S. , Sørensen Karina D. 
Published: August 2018

Abstract
Background: Treatment options for castration-resistant prostate cancer (CRPC) are limited and only a few agents (e.g. enzalutamide, docetaxel) are routinely used in the clinic. Unfortunately, CRPC tumors will invariable develop resistance to these agents and only a subset of patients will respond. Thus, novel predictive biomarkers are urgently needed to ensure that an expensive and potentially harmful agent is given only to patients who will benefit from it. Furthermore, to enable new treatment strategies, a better understanding of drug resistance mechanisms is required.
Methods: To identify novel drug resistance genes and mechanisms of therapy resistance, we performed genome-wide CRISPR-Cas9 knockout screens in LNCaP (hormone naïve) and in the isogenic C4 (castration resistant) PC cell line, respectively. Using 77,441 unique sgRNAs (Brunello library), a total of 19,114 protein-coding genes were tested for their potential functional role in enzalutamide or docetaxel resistance. Both IC50 and IC90 values were used for selection. MAGeCK was used to identify enriched and depleted sgRNAs (treatment vs. DMSO).
Results: Among the highest ranked hits for the C4 dropout screens, several potential genetic vulnerabilities and mechanisms of resistance were identified, as knockout of specific genes sensitized C4 cells to enzalutamide. None of these hits were observed in LNCaP, which suggest CRPC-specific resistance mechanisms. For the positive screens, increased enzalutamide resistance was observed after knockout of genes encoding e.g. phosphokinases and specific solute carriers (SLCs) for C4 and LNCaP, respectively. Lastly, our results suggest that knockout of specific zinc finger nucleases (ZFNs), posttranslational modification enzymes or microtubule components may modulate docetaxel resistance in C4 cells.
Conclusion: Drug resistance is a major clinical problem. Here, we identified genetic vulnerabilities that may be translated into predictive biomarkers, combination therapies and/or novel drug development strategies for CRPC.
Citation Format: Jakob Haldrup, Linnéa Schmidt, Jakob S. Pedersen, Karina D. Sørensen. Genome-wide CRISPR-Cas9 screening identifies genetic vulnerabilities and potential therapeutic targets in castration resistant prostate 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 5899.
Abstract 5930: Oral siRNA delivery for colorectal liver metastases cancer therapy
Authors: Kang Sung-Hun , Revuri Vishnu , Cho Sungpil , Park In-Kyu , Cho Kwang Jae , Bae Woo Kyun , Lee Yong-Kyu 
Published: August 2018

Abstract
Liver metastasis (CLM) is the lethal secondary hepatic cancer with 5 - 20 months' average survival rate and mostly originated from colorectal cancer (CRC). Surgery and systemic chemotherapy are the currently best options to treat patients. However, over 60% of recurrence rate and severe side effects such as sinusoidal obstruction syndrome and nodular regenerative hyperplasia from the systemic chemotherapy significantly impact on patient's recovery from the treatment. To overcome these side effects and also achieve the synergistic therapeutic effect, we developed a dual padlock system (AR-GT) for oral siRNA delivery to regulate PI3K/Akt signaling pathway, which is highly associated with the progression of CRC to CLM. AR-GT is an about 130 nm nanoparticle consisted of a gold nanoparticle core anchoring siAkt RNA (AR) and a single outer layer of glycol chitosan-taurocholic acid (GT) conjugate. GT layer plays several roles in oral siRNA delivery such as the protection of siRNA in the gastrointestinal (GI) environment, facilitation of ileac uptake of AR-GT in the small intestine and transportation of AR-GT through enterohepatic circulation into the liver. In vitro characterization of AR-GT demonstrated the protection of siRNA under simulated GI pHs for 5 days, facilitation of the trans-epithelial transport in the intestinal Caco2 and ASBT positive cells, and reduction of Akt protein by successful release of siAKT from the AR-GT. Following oral delivery of AR-GT to CLM mouse model, we observed high biodistribution of AR-GT in the ileum, liver, and kidney through intestinal uptake, enterohepatic transportation, and renal excretion. Moreover, CLM mouse after oral delivery of AR-GT (100 μg/kg) manifested about 58 % reduction of the numbers of tumor nodules in the liver and near 100% survival benefit compared to control mouse fed with either saline or AR-Chitosan nanoparticles. Further analysis of liver samples obtained from CLM mouse after oral delivery of AR-GT indicated about 38% reduction of pAkt expression and the enhancement of apoptotic protein expressions such as 2 times or 1.5 times increase of caspase 9 and bax. Theses observation suggests survival benefit and tumor nodule reduction in CLM mouse root on successful AR-GT mediated oral siAkt RNA delivery. we conclude AR-GT oral siRNA delivery system is beneficial in the CLM treatment and further suggest its application to target other cancers.
Citation Format: Sung-Hun Kang, Vishnu Revuri, Sungpil Cho, In-Kyu Park, Kwang Jae Cho, Woo Kyun Bae, Yong-Kyu Lee. Oral siRNA delivery for colorectal liver metastases cancer therapy [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 5930.
Abstract 597: Lung tumor histology as prognostic factor for short-term postoperative outcomes
Authors: Gerard Roger , Velez-Cubian Frank , Moodie Carla , Garrett Joseph , Fontaine Jacques , Toloza Eric 
Published: August 2018

Abstract
Introduction: Based on the 2015 World Health Organization (WHO) Classification of Lung Tumors, we sought to investigate the relationship of common lung tumor histologies and their utility as prognostic clinical correlates of short-term perioperative outcomes.
Methods: We retrospectively analyzed patients who underwent robotic-assisted video-thoracoscopic lobectomy by one surgeon over 81 months. Patients were grouped based on tumor histology on their final surgical pathology report. Patients' demographics, smoking history, lobar distribution, extent of resection, intraoperative outcomes, perioperative complications, and hospital length of stay were compared among the groups.
Results: Among 420 study patients, the most common tumor type was adenocarcinoma (AD, 59.8%), followed by squamous cell carcinoma (SQ, 19.3%) and neuroendocrine carcinoma (NEC, 11.7%). Final histology for the remainder of the cohort consisted of adenosquamous carcinoma (AdSq, 2.1%) and pulmonary metastasis (7.1%). All patients with AdSq tumor histology had a positive smoking history, which was a significantly higher proportion than for those with NEC tumor type (100% vs 71.4%; p&lt;0.001). Those with AdSq tumor histology were both significantly older and developed significantly larger tumors by time of resection (p&lt;0.001 and p=0.003, respectively). Patients with AdSq tumors required more extensive resections compared to the remaining groups (p&lt;0.004). They also experienced significantly greater estimated blood loss (EBL) and significantly longer operative times (p=0.005 and p=0.018, respectively) than the remaining groups. Patients with SQ or pulmonary metastasis had slightly more postoperative complications, but this was not statistically significant (p=0.990).
Conclusion: Patients with AdSq histology type were older and had larger tumors, which put them at risk of intraoperative difficulties, with more extensive resections, longer operative times, and greater EBL. Despite this, AdSq histology did not affect the postoperative course.
Citation Format: Roger Gerard, Frank Velez-Cubian, Carla Moodie, Joseph Garrett, Jacques Fontaine, Eric Toloza. Lung tumor histology as prognostic factor for short-term postoperative outcomes [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 597.
Abstract 6: Role of Notch signaling in bevacizumab-induced vascular normalization in glioblastoma
Authors: Saito Norihiko , Aoki Kazuya , Hirai Nozomi , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Sakurai Takatoshi , Iwabuchi Satoshi 
Published: August 2018

Abstract
Tumor angiogenesis occurs in the setting of a defective vasculature, which is associated with increased vascular permeability and enhanced tumor permeability. Bevacizumab is used to treat malignant glioma and was found to reduce microvascular density and prune abnormal tumor microvessels. Using electron microscopic observation of two autopsy cases, we investigated the effects of blood vessel normalization in glioblastomas treated with bevacizumab. Notch-1 and SMA immunostaining were used to compare initial surgical specimens with postmortem specimens obtained after bevacizumab treatment. Postmortem samples showed marked proliferation of SMA-positive cells (pericytes) in tumor vessels and marked proliferation of Notch-1–positive cells around vessels. Electron microscopic images confirmed the presence of pericytes surrounding the vascular endothelium. These findings suggest that bevacizumab treatment promotes vascular normalization by recruiting mature pericytes. Next, we investigated the effects of bevacizumab on VEGF inhibition in glioma stem cells. Bevacizumab treatment attenuated activation of VEGFR2 and increased Notch signaling expression. VEGF inhibition by bevacizumab treatment attenuated proliferation and self-renewal of glioma stem cells and induced endothelial and pericyte differentiation. In tumor angiogenesis, vascular endothelial growth factor induces sprouting angiogenesis and recruitment of vascular endothelial cells such as tip cells, stalk cells, and phalanx cells. Fully mature phalanx cells are in close contact with pericytes. Our results suggest that bevacizumab treatment induces glioma stem cells to differentiate to endothelium and pericytes. These mechanisms might be important in normalizing tumor vasculature after bevacizumab treatment and could be useful in improving the effectiveness of current glioma therapy.
Citation Format: Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Takatoshi Sakurai, Satoshi Iwabuchi. Role of Notch signaling in bevacizumab-induced vascular normalization in glioblastoma [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 6.