bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3545: High expression of miR-30a is associated with favorable breast cancer survival
Authors: Obata Yuki , Katsaros Dionyssios , Biglia Nicoletta , Shen Yi , Fu Yuanyuan , Wang Zhanwei , Yu Herbert 
Published: August 2019

Abstract
Introduction: MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs, consisting of about 20 nucleotides and studies have shown that miRNAs may play important roles in the development and progression of cancer. Members of the miR-30 family, including miR-30a, are reported to play different roles as oncogenes or tumor suppressor genes depending on the type of cancer in several studies. We studied miR-30a expression in breast cancer in relation to disease features and patient survival.
Methods: We measured miR-30a expression in tumor samples of 509 breast cancer patients by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Using the study-specific tertile distribution as cut-off, miR-30a expression data were grouped into low, medium, and high three categories. Hazards ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the association between miR-30a expression and breast cancer survival using the Cox proportional hazards regression model, and the analysis was adjusted for age at surgery, tumor grade, disease stage, and hormone receptor status. Overall survival (OS) was defined as the time interval from the date of surgery to the date of death or last follow-up. Disease-free survival (DFS) was the time interval from surgery to recurrence or last follow-up. We also retrieved breast cancer provisional data in The Cancer Genome Atlas (TCGA) using the web-based tool cBioPortal (http://www.cbioportal.org/index.do) and analyzed the association between miR-30a and breast cancer survival.
Results: Patients with estrogen receptor (ER)-positive tumors had higher expression of miR-30a compared to those with ER-negative tumors (p = 0.0080). Patients with progesterone receptor (PR)-positive tumors also had higher miR-30a expression than those with PR-negative tumors (p = 0.0038). Survival analysis showed that patients with high expression of miR-30a had 58% reduction in risk of relapse (HR = 0.42, 95% CI = 0.21-0.83, p = 0.013) compared to those with low expression. This association remained significant (HR = 0.43, 95% CI = 0.21-0.89, p = 0.023) after adjustment for age at surgery, disease stage, tumor grade, and hormone receptor status. A significant association between miR-30a and overall survival was also observed in the TCGA data (HR = 0.60, 95% CI = 0.41-0.88, p = 0.0088).
Conclusions: Our results suggest that high expression of miR-30a may reduce the risk of breast cancer relapse and miR-30a may act as a tumor suppressor in breast cancer.
Citation Format: Yuki Obata, Dionyssios Katsaros, Nicoletta Biglia, Yi Shen, Yuanyuan Fu, Zhanwei Wang, Herbert Yu. High expression of miR-30a is associated with favorable breast cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3545.
Abstract 3555: miR-374a-5p induces tumor progression in triple negative breast cancer
Authors: Kim Yesol , Son Dasom , Kim Do Yeon , Park Jong Hoon 
Published: August 2019

Abstract
Triple negative breast cancer (TNBC) has higher aggressiveness and poorer outcomes compared with other subtypes of breast cancer. However, the genomic and molecular aberrations of TNBC are largely unknown, with cytotoxic chemotherapy remaining the major treatment for TNBC patients. In this study, miR-374a-5p was discovered as a novel TNBC-specific miRNA and its functions and the molecular mechanisms involved were investigated. Combined gene expression profiling of miRNA-microarray and human transcriptome dataset analysis revealed that miR-374a-5p is specifically upregulated in TNBC patients. Functional studies using in vitro and in vivo TNBC models, as well as survival analysis of TNBC patients, indicated that upregulated miR-374a-5p promotes tumor progression in TNBC. miR-374a-5p was also found to directly target arrestin beta 1 (ARRB1) that is specifically downregulated in TNBC patients in several human genomic datasets. Overexpressed ARRB1 reduced TNBC cell growth and migration, and the ARRB1 expression level is inversely correlated with the histological grade of the breast cancer and positively associated with TNBC patient survival, suggestive of a tumor-suppressive function of ARRB1 in breast cancer. Interestingly, increased ARRB1 activates AMPK in TNBC cells, which is associated with the expression of miR-374a-5p. Taken together, the findings suggest that miR-374a-5p is a novel prognostic marker and therapeutic target in the treatment of TNBC.
Citation Format: Yesol Kim, Dasom Son, Do Yeon Kim, Jong Hoon Park. miR-374a-5p induces tumor progression in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3555.
Abstract 3574: Identification of long non-coding RNAs involved in chromosomal instability in a cellular model of prostate cancer
Authors: Manriquez Rogelio Montiel 
Published: August 2019

Abstract
Most of the human genome is transcribed into RNA, but only 2% encodes proteins, leading to a large group of non-coding RNA which, without constitutive RNA, is divided into 2 groups: small (sncRNA) and long (lncRNAs) non-coding RNAs. In this study we used RNA-seq data to identify new lncRNAs which could be involved in chromosomal instability (CIN) in prostate cancer (PCa). Our aim is to study their molecular mechanism and potential role as prognostic biomarkers in this disease.
Using RNA-seq data from two prostate cell lines, neoplastic (LNCaP) and non-neoplastic (PrEC), we have identified an unannotated long lncRNA adjacent to CEP55 (centrosomal protein 55), a gene associated with CIN. We have named this 1.6 kb transcript as lncRNA- CEP55. qPCR experiments showed it is downregulated in the neoplastic cell line, in contrast to the adjacent coding gene, CEP55, which is upregulated in the same cell line and downregulated in PrEC. Our data suggest this new lncRNA might be a possible repressor for CEP55. Changes in expression of CEP55 have been associated to CIN in other cancer cell lines.
LINC02043 is an annotated lncRNA. We identified a differential expression between PrEC and LNCaP using RNA-seq data. LINC02043 is adjacent to the protein-coding gene RFC4; this gene is associated with CIN in different human cancers. We performed qPCR experiments and found LINC02043 to be downregulated in LNCaP, whereas the adjacent coding gene RFC4 is upregulated; the opposite is found in PrEC cell line. Our findings suggest LINC02043 could have a possible repressor role in RFC4. This protein-coding gene is related to mismatch repair and DNA double-strand break repair, abnormalities in this coding gene have been associated with CIN in other cancer cell lines. LINC02043 could play an important role in the cis-regulation of RFC4.
lncRNA-CEP55 and LINC02043 are important targets of study, these lncRNAs could play an essential role in regulating the expression of adjacent genes related to CIN, an enabling characteristic that facilitates the development of the hallmarks of cancer. Further analysis is needed to validate their mechanisms of action and their potential use as prognostic biomarkers in PCa.
Particularly in PCa, CIN has lately been related to cancer progression. The role of lncRNAs as drivers of CIN in PCa is a promising field in order to understand PCa progression and may play a potential role as biomarkers in this disease.
Citation Format: Rogelio Montiel Manriquez. Identification of long non-coding RNAs involved in chromosomal instability in a cellular model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3574.
Abstract 3582: Circular RNA circPLEHM3 acts as the sponge of microRNA-9 to suppress ovarian carcinoma progression
Authors: Zhang Lei , Liu Pengyuan , Lu Bingjian , Lu Weiguo , Lu Yan 
Published: August 2019

Abstract
Circular RNAs(circRNAs) are a class of stable and widespread endogenous noncoding RNA. CircRNAs have been reported to play essential roles in cancer biology, and have potential as biomarkers and therapeutic targets for cancer intervention. Here, we screened the expression profiles of human circRNAs in 27 ovarian cancer and 26 normal ovary tissues, and found circPLEKHM3 (hsa_circ_0001095) was significant down-regulated in ovarian cancer tissues. Patients with lower circPLEKHM3 expression tended to have poorer prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial-mesenchymal transition (EMT) in vitro and in vivo, but its knockdown reversed these effects. Further analyses showed that circPLEKHM3 sponges miR-9 to regulate the expression of BRCA1, DNAJB6 and KLF4, and inactivates the AKT1 expression. In addition, AKT inhibitor MK-2206 blocked the tumor-promoting effect of circPLEKHM3 knockdown, and potentiated taxol induced growth inhibition of ovarian cancer cells. Taken together, our findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR- 9/BRCA1/DNAJB6 /KLF4/AKT1 axis and may provide a prognostic biomarker and therapeutic target in ovarian cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Lei Zhang, Pengyuan Liu, Bingjian Lu, Weiguo Lu, Yan Lu. Circular RNA circPLEHM3 acts as the sponge of microRNA-9 to suppress ovarian carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3582.
Abstract 3589: Targeting metabolic reprogramming and OXPHOS as a viable anti-melanoma strategy
Authors: Cheng Gang , Zielonka Jacek , Hardy Micael , Dwinell Michael B. , Kalyanaraman Balaraman 
Published: August 2019

Abstract
Invasive melanoma is an aggressive form of skin cancer with poor clinical outcomes. Nearly 50% of melanoma patients exhibit oncogenic BRAFV600E mutations. Existing BRAF kinase inhibitor drugs provide a short-term benefit prior to the rapid onset of drug resistance. Emerging results suggest that BRAF and other kinase inhibitors induce metabolic reprogramming from glycolytic energy production to oxidative phosphorylation (OXPHOS) in a subset of malignant melanomas. Metabolic reprogramming to OXPHOS is emerging as an important mechanism of resistance to BRAF kinase inhibitors and is associated with worse prognosis. Consequently, there is a significant opportunity for multimodal therapeutic approaches that selectively target the metabolic reprogramming associated with resistance to BRAF kinase inhibitors and promote immune-targeted therapy. We have previously developed mitochondria-targeted drugs by exploiting the enhanced negative mitochondrial membrane potential of cancer cells to selectively target and disrupt tumor growth. We hypothesized that metabolic reprogramming from glycolysis to OXPHOS in BRAF inhibitor-resistant melanoma cells would make them susceptible to OXPHOS inhibitors. In this study, we have modified the structure of a naturally occurring polyphenol, magnolol into a mitochondria-targeted-magnolol (Mito-MGN). We tested the effects of Mito-MGN on mitochondrial respiration and bioenergetic function, cellular redox status, and mitophagy in wild type (WT) and BRAF-resistant (metabolically reprogrammed) melanoma cells. Our data show that Mito-MGN inhibits mitochondrial respiration, melanoma cell proliferation and invasion at concentrations more than 200-fold lower than that of magnolol. Furthermore, Mito-MGN increases ROS formation and oxidation of mitochondrial peroxiredoxin. Preliminary results also indicate that BRAF inhibitor resistant melanoma cells exhibit enhanced OXPHOS as a consequence of metabolic reprogramming and that Mito-MGN effectively inhibits proliferation and mitochondrial respiration in the resistant cells. Mito-MGN inhibited mitochondrial complex I activity in both WT and resistant cells. The IC50 values to inhibit complex I-mediated respiration was consistent with the values calculated for inhibition of cell respiration. We conclude that inhibition of complex I is a key initial event that is responsible for the anti-proliferative effects observed in the presence of Mito-MGN against wild-type as well as drug-resistant melanoma cells.
Citation Format: Gang Cheng, Jacek Zielonka, Micael Hardy, Michael B. Dwinell, Balaraman Kalyanaraman. Targeting metabolic reprogramming and OXPHOS as a viable anti-melanoma strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3589.
Abstract 3597: BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of diffuse large B-cell lymphoma (DLBCL)
Authors: Eheim Ashley , Christian Sven , Meyer Hanna , Stoeckigt Detlef , Merz Claudia , Zimmermann Katja , Bauser Marcus , Haegebarth Andrea , Ferrara Steven , Sykes David B. , Scadden David T. , Gradl Stefan , Janzer Andreas 
Published: August 2019

Abstract
DLBCL is the most common type of non-Hodgkin lymphoma. It is an aggressive and fast growing tumor with two major molecular subtypes: germinal center (GCB) and activated B-cell like (ABC). While the majority of patients are 60 years or older, DLBCL can occur at any age.
Despite a cure rate of around 50% the need for novel therapies remains high, especially for relapsed/refractory DLBCL patients not eligible for stem cell transplant.
DHODH is a key enzyme in the de novo pyrimidine synthesis converting dihydroorotate to orotate. We recently discovered its role in AML differentiation (Sykes et al 2016, Cell) and we are investigating the novel DHODH inhibitor BAY 2402234 in an ongoing phase I study in myeloid malignancies (NCT03404726). Further screening of non-leukemia cancer types identified DLBCL as highly responsive to DHODH inhibition in preclinical studies.
Here, we disclose for the first time the functional preclinical characterization of BAY 2402234 in DLBCL. BAY 2402234 is a selective low-nanomolar inhibitor of human DHODH enzymatic activity. In vitro it potently inhibits proliferation of DLBCL cell lines in the sub-nanomolar to low-nanomolar range. The anti-proliferative effects can be rescued by uridine supplementation which bypasses DHODH via the salvage pathway and demonstrates the on-target specificity of the inhibitor. In vivo, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in subcutaneous models derived from patient-derived xenograft (PDX) and cell lines representing various DLBCL subtypes, including GCB and ABC. Dose dependent target engagement and drug exposure of BAY 2402234 could be observed by increases in plasma dihydroorotate levels and unbound plasma drug levels after treatment with the inhibitor.
Based on preclinical data presented herein we plan to start clinical investigations of BAY 2402234 in patients with DLBCL in early 2019.
Citation Format: Ashley Eheim, Sven Christian, Hanna Meyer, Detlef Stoeckigt, Claudia Merz, Katja Zimmermann, Marcus Bauser, Andrea Haegebarth, Steven Ferrara, David B. Sykes, David T. Scadden, Stefan Gradl, Andreas Janzer. BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3597.
Abstract 3599: BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas
Authors: Merz Claudia , Christian Sven , Eheim Ashley , Seidel Henrik , Lesche Ralf , Eversloh Merlin Luetke- , Meyer Hanna , Ferrara Steven , Bauser Marcus , Haegebarth Andrea , Gradl Stefan , Janzer Andreas 
Published: August 2019

Abstract
Colorectal carcinoma (CRC) is the third most common malignancy in the US, being responsible for approximately 50,000 deaths per year. The overall 5-year survival rates are high for localized disease (~90%), but low for metastatic disease (~14%), thereby underlining the high unmet medical need for novel therapeutics for CRC patients.
DHODH is a key enzyme in the de novo pyrimidine synthesis, converting dihydroorotate to orotate. We recently discovered its role in AML differentiation (Sykes et al 2016, Cell) and we are investigating BAY 2402234 in an ongoing phase I study in myeloid malignancies (NCT03404726). Since then, several publications have also described a role of DHODH in solid tumor indications.
Herein we disclose the functional preclinical characterization of the novel DHODH inhibitor BAY 2402234 in CRC. BAY 2402234 is a selective low-nanomolar inhibitor of human DHODH enzymatic activity. In vitro it potently inhibits proliferation of CRC cell lines in the sub-nanomolar to low-nanomolar range. The anti-proliferative effects can be rescued by uridine supplementation which is known to bypass DHODH via the salvage pathway and demonstrates the on-target specificity of the inhibitor. Interestingly, not all CRC cell lines are sensitive to the inhibitor. Similar to the in vitro observations, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in some, but not all, subcutaneous CRC xenograft models. A large CRC PDX in vivo screen revealed tumor growth inhibition in over 60% of the models in response to BAY 2402234 treatment. To elucidate the mode of action of BAY 2402234 in CRC we analyzed transcriptomic changes in CRC PDX models in vivo after single treatment with BAY 2402234, and identified several hundred differentially regulated genes at early time points. These in vivo PDX models were also used to explore potential effects of BAY 2402234 treatment on a large panel of metabolites.
These preclinical results support the clinical evaluation of BAY 2402234 in patients with CRC, and such a clinical study is planned for early in 2019.
Citation Format: Claudia Merz, Sven Christian, Ashley Eheim, Henrik Seidel, Ralf Lesche, Merlin Luetke- Eversloh, Hanna Meyer, Steven Ferrara, Marcus Bauser, Andrea Haegebarth, Stefan Gradl, Andreas Janzer. BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of colorectal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3599.
Abstract 3615: Design for a flexible localized drug delivery system
Authors: Wiranowska Marzenna , Toomey Ryan , Falahat Rana , Alcantar Norma 
Published: August 2019

Abstract
This project focuses on studying the optimal design of a drug delivery system based on niosomes (non-ionic surfactants vesicles) embedded in a hydrogel network (chitosan) to ensure full control of the release time and dosage of cancer treatment drugs for localized delivery. Here we present data on the molecular interactions facilitating specific binding at tumor cell surfaces to aid in the treatment of ovarian, brain and lung cancers to name a few. We have done three types of characterizations to determine the basic design parameters for a personalized cancer treatment. First, we determined how fundamental surface interactions can be optimized to target and attack tumor integrity and boundaries. We used confocal microscopy and Xenogen imaging to determine how data from cells and in-vivo models compare. Second, we determined the parameters of chemotherapeutic agents that can act individually or in a cocktail configuration in both in-vitro and in-vivo studies. We used light scattering and transmission electron microscopy to determine the topography for guidance on the design of the drug delivery process. Third, we found that specific targeting can be accomplished by optimizing the binding between drug molecules and mucin 1 (MUC1) found on the surface of epithelial-derived tumors. We used attenuated total internal reflection Fourier transform infrared (ATR-FTIR) spectroscopy to elucidate the interactions that enhance the selectivity of our drug delivery system with respect to model cancer systems. In addition, we used chlorotoxin, a carrier-type polypeptide known to bind to a broad number of tumors. By identifying and optimizing these two methodologies, we have found that tumor and normal cells can be selectively targeted. The significant advantage of applying a localized treatment is the avoidance of systemic exposure to chemotherapy drugs thereby limiting their side effects.
Citation Format: Marzenna Wiranowska, Ryan Toomey, Rana Falahat, Norma Alcantar. Design for a flexible localized drug delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3615.