bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3661: Association of mammographic density with blood DNA methylation
Authors: Lucia Rachel McFarland , Huang Wei-Lin , Alvarez Andrea , Masunaka Irene , Ziogas Argyrios , Goodman Deborah , Odegaard Andrew O. , Norden-Krichmar Trina M. , Park Hannah Lui 
Published: September 2020

Abstract
Background: Mammographic density is a strong risk factor for breast cancer. While numerous genetic variations have been shown to be associated with mammographic density, an epigenetic signature of mammographic density has not yet been identified. The objective of this study was to identify a DNA methylation signature associated with mammographic density.
Methods: Blood samples were collected from 197 postmenopausal women 45-65 years old with no personal history of breast cancer. For each participant, mammographic density according to the BI-RADs density classification was obtained from the most recent mammogram report. White blood cell DNA methylation at more than 850,000 CpG sites was measured using the Illumina HumanMethylationEPIC BeadChip. Differential methylation was assessed using genome-wide, probe-level, and regional approaches after filtering and normalization using the recommended steps for DNA methylation microarray data. All analyses were adjusted for appropriate confounding variables.
Results: On average, genome-wide DNA methylation was higher in women with elevated mammographic density. Additionally, DNA methylation at 343 individual sites and in 34 regions was significantly associated with mammographic density after false discovery rate correction. Most density-associated sites were hypermethylated. The top differentially methylated sites were located near cell cycle regulatory genes (ICMT, DESI2, TCF21/TARID, ROBO3), as well as those encoding cytoskeletal or plasma membrane proteins (PALLD, ANO7, ATP8B3, MTUS2). We observed hypermethylation near the promoters of genes including RUFY1 and SLFN12 and within the bodies of genes including LCN6, SNED1, and LRFN1. Functional analysis of the differentially methylated sites revealed enrichment of gene ontology categories including angiogenesis and regulation of cell adhesion, as well as apoptotic signaling in response to DNA damage.
Conclusions: White blood cell DNA methylation differed according to mammographic density in a sample of postmenopausal women. Probe-based and regional analysis identified differentially methylated regions located near genes implicated in cancer. These differentially methylated regions may serve as a signature of mammographic density, and future studies of the genes implicated may provide a deeper understanding of the connection between mammographic density and breast cancer risk.
Citation Format: Rachel McFarland Lucia, Wei-Lin Huang, Andrea Alvarez, Irene Masunaka, Argyrios Ziogas, Deborah Goodman, Andrew O. Odegaard, Trina M. Norden-Krichmar, Hannah Lui Park. Association of mammographic density with blood DNA methylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3661.
Abstract 3681: Selective vulnerability of GBM PDX to a panel of EGFR tyrosine kinase inhibitors
Authors: Tang Nanyun , Reid George , Miller C Ryan , Berens Michael E. 
Published: September 2020

Abstract
Glioblastoma (GBM), a particularly aggressive form of primary brain tumor, has poor survival due to a lack of effective treatments and high recurrence. Epidermal growth factor receptor (EGFR) (mapped to 7p 11.2), is frequently amplified and mutated (&gt;50%) in GBM, and is suggested as a potential therapeutic target. To correlate chemo-vulnerability with genomic aberrations and further determine biomarkers for targeted therapies, a panel of seven EGFR tyrosine kinase inhibitors were tested in a selected nine human GBM patient-derived xenograft (PDX) panel; these preclinical models harbor different mutation combinations of CDKN2A deletion (C), PTEN deletion (P), wild-type EGFR (E) and/or EGFRvIII (Ev3) overexpression. A single agent drug dose response assay (DDR) was performed on GBM PDX neurospheres using drug concentrations ranging from 100uM to 0.5nM with a 12-point serial 3-fold dilution scheme. The cytotoxic efficacy of EGFR inhibition was dependent on both the PDX line and the EFGR inhibitor applied. GBM59 and GBM76 – both triple CEv3P mutants – were the most responsive to EGFR inhibition relative to the other GBM models tested. For GBM59, the IC50 values of afatinib, canertinib and neratinib, were sub-micromolar, and low micromolar (&lt;3uM) for erlotinib, gefitinib and lapatinib. GBM76 had IC50 values of 1-8uM with all seven EGFR inhibitors including AZD3759. However, GBM155 and GBM126 with CEv3 but wildtype PTEN only responded to afatinib, canertinib and neratinib at low micromolar IC50 values (&lt;3uM) but not to erlotinib, gefitinib and lapatinib. A deletion in PTEN may sensitize GBM cells with CEv3 mutations to erlotinib, gefitinib and lapatinib in vitro. The other group of GBM PDX lines (C only) represented by GBM122, GBM150 and GBM182 responded well to afatinib, canertinib and neratinib with IC50 values of 2- 9uM. GBM156 with CE had a similar profile to the group of C only or CEv3. GBM56 with CP showed the most resistance with mild responses to afatinib, canertinib and neratinib, as observed in its high micromolar IC50 values (6-9uM). Overall, neratinib is the most effective compound among the tested EGFR inhibitors based on IC50 values. Canertinib, the triple tyrosine kinase inhibitor against EGFR/HER2/ErbB-4, is the second most effective agent. Afatinib has similar drug efficacy to canertinib. All three compounds moderately inhibit all GBM PDX lines. The drug response mechanism and its correlation with the mutation status of CDKN2A, EGFR, and PTEN will be further investigated cross a broad array of GBM PDX models. Supported by NIH NCI R01 CA204136
Citation Format: Nanyun Tang, George Reid, C Ryan Miller, Michael E. Berens. Selective vulnerability of GBM PDX to a panel of EGFR tyrosine kinase inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3681.
Abstract 3710: Combinatorial micro RNA therapy can be used as potential cell cycle inhibitors to treat lung cancer
Authors: Hossian A K M Nawshad 
Published: September 2020

Abstract
Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Among the 18.1 million of total cancer patients last year, 2.1 million of the new cases were of LC worldwide. The poor prognosis, higher incidence, and mortality rate make this disease a devastating type of cancer. Cell cycle inhibition is one of the prominent choices among researchers in cancer treatment. Different cell cycle inhibitors are developed by scientists where the cyclin-dependent kinase (CDK) inhibitors are among the most frequently researched. Just recently, 3 CDK inhibitors received FDA-approval for treatment of specific breast cancer subtypes, but no CDK inhibitors currently exist for LC patient treatment. Thus, there is a need for molecules that regulate cell cycle progression and CDK expression. Micro RNAs (miRNAs) are gene-expression regulatory molecules. Among several miRs, we selected miR-143 and miR-506 to regulate CDK1 and CDK4/6, respectively. qPCR and RNA-sequencing indicated that this combinatorial miR therapy caused downregulation of the respective CDK1, 4, and 6 genes in H358 and H1975 lung cancer cell lines. This RNA inhibition corresponded to protein levels downregulation, as detected by western blot analysis. Further investigation found that this treatment caused significant halt of the cell cycle progression, which is markedly stronger than the commercially available CDK inhibitors, Ribociclib and Flavopiridol. We also identified the combined miR-143 and miR-506 caused significant increase of the apoptotic cell population at both 24 and 48 h post-treatment, as detected by an Annexin V/PI analysis. Interestingly, low or no apoptotic impact was observed in HFL1 normal lung fibroblast cells by the combinatorial miR treatment, indicating a cancer-cell specific activity. Upstream pathway analysis through RNA-sequencing using Ingenuity Pathway Analysis software (IPA; Qiagen) indicated a potential ERK-mediation on the activity of the combinatorial miR treatment. Our analysis of the ERK pathway using MAPK (ERK) inhibitors indicated an ERK-independent cell cycle inhibitory activity of the two miRs. Through further analysis of the RNA-Seq data, we observed a potential inhibition of the cellular migration and invasion activity of the cells, which was confirmed by a cell migration assay. In summary, combinatorial treatment of miR-143 and miR-506 has a significant impact on the cell cycle, overall survival, and migration of LC cells, which still merits further study.
Citation Format: A K M Nawshad Hossian. Combinatorial micro RNA therapy can be used as potential cell cycle inhibitors to treat lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3710.
Abstract 3724: BMAL1 rewires mitochondrial metabolism and promotes tumor progress of triple negative breast cancer during insulin resistance
Authors: Ramos Cassandra A. , Ouyang Ching , Qi Yue , Chung Yiyin , Cheng Chun-Ting , LaBarge Mark A. , Seewasldt Victoria L. , Ann David K. 
Published: September 2020

Abstract
Insulin resistance is a hallmark of metabolic diseases and negatively associated with breast cancer outcomes. While much work has dedicated to circadian dysregulation, metabolic diseases in breast cancer progression, the molecular mechanism connecting all these perspectives together has not yet established. To understand this underlying mechanism, we use in vitro and in vivo insulin-resistant triple-negative breast cancer (TNBC) models, illustrating that insulin resistance in TNBC reciprocally alters mitochondrial respiration and the expression of genes in the circadian rhythm pathway. Furthermore, genetic knockdown of BMAL1, an important circadian transcription factor, ablates key adaptations to insulin resistance, such as increased pyruvate flux, oxygen consumption, and lipid storage. Our in vivo study demonstrates that orthotopically transplanted E0771 mouse breast cancer cells with BMAL1 knocked down grow significantly faster than the parental counterpart in mice fed with the high-fat diet. This new understanding of BMAL1 expands our insights into circadian control of tumor metabolism and may lead to novel treatments for breast cancer.
Citation Format: Cassandra A. Ramos, Ching Ouyang, Yue Qi, Yiyin Chung, Chun-Ting Cheng, Mark A. LaBarge, Victoria L. Seewasldt, David K. Ann. BMAL1 rewires mitochondrial metabolism and promotes tumor progress of triple negative breast cancer during insulin resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3724.
Abstract 3757: Examination of the epidermal growth factor 3 (HER3) dysregulations in hepatocellular carcinoma
Authors: Ming Sheung In , Chan Lo Kong , Ho Daniel W.H. , Ng Irene O.L. 
Published: September 2020

Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a particularly high mortality rate. Treatment options for HCC are limited. Curative treatments including surgical resection and liver transplantation are only applicable to early diagnosed patients. For advanced HCC patients, the currently available first-line molecularly targeted medications are suffering from low rates of response and high inter-patients variability providing limited survival benefits. Receptor tyrosine kinases (RTKs) are plasma membrane-associated protein kinases which control the activation of intracellular signal transductions in response to the extracellular stimuli. Activation of specific RTKs has been implicated in various kinds of human cancers, and pharmacological inhibition of cancer associated RTKs is one of the key strategies of modern targeted therapy. However, a comprehensive and systematic assessment of the RTKs dysregulations in terms of expression and mutation in HCC is still much awaited.
In this study, RNA-sequencing analysis was performed in paired HCC tissues to examine the expression profiles of 58 RTKs. Also, the mutational status of these RTKs in HCC tissues was examined by targeted DNA-sequencing analysis. Our systemic analyses have revealed that Epidermal Growth Factor Receptor 3 (HER3) was significantly upregulated and recurrently mutated in HCC. Independent qPCR analysis for HER3 in 101 paired HBV-associated HCC tumor and non-tumorous samples validated that HER3 was upregulated in HCC. More importantly, upregulation of HER3 was found to be significantly correlated with the presence of metastatic features of HCC including tumor microsatellite formation (p=0.015) and venous invasion (p=0.001). Neuregulin-1 (NRG-1) is the best-known ligand for HER3. Stimulation of HER3 activation by the ligand NRG-1 could induce HER3 phosphorylation, and activate the downstream PI3K/AKT and MAPK signaling pathways, and signficantly promoted the proliferation and migration of HCC cells. Conversely, CRISPR/Cas9-mediated HER3 knockout in Huh7 and PLC cells significantly reduced the NRG-1 induced functional changes. Consistently, our preliminary results demonstrated that HER3 knockout Huh7 cells forms relatively smaller tumors in a subcutaneous tumor xenograft model in vivo. Together, our results demonstrated that HER3 dysregulation plays a supporting role in HCC development. Targeting HER3 may potentially derive new therapeutic strategy for treatment of HCC.
Citation Format: Sheung In Ming, Lo Kong Chan, Daniel W.H. Ho, Irene O.L. Ng. Examination of the epidermal growth factor 3 (HER3) dysregulations in hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3757.
Abstract 3929: Patient-derived pancreatic cancer organoids as in-vitro cancer models for personalizing therapy
Authors: Chew Claire Alexandra Zhen , Tay Li Min , Hooi Lissa , Chow Edward Kai-Hua , Bonney Glenn K. , Chan Shing Leng 
Published: September 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive solid tumor. Unfortunately, patients with this disease have not benefited from the advances in precision medicine seen in other malignancies. The lack of actionable mutations as well as predictive biomarkers has hampered progress in this area. Combination therapy remains the cornerstone of systemic treatment, with FOLFIRINOX being the most effective therapeutic regimen in PDAC. However, it is clear that only subset of patients are responsive, and the toxicities of this 4-drug combination are intolerable to many patients particularly in the adjuvant setting. There is a clear need for more personalized rational drug combinations that are optimized to maximize efficacy while minimizing toxicity.
We have established a protocol for the generation of PDAC organoids from endoscopic ultrasound biopsies for personalizing systemic therapy based on the principle of phenotype driven oncology. Organoids generated are analyzed for KRAS and p53 mutations to confirm their tumor origin. By applying a phenotypic optimization platform (QPOP) on these organoids, we are able to identify optimized drug combinations from a pool of both FDA-approved and preclinical drugs. As expected, FOLFIRINOX did not always rank high by treatment efficacy suggesting that alternative treatment may be more beneficial for these patients. In addition, we identified that the efficacy of FOLFIRINOX was driven by two-drug synergistic combinations which varied between patients. This can potentially advise modifications to this regimen when toxicity arises. From a discovery perspective, our platform has the capability of deriving novel drug combinations. The combination of gemcitabine and Abraxane with a WEE1-inhibitor was found to be synergistic in selected PDAC patients. Furthermore, patients with similar drug response profiles can be studied together to identify predictive markers of sensitivity.
To demonstrate that this platform can indeed be applied to prospectively recommend treatment strategies for patients with progressive disease on first-line chemotherapy, we are establishing a clinical trial to personalize second-line therapy, with the endpoint of overall response rate. Overall, by combining patient-derived organoids with rational optimized drug combinations, we aim to personalize therapy for patients with PDAC to improve overall survival.
Citation Format: Claire Alexandra Zhen Chew, Li Min Tay, Lissa Hooi, Edward Kai-Hua Chow, Glenn K. Bonney, Shing Leng Chan. Patient-derived pancreatic cancer organoids as in-vitro cancer models for personalizing therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3929.
Abstract 3964: Integrin α2-collagen I axis promotes proliferative and migratory phenotypes in intrahepatic cholangiocarcinoma
Authors: Rattanasinchai Chotirat , Navasumrit Panida , Ruchirawat Mathuros 
Published: September 2020

Abstract
Cholangiocarcinoma (CCA) is a deadly cancer of the bile duct and is considered an incurable disease with no efficacious treatment option. CCA arises as a consequence of chronic inflammation and tissue damage to the biliary epithelium. Thus, one of the crucial characteristics of CCA is its tumor microenvironment high in stromal extracellular matrices (ECMs), especially collagen I. Herein, the direct impact of collagen I on intrahepatic CCA (iCCA) cell lines were investigated. Our data demonstrate that iCCA cells mainly interact with collagen I, while cholangiocyte cells preferentially binds to fibronectin in cell adhesion assays. Correspondingly, iCCA cell lines exhibit over 20 fold-upregulation of ITGA2 gene, which encodes collagen-binding integrin α2, when compared with non-cancerous cholangiocyte cells. Furthermore, the result from the GEO dataset of 92 iCCA patients demonstrate that ITGA2 gene expression in iCCA tumors is 13 folds greater than their adjacent normal tissues and is positively correlated with expressions of two isoforms of collagen I gene, COL1A1 and COL1A2. Collagen I is also sufficient to drive proliferation of iCCA cells in a serum-restricted condition and this effect is mediated by integrin α2 as proven by ITGA2 silencing or α2β1-selective inhibitor treatment. In contrast to round-shaped, multicellular colonies of iCCA cells in clonogenic assays, iCCA colonies exhibit migratory phenotypes in the presence of collagen I. Likewise, this phenotype can be inhibited by α2β1-selective inhibitor treatment. Taken together, these data suggest that stromal collagen I could be one of the tumor microenvironmental factors directly facilitating iCCA progression. Thus, targeting the integrin α2-collagen I axis could be a promising therapeutic strategy for combating this cancer.
Citation Format: Chotirat Rattanasinchai, Panida Navasumrit, Mathuros Ruchirawat. Integrin α2-collagen I axis promotes proliferative and migratory phenotypes in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3964.
Abstract 3985: GDF15 expression level impacts the canonical pathways of the tumor microenvironment and ovarian tumors with wild-type p53 in response to chemotherapy
Authors: Izaguirre Daisy I. , Tsang Yvonne TM , Kun Eucharist H. , Gershenson David M. , Wong Kwong-Kwok 
Published: September 2020

Abstract
Background
The standard treatment for ovarian cancer is surgery, followed by chemotherapy with a platinum agent, such as cisplatin or carboplatin, and a taxane, such as paclitaxel. We previously observed that patients with ovarian cancer that was wild-type for p53 had a lower survival rate than did those with p53 mutations. A better understanding of the molecular changes that occur in epithelial ovarian cancer cells with wild-type p53 in response to cisplatin treatment could reveal a novel mechanism of chemoresistance. Therefore, we might be able to develop novel strategy to overcome chemoresistance.
Methods
Gene expression profiling was performed on the wild-type p53 ovarian cancer cell line A2780 to identify genes that are highly induced by cisplatin. Growth differentiation factor 15 (GDF15) was identified as being highly induced by cisplatin or carboplatin. This finding was validated in a panel of wild-type and mutant p53 ovarian cancer cell lines. Mouse orthotopic models were used to further investigate the induction of GDF15 by cisplatin in vivo and the effect of GDF15 knockdown (GDF15-KD) on tumor growth and cisplatin response. A novel analysis was performed of RNAseq data generated from tumors formed in cisplatin-treated orthotopic mouse models to understand the tumor and stromal cell signaling changes.
Results
The induction of GDF15 was demonstrated in vivo, and the serum level of GDF15 after cisplatin treatment was also found to be significantly up-regulated in an A2780 ovarian cancer orthotopic mouse model. More importantly, cisplatin treatment was more effective in shrinking the mouse tumors developed from GDF15-KD A2780 cell line than did control tumors. Histopathological and novel RNAseq analyses of mouse tumors revealed that GDF15-KD tumors had a lower stromal component than did control tumors after cisplatin treatment. GDF15-KD tumors also had a different repertoire of activated and inhibited canonical pathways in their stromal cell and cancer cell components than did control tumors in response to cisplatin treatment.
Conclusions
GDF15 expression in wild-type p53 ovarian cancer cells can modulate the canonical pathways in the tumor microenvironment in response to cisplatin and may be a mechanism of chemoresistance. Targeting GDF15 signaling could be a novel strategy to enhance the effectiveness of chemotherapy.
Citation Format: Daisy I. Izaguirre, Yvonne TM Tsang, Eucharist H. Kun, David M. Gershenson, Kwong-Kwok Wong. GDF15 expression level impacts the canonical pathways of the tumor microenvironment and ovarian tumors with wild-type p53 in response to chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3985.