bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 304: Dual PI3K/BCL-2 family inhibition in colorectal cancers with Apc and Pik3ca mutations
Authors: Miller Devon D. , Babiarz Christopher P. , Payne Susan N. , Pasch Cheri A. , Clipson Linda , Matkowskyj Kristina A. , Deming Dustin A. 
Published: August 2018

Abstract
Background: Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States. Approximately 20% of human CRCs possess mutations in the PIK3CA gene, resulting in a constitutively active form of phosphoinositide-3 kinase (PI3K). These PIK3CA mutations most commonly occur concomitantly with the loss of adenomatous polyposis coli (APC). Copanlisib is a beta-isoform sparing PI3K inhibitor. Here we examine the response of CRCs with Apc and Pik3ca mutations to copanlisib alone and in combination with navitoclax, a BCL-2, BCL-xL, and BCL-w inhibitor.
Methods: Murine-derived organotypic cancer spheroids (MDOCS) with Apc and Pik3ca mutations generated from transgenic mice were cultured in Matrigel and treated by exchanging feeding media containing desired concentration of each agent over the spheroids. Spheroids were treated with feeding media (control), 200nM ABT263, 200nM copanlisib, or the combination of both treatments. The spheroid culture response was quantified as the median relative change in the sphere diameter, comparing pre- and posttreatment 4x optical microscopic images to those obtained 48 hours post-treatment.
Results: Untreated MDOCS had a median growth in sphere diameter of 137%. ABT263 did not significantly affect growth; however, copanlisib significantly reduced median sphere size by 24.6% (p&lt;0.001) and the combination treatment reduced median sphere size by 33% which was significant to both control and copanlisib only treated spheres (p&lt;0.001 and p=0.014, respectively). Phosphorylation of ribosomal protein S6 and 4EBP1 were suppressed with copanlisib treatment. Induction of apoptosis in these spheres treated with the combination regimen was confirmed with immunofluorescence for cleaved caspase 3 with minimal apoptosis observed in those spheres treated with copanlisib alone.
Conclusion: In this study, we demonstrated the ability of copanlisib alone and combined with ABT263 to cause a marked decrease in sphere size of CRC MDOCS with Apc and Pik3ca mutations. Future tests will examine this novel regimen in vivo and potentially in future clinical trials.
Citation Format: Devon D. Miller, Christopher P. Babiarz, Susan N. Payne, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Dustin A. Deming. Dual PI3K/BCL-2 family inhibition in colorectal cancers with Apc and Pik3ca mutations [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 304.
Abstract 3046: Evaluation of pancreatic ductal adenocarcinoma with acidoCEST MRI
Authors: High Rachel A. , Randtke Edward A. , Jones Kyle M. , Pagel Mark D. 
Published: August 2018

Abstract
Introduction: Our goal is to evaluate the role of using extracelluar pH (pHe) as a predictor of pancreatic ductal adenocarcinoma (PDAC) development using a non-invasive, in vivo imaging technique called acidoCEST MRI, to improve early detection of pancreatic tumors.
Methods: Spontaneous PDAC development was initiated by administering 14 caerulein injections over a 62 hour period to a KrasLSL.G12D/+; PdxCre mouse model. Caerulein induces pancreatitis which drives tumor development in the context of a Kras mutation. Animals were imaged with a Bruker BioSpin 7T MRI scanner with an acidoCEST MRI protocol at pre-injection, 1 hour and 48 hours post final injection of caerulein, and weekly until tumors reached a size of 200mm3. During all MR imaging, mice were anesthetized with 2.0% isofluorane, maintained at a respiration rate of 35-40 bpm, and maintained at a body temperature of 37°C. For acidoCEST MR imaging, mice were injected with 370 mg/mL iopamidol (200 μL IV bolus and 400 μL/hr IV infusion) and scanned with a 6 sec saturation time at 3.5 μT, with a 300 ms acquisition time. Pixel-wise parametric maps of pancreatic pHe values were generated via fitting the CEST spectrum with the Bloch-McConnell equations in MATLAB R2016a. Average pancreatic pHe was recorded.
Results: AcidoCEST MRI was successful in acquiring in vivo pHe of normal and tumor pancreatic tissue, both with sufficient uptake of the iopamidol contrast agent. The pHe values for healthy pancreatic tissue ranged from 6.83 to 7.33 with an average of 6.96 (n=14). 1 hour after the last caerulein injection, during pancreatic inflammation, pHe ranged from 6.78 to 7.00, with an average of 6.92 (n=6). Tumors began to reach a size of 200mm3 at 5 weeks post caerulein injections. In tumor tissue, pHe was 6.59 (n=1), demonstrating tumor acidosis.
Conclusions: We have demonstrated that acidoCEST MRI can be used to quantify pHe in healthy pancreatic tissue, pancreatitis, and pancreatic ductal adenocarcinoma. These pHe values will be used to determine if acidity in pancreatitis correlates with future development of PDAC and/or a more aggressive phenotype. Further pre-clinical studies using acidoCEST MRI may be performed to monitor early therapeutic response to pancreatic tumor treatment.
Citation Format: Rachel A. High, Edward A. Randtke, Kyle M. Jones, Mark D. Pagel. Evaluation of pancreatic ductal adenocarcinoma with acidoCEST MRI [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 3046.
Abstract 3051: Prognostic value of 18F-FDG PET/CT parameters in patients with primary pulmonary lymphoepithelioma-like carcinoma
Authors: Fang Yueh-Fu , Lin Chun-Yu 
Published: August 2018

Abstract
Introduction Pretreatment tumor metabolic burden, which measured by fluorine-18 fluorodeoxyglucose positron emission tomography/computerized tomography (18F-FDG PET/CT) have been shown to predict outcomes in various malignancies. Epstein-Barr virus (EBV) serology titer in pulmonary LELC is correlated to stage. However, the prognostic value of 18F-FDG PET/CT in patients with pulmonary lymphoepithelioma-like carcinoma (LELC) and the relationship between EBV viral load remained unknown. The current study aims to investigate the prognostic value and association between functional parameters of 18F-FDG PET/CT and serum EBV DNA in patients with pulmonary LELC.
Methods This retrospective study comprised 32 patients with pulmonary LELC who underwent pretreatment 18F-FDG PET/CT between January 2008 and December 2016. The EBV viral load and the functional parameters of 18F-FDG PET/CT were used for survival analysis.
Results The value of pre-treatment serum EBV DNA had significantly positive correlation with whole MTV (r = 0.63, P = 0.0337) and whole TLG (r = 0.77, P = 0.0093). Advanced tumor stage (≥III) and high whole MTV (≥72.58) significantly predicted poor PFS. Multivariate survival analysis for PFS showed that there was a trend toward a lower risk of recurrence in patients with early tumor stage (≤II) (HR = 0.112, 95% CI =0.011-1.117, P = 0.062, Table 3), albeit not significantly so. Advanced tumor stage (≥III), high whole MTV (≥72.58) and high whole TLG (≥278.4) were predictors of poor OS. However, in multivariate survival analysis, none of them were independent predictors for OS. EBV viral load was not prognostic factor for both PFS and OS.
Conclusion Greater whole MTV and whole TLG predicted poorer OS in patients with primary pulmonary LELC. Functional parameter of 18F-FDG PET/CT may provide useful prognostic information. Serum EBV DNA was closely related to whole MTV and TLG, but not a prognostic factor.
Citation Format: Yueh-Fu Fang, Chun-Yu Lin. Prognostic value of 18F-FDG PET/CT parameters in patients with primary pulmonary lymphoepithelioma-like 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 3051.
Abstract 3052: Identification and characterization of DPPA2 as a potential cancer stem cell marker in hepatocellular carcinoma
Authors: Yu Dandan , Yan Qian , Zhang Yu , Guo Ling , Wu Chuanyue , Guan Xin-yuan 
Published: August 2018

Abstract
Cancer stem cells (CSC) are a small subpopulation of tumor cells that share many properties with embryonic stem cells, including the ability to differentiate and self-renew. The study of stemness-associated genes might give us a hint on the tumorigenesis and tumor progression. By comparing the expression profiles of human embryonic stem cells (ESC), endoderm, liver progenitors, premature hepatocytes as well as two pairs of non-tumor and tumor tissues of hepatocellular carcinoma (HCC), we found that the gene Developmental Pluripotency Associated 2 (DPPA2) was highly expressed in the stage of ESC, and decreased dramatically along with development, suggesting its role as a stemness associated gene. Analysis of HCC clinical samples showed that elevated expression of DPPA2 was significantly associated with differentiation, TNM stage, the number of tumor nodules and thrombus, as well as poorer prognosis. Functional studies demonstrated that DPPA2 - overexpressed cells displayed enhanced stemness feature, increasing the ability of self-renewal, tumorigenicity and chemo-resistance. We also found that overexpression of DPPA2 could increase the expression of some cancer stem cell markers. RNA-sequencing results suggested that Wnt signaling was abnormally activated after DPPA2 overexpression. Our findings point to a new potential cancer stem cell marker which may provide an attractive therapeutic target for HCC patients.
Citation Format: Dandan Yu, Qian Yan, Yu Zhang, Ling Guo, Chuanyue Wu, Xin-yuan Guan. Identification and characterization of DPPA2 as a potential cancer stem cell marker in hepatocellular 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 3052.
Abstract 3059: SOX2 is a novel biomarker for poor long-term outcomes in oral cancer
Authors: Zhang Xuefeng , Xu Hao , Sun Chongkui , Liang Xinhua , Deng Peng , Zeng Xin , Chen Qianming 
Published: August 2018

Abstract
Purpose: Sex determining region Y-BOX2 (SOX2), a key regulator of the self-renewal ability of stem cells, plays a role in the initiation and development of head and neck squamous cell carcinoma (HNSCC). However, the association between SOX2 expression and the outcomes of patients with oral squamous cell carcinoma (OSCC) has not been investigated. Thus, in this study, we investigated the possibility of predicting the survival outcomes of patients with OSCC by evaluating SOX2 expression.
Experiment design: First, we analyzed SOX2 expression in patients with OSCC in The Cancer Genome Atlas (TCGA) dataset by a bioinformatics approach. In addition, samples of 219 patients with OSCC from two independent Chinese centers were collected. The median follow-up time and 95% confidence interval (CI) for the cohorts were 36 (25.06, 46.93) months and SOX2 expression in these samples was determined by immunostaining using tissue microarray. The Kaplan-Meier analysis, log-rank test, and Cox proportional hazards regression model were used to determine univariate and multivariate analyses, and hazard ratios for overall survival (OS), respectively.
Results: In TCGA database, amplification of SOX2 was negatively correlated with the OS rate for patients who survived more than 300 days after the first diagnosis. Moreover, 39.7% of the samples from the cohorts showed high SOX2 expression. We found a significant difference in the survival rate between patients with high and low SOX2 expression ranging from 13 to 126 months.
Conclusion: High SOX2 expression can predict poor long-term, but not short-term, survival outcomes in patients with OSCC. Our findings not only indicated that SOX2 may be a novel biomarker for the long-term prognosis of OSCC but also strongly supported the cancer stem cell theory that dysregulation of the self-renewal ability of stem cells may contribute to the development of OSCC.
Citation Format: Xuefeng Zhang, Hao Xu, Chongkui Sun, Xinhua Liang, Peng Deng, Xin Zeng, Qianming Chen. SOX2 is a novel biomarker for poor long-term outcomes in oral 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 3059.
Abstract 3062: Ablation of parathyroid hormone-related protein in the triple negative human breast cancer line MDA-MB-231 inhibits its cancer stem cell phenotype
Authors: Li Jiarong , Doré-Savard Louis , Sellin Karine , Camirand Anne , Kremer Richard 
Published: August 2018

Abstract
Parathyroid hormone-related protein (PTHrP) is a pleiotropic hormone involved in a wide range of developmental & physiological processes. It is also dysregulated in advanced cancers where it causes malignancy-associated hypercalcemia & plays a major role in the progression of bone metastases. We have shown previously that PTHrP ablation delays tumor initiation & that it is preferentially expressed in triple negative breast cancer (TNBC).Here we investigated how PTHrP can influence the phenotype of the human TNBC cell line MDA-MB231 using CRISPR/cas 9 knockout technology. We used U6G RNA-Cas9-2A-red fluorescence protein (RFP) vector with a human PTHrP specific guide RNA directed to exon 4(knockout/KO) or an empty vector as control. PTHrP KO cells (RFP+) were isolated using AutoMacs Pro Separator & single cells were exp&ed in 96 well plates. Positive clones were confirmed by DNA sequencing. Real time PCR & immunofluorescence staining confirmed that 5/96 KO clones had between 95-99% decrease in PTHrP expression compared to control cells. We then assessed cancer stem cell (CSC) characteristics of both KO & control cell lines. Mammosphere formation was reduced by over 60% in KO cells. Stem cell phenotype assessed by ALDH1 & CD44+/CD24 low using FACS analysis were significantly reduced by over 30% in KO cells. Cell morphology analysis showed a shift from a mesenchymal phenotype towards an epithelial phenotype. Overall our data show that PTHrP regulates TNBC towards a more aggressive phenotype & suggest that it could be targeted therapeutically.
Citation Format: Jiarong Li, Louis Doré-Savard, Karine Sellin, Anne Camirand, Richard Kremer. Ablation of parathyroid hormone-related protein in the triple negative human breast cancer line MDA-MB-231 inhibits its cancer stem cell phenotype [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 3062.
Abstract 3065: Role of noncoding RNA miR 146 alpha and let 7c in epithelial mesenchymal transition, proliferation, and cancer stem cell-like transformation analyzed by gene expression studies in a cohort of prostate cancer patients
Authors: Banerjee Hirendra N. , Sarkar Fazlul , Worthington Myla , Hodge Sasha , Verma Mukesh , Mandal Santosh 
Published: August 2018

Abstract
Mir 146 alpha and let 7c are considered tumor suppressor miRs and are responsible for downregulating polycomb repressor proteins like EZH2, SUZ12, etc., and thereby prevent epithelial-mesenchymal transition (EMT),proliferation, spheroid formation and metastasis in prostate cancer cells. In this study, we investigated the role of these microRNAs in a cohort of 105 patients, both White (CA) and African American (AA), by gene expression studies using real-time PCR techniques. Our results showed definite downregulation of these noncoding RNAs in the cDNAs obtained from the matched biopsy samples of normal and cancer tissues. We further transfected these miR full-length constructs in PC3 prostate cancer cell lines and validated their effects by downregulation of their target 3'UTR target mRNAs. Our results showed decrease in EMT markers ALDH, increase in EMT marker E-cadherin, decrease in cell proliferation and spheroid formation; fluorescence microscopy studies showed a decrease in CD44-positive cells in the spheroids, signifying a possible hindrance in the growth of cancer stem cells (CSCs). Thus, miR 146 alpha and let7c could be ideal targets for diagnosis, prognosis and therapeutic intervention.
Citation Format: Hirendra N. Banerjee, Fazlul Sarkar, Myla Worthington, Sasha Hodge, Mukesh Verma, Santosh Mandal. Role of noncoding RNA miR 146 alpha and let 7c in epithelial mesenchymal transition, proliferation, and cancer stem cell-like transformation analyzed by gene expression studies in a cohort of prostate cancer patients [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 3065.
Abstract 3066: Chemotherapy-induced GSTO1 interacts with ryanodine receptor RYR1 to trigger Ca2+-dependent breast cancer stem cell enrichment
Authors: Lu Haiquan , Semenza Gregg 
Published: August 2018

Abstract
Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we demonstrate that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with ryanodine receptor RYR1 and promotes calcium release from endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer.
Citation Format: Haiquan Lu, Gregg Semenza. Chemotherapy-induced GSTO1 interacts with ryanodine receptor RYR1 to trigger Ca2+-dependent breast cancer stem cell enrichment [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 3066.
Abstract 307: Targeting BCL-2 and BCL-xL with a novel dual inhibitor APG-1252 triggers cell death and inhibits tumor growth in small cell lung cancer models
Authors: Wang GuangFeng , Min Ping , Wu MiaoYi , Dang Shuo , Tang ChuanYan , Zhang Fei , Guo Ming , Wang Shaomeng , Deng Jing , Fang Douglas D. , Yang DaJun , Zhai YiFan 
Published: August 2018

Abstract
Small cell lung cancer (SCLC) is one of the most deadly diseases with a dismal five year survival rate less than 7%. Even though most SCLC patients respond to the initial platinum-based cytotoxic or radiation therapies, they inevitably relapse and succumb to the disease. Anti-apoptotic proteins BCL-2 and BCL-xL, which are highly expressed in 40-60% of SCLCs and play a critical role in tumorigenesis and drug resistance, have been emerging as a promising target for therapeutic intervention. We have recently developed a novel dual BCL-2/BCL-xL inhibitor APG-1252 for cancer therapy. In this study, the effect of APG-1252 was evaluated in a panel of SCLC cell lines for discovery of indications and predictive biomarkers. The results show that the sensitivity of SCLC cell lines with sub-µM or nM IC50 values are correlated with the higher expression levels of BCL-2/BCL-xL, BIM and/or PUMA but lower levels of MCL-1. Conversely, the resistant cell lines either lack of BCL-2/BCL-xL protein, or exhibit higher level of MCL-1 protein. In xenograft tumor models, consistent with in vitro results, APG-1252 exhibits antitumor activities in the models derived from the sensitive cells but not in those from the resistant cells. Interestingly, while ABT-263 failed to inhibit H146 xenograft tumor growth, despite of its similar in vitro killing ability as APG-1252, APG-1252 showed potent antitumor activity in the xenograft model. To overcome the drug resistance conferred by MCL-1 in the resistant cells, we explore the combination therapy with other targeted agents. We found that our novel MDM2 inhibitor APG-115 was able to overcome the intrinsic resistance and sensitize those cells to APG-1252 in vitro, suggesting that reducing the apoptotic threshold by inhibiting other anti-death proteins like MCL-1 or increasing apoptotic function through p53 can enhance SCLC sensitivity to APG-1252. Collectively, APG-1252 represents a novel opportunity that can neutralize the protection from BCL-2/BCL-xL and trigger cell death and inhibit tumor growth in SCLC models. With the significance of these preclinical data, APG-1252 has been granted for phase 1 clinical trials in USA (NCT03080311) and China.
Citation Format: GuangFeng Wang, Ping Min, MiaoYi Wu, Shuo Dang, ChuanYan Tang, Fei Zhang, Ming Guo, Shaomeng Wang, Jing Deng, Douglas D. Fang, DaJun Yang, YiFan Zhai. Targeting BCL-2 and BCL-xL with a novel dual inhibitor APG-1252 triggers cell death and inhibits tumor growth in small cell lung cancer models [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 307.
Abstract 3072: MiRNA-2861 behaves as LCSC biomarker and regulates the HDAC5-ERK signal pathway
Authors: Zhu Yimin , Zhao Mengya , Li Lin 
Published: August 2018

Abstract
Cancer stem cells (CSCs) are responsible for cancer initiating, recurrence and drug-resistance. Discovery of novel biomarkers for CSCs is helpful for early diagnosis and prognosis. In our study, the important role of miR-2861 in maintaining the stemness of LCSCs was investigated. The LCSCs differentiation model was established through introducing serum into the medium of H460 spheres. MiR-2861 expression was significant higher in LCSCs no matter compared to the differentiation cells or normal cells. HDAC5 expression was positively correlated with miR-2861 in LCSCs and knockdown of miR-2861 decreased the expression of HDAC5, which implied that HDAC5 may be involved in the differentiation of LCSCs mediated by miR-2861.The role of HDAC5 in the regulation of LCSCs differentiation was further verified by the inhibitory effect of LMK-235 on the phosphorylation of ERK1/2, which was recognized as the regulator of CSCs differentiation. Our study provided a better understanding of miR-2861 and HDAC5 axis in maintaining the stemness of LCSCs and laid a foundation for molecular targeted therapy.
Citation Format: Yimin Zhu, Mengya Zhao, Lin Li. MiRNA-2861 behaves as LCSC biomarker and regulates the HDAC5-ERK signal 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 3072.