bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 398: Overriding drug resistance in Philadelphia chromosome-positive acute B lymphoblastic leukemia by targeting both BCR-ABL and MAP4K signaling pathways
Authors: Ren Ruibao , Xiao Xinhua , Zhang Jianming , Jiao Bo 
Published: August 2019

Abstract
The Philadelphia chromosome (Ph) translocation, which leads to creation of a fusion gene product BCR-ABL, is found in chronic myelogenous leukemia (CML) and 20% of adult and 2-5% pediatric acute B-lymphoblastic leukemia (B-ALL). The selective ABL tyrosine kinase inhibitor (TKI) has been shown a remarkable clinical activity in patients with CML. The ABL TKI has also improved the clinical outcome of Ph+ B-ALL dramatically in combination with standard chemotherapy, but the morbidity and mortality of this disease remain high. The existence of ABL inhibitor-resistant leukemia cells in these patients indicates the presence of additional oncogenic pathways in Ph+ B-ALL. Discovery of a new therapeutic strategy to eradicate Ph+ B-ALL cells is, therefore, urgently needed. By using a chemical genetics approach, we identified a novel small molecule, AR4-13, which shows robust ABL kinase inhibition and potent pharmaceutical efficacy in Ph+ leukemias among 1094 cell lines from the Cancer Cell Line Encyclopedia (CCLE) project. Interestingly, AR4-13 possesses preferable potency than Dasatinib, a potent dual SRC/ABL TKI approved to treat CML and Ph+ B-ALL, to kill Ph+ B-ALL cells, but not do so in CML cells, both in vitro and in vivo. In particular, AR4-13 inhibits S6 and p38 phosphorylation much more potently than that of Dasatinib. Furthermore, kinome profiling data indicate that AR4-13 also inhibits Mitogen-activated protein kinase (MAPK) kinase kinase kinases (MAP4Ks), which belong to a kinase family that controls the MAPK signaling in lymphoid cells. Consistently, RNAi-based synthetic lethal screen with TKIs show that suppression of MAP4Ks could significantly enhance the sensitivity to ABL TKIs in Ph+ B-ALL cells, implying that MAP4K family kinases function as a parallel pathway to BCR-ABL signaling and confer ABL TKI resistance in Ph+ B-ALL. Our findings indicate that simultaneous targeting both the ABL and MAP4K signaling pathways might serve as a promising TKI therapeutic strategy for Ph+ B-ALL.
Citation Format: Ruibao Ren, Xinhua Xiao, Jianming Zhang, Bo Jiao. Overriding drug resistance in Philadelphia chromosome-positive acute B lymphoblastic leukemia by targeting both BCR-ABL and MAP4K signaling pathways [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 398.
Abstract 3982: Isolation, culture & characterization ofthe circulating tumor cells from breast cancer patients’ peripheral blood in vitro
Authors: Zhao Pan , Zhang Huirong , Liu Chang , Wang Jianhong , Zhou Wenbin , Zou Chang 
Published: August 2019

Abstract
Background: Circulating tumor cells (CTCs) are rare tumor cells in peripheral blood. As a few studies showed CTCs would be a kind of intriguing drug targets and more beneficial for cancer patients if there genomic and proteomic information could be deciphered dynamically. However, the rarity, challenging isolation as well as the primary culture procedures limited the analysis of CTCs insightfully.
Methods: The method of density gradient centrifugation was used to obtain PBMCs. Cells adherent and suspension culture for collecting the CTCs.
Results: There was a cell cluster which named CTC-3 came out in the plate. CTC-3 steadily formed clones, displayed epithelial phenotype and showed stem-cell like properties. Immunofluorescence identification of CTC-3 were DAPI-positive, Cytokeratin-positive, and CD45-negative. The karyotyping results indicated that chromosomes were aneuploidthe, the chromosome number of CTC-3 varied from 56 to 60. CTC-3 had larger nuclear/cytoplasmic ratio and limitless replicative potential. Comparing with the MCF-7, CTC-3 grew more faster than MCF-7 from the fifth day. Furthermore, the sphere formation ability of CTC-3 was significantly higher than MCF-7 in vitro. Besides, the tumorigenesis of CTC-3 cells was almost the same as MCF-7 in vivo by the analysis of xenografting in immunodeficient mice. For drug resistance, CTC-3 cells were more resistant to anti-tumor drugs after 3D culture compared with 2D, survive rates of 3D CTC-3 cells after treatment were more than 80%. Finally, the RT-PCR results shows the expression of Vimentin, E-cadherin and CD44 were significantly higher in CTC-3.
Conclusion: We have successfully isolated and expanted a new breast cancer cell line from the breast cancer patient, which could provide more drug sensitivity information of the patient and open up novel avenues towards the understanding of breast cancer.
Keywords: Circulating tumor cell; Breast cancer
Citation Format: Pan Zhao, Huirong Zhang, Chang Liu, Jianhong Wang, Wenbin Zhou, Chang Zou. Isolation, culture & characterization ofthe circulating tumor cells from breast cancer patients’ peripheral blood in vitro [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 3982.
Abstract 3987: Predicting MCL1 inhibitor sensitivity in large cell line panels using a gene expression signature
Authors: Wernitznig Andreas , Rudolph Dorothea , Samwer Matthias , Schweifer Norbert , Trapani Francesca , Wunberg Tobias , Arnhof Heribert , Lee Teakyu , Sensintaffar John L. , Olejniczak Edward T. , Benes Cyril H. , Fesik Stephen W. , Kraut Norbert 
Published: August 2019

Abstract
MCL1, an anti-apoptotic member of the BCL-2 family of proteins, is a key regulator of cancer cell survival and a known resistance factor to anti-cancer drugs, making it a highly desirable target for therapeutic intervention. Recently several MCL1 inhibitors have entered Phase I clinical development. Data derived from large cancer cell line panels suggest, that cell lines of hematopoietic origin are more broadly sensitive to MCL1 inhibition, than cell lines derived from solid tumor types. In particular, for the therapy of solid tumor patients with an MCL1 inhibitor, a patient selection biomarker would be highly desirable.
Published in vitro data using various MCL1 inhibitors, siRNA or CRISPR/Cas9 technology show that tumor cell lines with low BCL-XL gene expression are mostly sensitive to MCL1 inhibition, down-regulation or inactivation. Here we show that by adding the gene expression data of additional six genes (including the MCL1 binding partner BAK1) to BCL-XL, a supervised learning predictor was applied and could reach a performance of almost 80% correctly classified solid tumor cell lines. This new predictor has been applied to either tumor samples, adjacent normal tissues or normal tissue samples from TCGA and GTEx. Briefly, most normal tissue samples are categorized as being sensitive. Moreover, solid tumor samples in contrast to solid tumor cell lines are predicted to be broadly sensitive to MCL1 inhibition with a predicted anti-tumor effect rate of 60% to 95%. In summary, our work describes the translational challenges using cell line-derived predictors on ex vivo tumor samples.
Citation Format: Andreas Wernitznig, Dorothea Rudolph, Matthias Samwer, Norbert Schweifer, Francesca Trapani, Tobias Wunberg, Heribert Arnhof, Teakyu Lee, John L. Sensintaffar, Edward T. Olejniczak, Cyril H. Benes, Stephen W. Fesik, Norbert Kraut. Predicting MCL1 inhibitor sensitivity in large cell line panels using a gene expression signature [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 3987.
Abstract 3988: Identifying prognostic biomarkers of hepatocellular carcinoma by weighted gene coexpression network analysis
Authors: Bai Yi , Long Junyu , Lin Jianzhen , Yang Xu , Wang Dongxu , Yang Xiaobo , Sang Xinting , Liu Jiahui , Zhao Haitao 
Published: August 2019

Abstract
Purpose: Exploring the molecular mechanisms of prognosis in patients with hepatocellular carcinoma (HCC) could assist in identifying novel biomarkers for effective therapy against this deadly disease. Hence, this study was designed to determine the prognostic biomarkers of HCC and to investigate potential mechanisms. Experimental Design: The RNA-Seq data as well as clinical data were downloaded from The Cancer Genome Atlas (TCGA) database, aiming at identifying differentially expressed genes (DEGs) between nontumorous tissues and HCC. Then, weighted gene coexpression network analysis (WGCNA) was performed for determining significant modules associated with overall survival (OS). Results: The mRNA expression profiles from 374 HCC patients in TCGA were included to determine 3270 DEGs. Then, WGCNA was carried out on the 3270 DEGs, and 10 coexpressed gene modules were determined. Pearson’s correlation analysis revealed that the turquoise module significantly positively correlated with OS and the blue module significantly negatively correlated with OS, followed by seven hub genes with high connectivity were identified in these two modules. Based on the Kaplan-Meier (K-M) survival curves and receiver operating characteristic (ROC) curves, the seven hub genes could predict prognosis for patients with HCC well, and the results were validated by GSE54236 dataset contained 78 HCC patients. Additionally, the univariate and multivariate Cox regression analyses showed that the seven hub genes were independent prognostic factors for patients with HCC. Conclusions: In conclusion, the current results provide novel insights into the prognostic biomarkers of HCC, which may contribute to the development of molecular targeted therapy for HCC.
Citation Format: Yi Bai, Junyu Long, Jianzhen Lin, Xu Yang, Dongxu Wang, Xiaobo Yang, Xinting Sang, Jiahui Liu, Haitao Zhao. Identifying prognostic biomarkers of hepatocellular carcinoma by weighted gene coexpression network analysis [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 3988.
Abstract 3989: Identification of biomarkers for UM-164 in triple-negative breast cancer
Authors: Merrill Nathan M. , Vandecan Nathalie M. , Lloyd John P. , Lachacz Eric J. , Ulintz Peter J. , Merajver Sofia D. , Soellner Matthew B. 
Published: August 2019

Abstract
Triple negative breast cancer (TNBC) is one of the deadliest forms of breast cancer due to limited treatment options beyond conventional chemotherapy. While making up approximately 10-20% of total breast cancer cases in the US, TNBC carries a serious burden of disease as it tends to be more aggressive, higher grade, and have a poorer prognosis than other forms of breast cancer. Though new therapies, such as PARP inhibitors, have shown promise in clinical trials in very select patients (e.g. BRCA1 mutation carriers), there is a general lack of predictive markers of therapeutic efficacy to identify subsets of patients most likely to positively respond to a given targeted or conventional therapy. Thus, there is a critical need for biomarkers of drug efficacy in TNBC to help design precision medicine clinical trials based on systematically derived predictive biomarkers. To fill this gap, we devised a strategy to identify biomarkers of drug efficacy in TNBC. As a paradigm of our approach, we treated a panel of 23 TNBC cell lines with our potent c-Src/p38 inhibitor, UM-164, and determined a drug sensitivity score (DSS) in each line. We then calculated correlations of DSS with a variety of molecular readouts, including RNA sequencing, reverse-phase protein array, DNA sequencing array, and Nanostring RNA and miRNA arrays. From these correlations, we have identified expression DJ1, MAPK11, and PCM1 as strong predictors of UM-164 efficacy in TNBC. Building on this, we used our results to identify companion drugs that lead to synergy or test others that could instead result in antagonism when used in combination. To verify our results, independently targeting the DJ1 pathway, we show that AKT inhibition results in synergy when combined with UM-164. The outcome of this research yields a robust and generalizable methodology for the identification of biomarkers in cancer to design Phase I-III trials and for generating the mechanistic evidence of effective rational combinations.
Citation Format: Nathan M. Merrill, Nathalie M. Vandecan, John P. Lloyd, Eric J. Lachacz, Peter J. Ulintz, Sofia D. Merajver, Matthew B. Soellner. Identification of biomarkers for UM-164 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 3989.
Abstract 3990: Circulating tumor DNA assessed through amplicon-based next-generation sequencing and its clinical application
Authors: Zembutsu Hitoshi , Osumi Hiroki , Shinozaki Eiji , Yamaguchi Kensei , Ozaka Masato , Sasaki Takashi , Muramatsu Marie , Sasahira Naoki 
Published: August 2019

Abstract
Circulating tumor DNA (ctDNA) studies focusing on only one or a few genes to monitor the disease progress or treatment response are unlikely to find its clinical significance. Hence, the development of cell-free DNA (cfDNA) panel covering hundreds of mutation hotspots is important for the establishment of clinically practical ctDNA detection system. We enrolled 101 patients with metastatic colorectal cancer (mCRC) who received chemotherapy. Amplicon-based genomic profiling of 14 genes, which are commonly mutated in CRC, in plasma by next-generation sequencing (NGS) was performed to evaluate the feasibility of this assay, and was compared with their clinical parameters and RAS status in matched tissue samples. Somatic mutations of the 14 genes in plasma cfDNA were detected in 88 patients (87.1%) with mCRC. Mutations in TP53, KRAS and APC genes were detected in 70 (69.3%), 39 (38.6%) and 24 (23.7%) patients, respectively. Mutant allele frequencies in cfDNA were significantly associated with metastasis (liver, P=0.00004, lymph node, P=0.008, number of metastatic organs, P=0.0006), tumor markers (CEA, P=0.000007, CA19-9, P=0.006, LDH, P=0.00001), and tumor diameter (maximum, P=0.00002, sum of diameter, P=0.00009). The overall concordance rate of RAS status between ctDNA and matched tissue was 77.2% (78/101). Furthermore, we enrolled 76 patients with stage lV pancreatic cancer, and their genomic profiling of 14 genes in plasma were performed to evaluate the feasibility of the cfDNA panel. We observed that patients with lower ctDNA level showed significantly longer overall survival (P=0.00000026). Our data confirmed that mutant allele in cfDNA can be sensitively detected by amplicon-based NGS system. These results suggest that ctDNA could be a novel diagnostic biomarker to monitor changes in mutational status and tumor burden in patients with mCRC, and a predictive marker for survival in patients with advanced pancreatic cancer.
Citation Format: Hitoshi Zembutsu, Hiroki Osumi, Eiji Shinozaki, Kensei Yamaguchi, Masato Ozaka, Takashi Sasaki, Marie Muramatsu, Naoki Sasahira. Circulating tumor DNA assessed through amplicon-based next-generation sequencing and its clinical application [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 3990.
Abstract 4011: Notch 1/2/3 mutation as a potential biomarker for immunotherapy in smokers with non-small cell lung cancer via increasing tumor mutational burden
Authors: Hong Xiaohua , Shen Aijun , Xu Yu , Li Chengcheng , Wang Guoqiang , Liu Li , Qi Chuang 
Published: August 2019

Abstract
Background: Smoking status have been discovered to be associated with the response of anti-PD-1/PD-L1 treatment in advanced non-small cell lung cancer (NSCLC), on account of the smoking-induced higher tumor mutational burden (TMB). However, merely partial smokers with NSCLC exhibit high TMB and respond to anti-PD-1/PD-L1 therapy. The underlying signalling pathway that involved in the accumulation of mutational burden and response to immunotherapy in smokers with NSCLC has not been clarified.
Methods: Data from Rizvi study (n = 240, nivolumab, tissue-sample NGS) and OAK study (n = 642, atezolizumab vs. docetaxel, blood-sample NGS) was retrieved and analysed as training cohorts, followed with validation in our independent NSCLC cohort (n = 44, anti-PD-1/PD-L1, blood-sample NGS). In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model.
Results: In Rizvi cohort, mutation of Notch 1/2/3 was associated with higher TMB in smokers with NSCLC (P &lt; 0.001) not in non-smokers with NSCLC (P = 0.908). Notch 1/2/3mut was associated with prolonged progression-free survival (PFS) compared with Notch 1/2/3wt in smokers with NSCLC (P = 0.015; HR, 0.51, 95% CI, 0.30-0.88), while not in non-smokers with NSCLC (P = 0.73; HR, 0.83, 95% CI, 0.30-2.35). Consistent results were observed in OAK study that Notch 1/2/3mut was associated with higher TMB (P &lt; 0.001) and longer PFS exclusively in current smokers with NSCLC treated
with immunotherapy (P = 0.018; HR, 0.28, 95% CI, 0.10-0.81). No association of Notch 1/2/3 status and PFS was observed in smokers with NSCLC treated with chemotherapy (P = 0.80; HR, 0.92, 95% CI, 0.47-1.78). We further validated these results in our independent cohort. Similar upregulation of TMB was observed in the Notch1/2/3-mutated smokers with NSCLC, and Notch1/2/3mut improved DCR (100% vs. 41.2%, P = 0.065) and significantly prolonged PFS (P = 0.046; adjusted HR, 0.12, 95% CI, 0.01-0.96).
Conclusions: Notch1/2/3 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in smokers with NSCLC via upregulating TMB.
Citation Format: Xiaohua Hong, Aijun Shen, Yu Xu, Chengcheng Li, Guoqiang Wang, Li Liu, Chuang Qi. Notch 1/2/3 mutation as a potential biomarker for immunotherapy in smokers with non-small cell lung cancer via increasing tumor mutational burden [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 4011.
Abstract 4021: A seven-lncRNA signature has a good value of prognosis in esophageal squamous cell carcinoma
Authors: Weng Nuoqing 
Published: August 2019

Abstract
Background: Long non-coding RNAs (lncRNAs) were used as prognostic biomarkers in many types of cancer. We aimed to recognize a signature that can forecast the prognosis in patients with esophageal squamous cell carcinoma (ESCC).
Method: Using a 2520 probe microarray, we retrospectively analysed lncRNAs expression profiles in 141 samples of ESCC and 81 paired non-cancer specimens that were served as the training set from SUN YAT-SEN University Cancer Center (Guangzhou, China) to evaluate the association between the signature and clinical outcomes. We randomly selected 40 paired tumor tissues and adjacent normal tissues from the above samples for the quantitative RT-PCR to ensure the credibility of microarray data. Then we conducted the quantitative RT-PCR in another 103 samples of ESCC to identify the signature. We applied Kaplan-Meier method and log-rank tests to assess the prognostic power of signature with overall survival (OS) and disease-free survival (DFS).
Result: Being differently expression between esophageal squamous cell carcinoma tissues and no-cancer specimens, 338 lncRNAs were selected after filtration. A further analysis were conducted that identified a seven-lncRNA signature in the training set. We calculated the risk score according to the signature and classified ESCC patients as high-risk or low-risk group. Patients in high-risk group had shorter overall survival (HR = 3.555, 95%CI 2.195-5.757, p &lt; 0.0001) and disease-free survival (HR 2.537, 95%CI 1.646-3.909, p &lt; 0.0001) when compared with low-risk group in the training set, and we found the same conclusion in the independent set for OS (HR = 2.662, 95%CI 1.588-4.464, p &lt; 0.0001) and DFS (HR 2.389, 95%CI 1.447-3.946, p &lt; 0.0001). The multivariate Cox proportional hazards regression analysis indicated that the signature is an independent factor for predicting survival. Combing the signature and TNM stage was more powerful than TNM stage alone in prognosing outcomes both in the training set (AUC: 0.778 vs 0.681, p = 0.0127) and in the independent set ((AUC: 0.796 vs 0.713, p = 0.0539).
Conclusion: The seven-lncRNA signature might win a place as a valuable prognostic factor in patients survival with ESCC and guide a more individual treatment when cooperating with the TNM stage system.
Citation Format: Nuoqing Weng. A seven-lncRNA signature has a good value of prognosis in esophageal squamous cell carcinoma [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 4021.