bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2188: Comparing effects of small molecular weight compounds on proliferation and chemotaxis of pancreatic cancer cells
Authors: Yamamura Masahiro , Yamauchi Akira , Katase Naoki , Sakaguchi Masakiyo , Katata Yosuke , Tanioka Hiroaki , Okawaki Makoto , Nagasaka Takeshi , Yamaguchi Yoshiyuki 
Published: August 2019

Abstract
Background & Aims: The new therapy for pancreatic cancer which has the poorest prognosis among malignant tumors is high demand nowadays. The overall 5-year survival rate in all stages of this type of cancer is less than 5%, even with the multimodality therapy, including surgery, chemotherapy and radiotherapy. Although gemcitabine (GEM) is a key drug in the treatment of advanced pancreatic cancer, the therapeutic effect is limited because of drug resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of cancer cells, and its inhibition has shown promise in the treatment of solid malignancies. Src kinases work as a signal switch for multiple molecular signal transduction pathways. The objective of this study is to evaluate an antitumor effect of three kinds of small molecular weight compounds (antimetabolite Gemcitabine, HSP90 inhibitor NVP-AUY922, and Src kinase inhibitor Dasatinib) on tumor growth and chemotaxis in pancreatic cancer cell lines. Methods: Pancreatic cancer cell lines were treated with each of the 3 compounds to examine the effect on proliferation assay, apoptosis assay, Western blotting, and chemotaxis assay. Results: Of these compounds, HSP90 inhibitor inhibited cell proliferation in pancreatic cancer cells best in a dose- and time-dependent manner. Growth inhibitory effect of HSP90 inhibitor for pancreatic cancer cells were highest of the three. Further, HSP90 inhibitor inhibited the growth of gemcitabine sensitive and resistant pancreatic cancer cell lines. With flowcytometry and immunostaining, HSP90 inhibitor had higher apoptosis-inducing effect than gemcitabine. In the chemotaxis assay, HSP90 inhibitor inhibited the migration of pancreatic cancer cell best in the three compounds. In western blotting, HSP90 inhibitor suppressed the expression of multiple receptor tyrosine kinase proteins as well as the signal transduction in PI3K-Akt and RAS-MAPK pathways. Conclusion: In this study, HSP90 inhibitor was the best of 3 small molecular compounds and has proven effective in gemcitabine sensitive and resistant pancreatic cancer. The HSP90 inhibitor is useful as an antitumor drug by inhibiting proliferation and chemotaxis of pancreatic cancer cells through multiple kinase pathways.
Citation Format: Masahiro Yamamura, Akira Yamauchi, Naoki Katase, Masakiyo Sakaguchi, Yosuke Katata, Hiroaki Tanioka, Makoto Okawaki, Takeshi Nagasaka, Yoshiyuki Yamaguchi. Comparing effects of small molecular weight compounds on proliferation and chemotaxis of pancreatic cancer cells [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 2188.
Abstract 219: The potential benefit of lower drug-antibody ratio (DAR) on antibody-maytansinoid conjugate in vivo efficacy
Authors: Sinkevicius Kerstin W. , Lanieri Leanne , Lee Jenny , Boule Steven , Yoder Nicholas C. , Hicks Stuart W. , Pinkas Jan , Ponte Jose F. , Gregory Richard J. 
Published: August 2019

Abstract
The majority of antibody-drug conjugates (ADCs) with maytansinoid payloads in development are linked via lysine residues and target an average drug-antibody ratio (DAR) of 3.5. These ADCs demonstrate substantial preclinical potency while maintaining good biophysical and pharmacological properties. However, some targets are expressed in normal tissues at levels that result in target-mediated drug disposition (TMDD), which can impact systemic and tumor ADC exposure and tumor penetration. For targets with TMDD, lowering the DAR of the ADCs may be advantageous. Since ADC tolerability is generally determined by the payload dose, lower DAR ADCs can be dosed at a higher antibody concentration, resulting in an increased conjugate exposure which may improve efficacy by saturating TMDD and/or increasing tumor delivery and penetration of the conjugate. In preclinical cell line xenograft studies, lysine-conjugated 2.0 and 3.5 DAR ADCs had comparable efficacy when dosed by payload concentration. However, the effect of TMDD cannot be captured with these models because the antibody in the ADCs does not cross-react with murine target antigen expressed on normal tissues. To supplement our understanding of the factors that influence ADC activity, we generated a cross-reactive model system that utilizes a chimeric anti-murine folate receptor α (FRα) antibody that binds with similar affinity to mouse and human FRα. Using this cross-reactive system, where the target is also expressed in normal tissues, 2.0 DAR conjugates were more efficacious than 3.5 DAR conjugates when dosed at matched payload concentrations in multiple xenograft models, suggesting that lower DAR can be an effective strategy to compensate for TMDD. Additional studies using xenograft models with varying antigen expression levels are ongoing, and studies designed to assess different conjugation methods of generating lower DAR ADCs are planned. This work highlights some of the many factors that impact ADC activity and demonstrates that the DAR of an ADC should be optimized for each target.
Citation Format: Kerstin W. Sinkevicius, Leanne Lanieri, Jenny Lee, Steven Boule, Nicholas C. Yoder, Stuart W. Hicks, Jan Pinkas, Jose F. Ponte, Richard J. Gregory. The potential benefit of lower drug-antibody ratio (DAR) on antibody-maytansinoid conjugate in vivo efficacy [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 219.
Abstract 2190: Repurposing the FDA-approved antiviral drug ribavirin as targeted therapy for nasopharyngeal carcinoma
Authors: Ding Andy S. , Casaos Joshua , Huq Sakibul , Brem Henry , Skuli Nicolas , Tyler Betty 
Published: August 2019

Abstract
Purpose: Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma that is often diagnosed at an advanced stage, leading to poor disease-free and overall survival. Accumulating literature suggests that elevated protein expression of EZH2, eIF4E, and IMPDH correlates with poor prognosis in NPC. These three proteins are modulated by the FDA-approved antiviral drug ribavirin, which has recently been repurposed by our laboratory and others as a promising anti-cancer agent. Based on this intersection of molecular signature and drug targets, we investigated the potential use of ribavirin as a therapeutic agent for NPC.
Experimental Design: We assessed anti-neoplastic efficacy of ribavirin on human NPC cell lines in vitro using cellular growth assays, flow cytometry, and scratch wound assays. Mechanistic pathways involved were investigated using genomic expression datasets, western blots, and enzymatic activity assays. The effects of combining ribavirin with radiation were assessed via clonogenic assays and flow cytometry. Finally, we evaluated the effects of ribavirin on tumor growth in vivo using human cell line-derived xenograft models.
Results: Ribavirin significantly decreased NPC cellular proliferation and migratory capacity in addition to promoting cell cycle arrest and cell death. Modulation of the EZH2, Snail, eIF4E, and IMPDH pathways was observed in response to ribavirin treatment. Ribavirin significantly enhanced the cytotoxic effects of radiation therapy in NPC. Most importantly, ribavirin significantly reduced flank tumor growth in NPC xenograft models.
Conclusions: Our work suggests that ribavirin has potent anti-cancer effects in NPC and could represent a safe and promising addition to current NPC treatment regimens.
Citation Format: Andy S. Ding, Joshua Casaos, Sakibul Huq, Henry Brem, Nicolas Skuli, Betty Tyler. Repurposing the FDA-approved antiviral drug ribavirin as targeted therapy for nasopharyngeal 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 2190.
Abstract 2203: WSD1227: A BBB penetrable VEGFR small molecule for the treatment of primary and metastatic brain tumors
Authors: Zhang Jinqiang , Zhong Wei , Mu Zhihua , Sun Claire 
Published: August 2019

Abstract
Anti-angiogenesis has been proved to be a good strategy for cancer treatment (such as in GBM, NSCLC, mBC, CRC, OC, etc.) with satisfactory performance to extracranial lesions, but not in intracranial lesions. Insufficient penetration across BBB could be one of factors limiting intracranial activity for those approved anti-VEGF agents. There is a need to develop a BBB penetrable VEGFR inhibitor to clinic to assess the efficacy and safety. Here we report that WSD1227, a novel, selective VEGFR inhibitor, displays potent activity, excellent CNS penetration and preclinical safety and efficacy. The IC50 of WSD1227 against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFRα IC50 22.9nM, PDGFRβ IC50 19.4nM, cKit IC50 383nM, FLT3 IC50 555 nM and CSF1R IC50 1062nM. WSD1227 treatment resulted in significant anti-tumor activity in VEGF related extracranial and intracranial mice models, with superior efficacy than bevacizumab. There is no increased risk of CNS hemorrhage in intracranial tumor bearing mice treated with WSD1227. In addition, WSD1227 is predicted to be CNS penetrable with decent PK in human. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic to investigate anti-angiogenetic therapies for management of patients with primary or metastatic brain tumors.
Citation Format: Jinqiang Zhang, Wei Zhong, Zhihua Mu, Claire Sun. WSD1227: A BBB penetrable VEGFR small molecule for the treatment of primary and metastatic brain tumors [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 2203.
Abstract 2220: Benchmarking of somatic variant calling algorithms for detection of circulating tumor DNA
Authors: Bhetariya Preetida J. , Hellwig Sabine , Nix David A. , Marth Gabor T. , Bronner Mary P. , Underhill Hunter R. 
Published: August 2019

Abstract
Purpose: Establishing a reliable bioinformatics variant calling workflow is crucial for untargeted searches of low-frequency variants in plasma circulating cell-free DNA (ccfDNA). We sought to benchmark the performance of nine variant calling algorithms on simulated data and cancer patient ccfDNA sequencing samples.
Methods: A simulated tumor dataset was constructed by in-silico introduction of pathogenic variants (303 SNVs and 91 INDELs; VAF of 0.1-12%) into a healthy control sequencing sample (128 gene capture panel; 128kb; 4200X depth). An unspiked replicate served as a control. Tumor and control datasets were analyzed by nine somatic variant calling algorithms available in the public domain (Table 1). Sensitivity and specificity were calculated for each caller. Variant calling algorithms that proved most successful in synthetic data (Lofreq, Mutect) were applied to 24 EGFR-mutant lung cancer patient ccfDNA library samples captured and sequenced under conditions identical to the benchmarking data set. Droplet digital PCR (ddPCR) was used to independently determine the VAFs of two EGFR SNVs (T790M and L858R) and exon 19 deletions in all lung cancer libraries (detected range: 0.1-48.5%).
Results:
Table 1:Sensitivity (Sens.) and false discovery rate (FDR) as determined for 9 variant callers. For synthetic data, results are shown for 1.6% VAF (NC = no call)CallerSynthetic data (1.6% VAF)Lung cancer ccfDNASNVINDELSNVINDEL% Sens.% FDR% Sens.% FDR% Sens. &lt;1% VAF% Sens. &gt;1% VAF% Sens. &lt;1% VAF% Sens. &gt;1% VAFLofreq87.15.792.35.675.094.466.7100Mutect47.52.291.26.762.588.916.787.5Mutect235.63.296.71.1Strelka17.83.57.69.2FreebayesNCNCNCNCVarscanNCNCNCNCVardictNCNCNCNCLumpy13.986.17.792.1DellyNCNCNCNC
Conclusion: Performance of variant callers differed greatly, with Lofreq providing the best sensitivity at low VAF. In cancer ccfDNA libraries Lofreq detected most but not all low-frequency variants, indicating that ccfDNA diagnostics require optimized variant calling workflows to improve detection of variants with a VAF &lt;1%.
Citation Format: Preetida J. Bhetariya, Sabine Hellwig, David A. Nix, Gabor T. Marth, Mary P. Bronner, Hunter R. Underhill. Benchmarking of somatic variant calling algorithms for detection of circulating tumor DNA [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 2220.
Abstract 2233: Correlation between mutations found in FFPE tumor tissue and paired cfDNA samples
Authors: Saunders Lauren , Hur Antonia , Niccum Brittany , Patel Asmita 
Published: August 2019

Abstract
Cell free DNA (cfDNA) consists of small (150 - 500 bp) DNA fragments that circulate in the blood. cfDNA levels tend to be low in healthy, non-pregnant patients, and increase in patients with cancer, pregnancy, or extensive damage to tissue. cfDNA is believe to derive mostly from apoptotic cells, and biomarkers for a variety of diseases have been found in cfDNA. As cfDNA is extracted from blood, it is a non-invasive way to detect disease; however, there is some concern that cfDNA does not contain the same biomarkers as tumor tissue. This study measures the efficacy of cfDNA as a biomarker detection medium by comparing mutations found in both FFPE tumor samples and paired cfDNA samples. This study determines whether the same biomarkers are found in each sample type, and which of those can be used as biomarkers in both and which are preferred biomarkers for only a single sample type. Trends in mutation detection with the two different sample types are discussed.
Citation Format: Lauren Saunders, Antonia Hur, Brittany Niccum, Asmita Patel. Correlation between mutations found in FFPE tumor tissue and paired cfDNA samples [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 2233.
Abstract 2234: Monitoring of genetic change in circulating tumor DNA isolated from Her2 positive advanced gastric cancer patients
Authors: Kwon Woo Sun , Jung Seung-Hyun , Chung Yeun-Jun , Ahn Joong Bae , Chung Hyun Cheol , Rha Sun Young 
Published: August 2019

Abstract
Gastric cancer is the common solid cancer and a leading cause for cancer related mortality worldwide. Despite developments and improvement in diagnosis, surgical technique, chemotherapy and radiotherapy, median survival time of advanced/metastatic gastric cancer (AGC) patients who received systemic chemotherapy is between 15-18 months. Tumor heterogeneity is associated with heterogeneous genetic profiling, which lowers diagnostic precision and consequently becomes an obstacle to determining the appropriate therapeutic strategies for individual cancer patients. Therefore, predictive biomarkers for determining potential treatment strategy are needed to improve the prognosis of patients. Personalized medicine has emerged as the future of cancer care to ensure that patients receive individualized treatment specific to their needs. In order to provide such care, molecular techniques that enable oncologists to diagnose, treat, and monitor tumors are necessary. Liquid biopsy by genotyping circulating tumor DNA (ctDNA) has provided a non-invasive and real-time liquid biopsy approach in assessing tumor genomic alterations in clinical oncology. This ctDNA have been associated with poor prognosis and clinical outcome in various cancer including lung, breast and colorectal. In this study, we evaluated utility and genetic profiling of ctDNAs in AGC. Under IRB approval, blood samples were collected in Cell-Free DNA BCT® streck tubes from 14 Her2-positive. Depending on the treatment schedule, blood can be collected 2 to 5 times per patient sequentially. The isolated ctDNAs were analyzed to genetic profiling by OncoChase (95 genes) based on AmpliSeq. And tumor tissue genotyping by CANCER MASTER and compared different sample preparation conditions. Validation of blood-based tumor genomic profiling in additional multicenter outcome studies is necessary; however, ctDNA monitoring can provide clinically important actionable information for precision oncology approaches.
Citation Format: Woo Sun Kwon, Seung-Hyun Jung, Yeun-Jun Chung, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. Monitoring of genetic change in circulating tumor DNA isolated from Her2 positive advanced gastric cancer patients [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 2234.
Abstract 2236: Development and validation of urine cfDNA preservative kit for detection of genomic alterations in cancer
Authors: Li Zheng , Tang Haoran , Zhang Tiantian , Liu Chunxiao , Zhu Shengnan , Zhang Ying , Xiang Binggang , Zhao Zhixin 
Published: August 2019

Abstract
Introduction: cfDNA (circulating cell-free DNA), short DNA fragments shredded from dying normal and tumor cells, has been proved capable of serving as molecular biomarkers for clinical decision making, including but not limit to tumor diagnosis, treatment and monitoring. Urine, by its non-invasive nature and unique biological characteristics, is far superior comparing to other liquid biopsy specimens, such as blood and cerebrospinal fluid, and has broad clinical implications for genitourinary cancers. The challenge for urine cfDNA test, is the instability of cfDNA, caused by nuclease, high content of urea, and contamination from genomic DNA released from nucleated cells and microbials in urine. Here, we have developed a robust and user friendly urine preservative collection Kit to maintain integrity of cfDNA in urine and to facilitate transportation of urinary samples to clinical laboratory.
Methods: Urine samples from 5 donors collected using the developed urine collection kit were tested after incubation under 4°C and 37°C, mimicking extreme storage or transporting environments, and were compared to untreated urine and treated urine by another commercial preserve buffer. cfDNA was extracted after incubation of 0, 4, 7 days and then quantified by ddPCR with 3 markers: EGFR as an endogenous DNA marker, PSA (synthetic oligos containing intron-deleted sequence, pre-incubation spike-in) as an exogenous DNA marker, ARv7 (synthetic oligos containing intron-deleted sequence, post-incubation spike-in) as an inner control for the extraction and detection assays.
Results While untreated urine showed significant decrease after incubation under 37°C, cfDNA derived from urine stored in developed urine collection tubes remained stable till day 7. There is no significant change on normalized copies of EGFR and PSA in the treated urine samples under 4°C for up to 7 days.
Conclusion: the developed Urine Collection Kit demonstrated great urine cfDNA preserving capacity under different temperatures for at least 7 days, on par with commercially available preserve buffer and even outperforming it under certain circumstances. The developed kit provides an easy-to-use solution of obtaining stable urine cfDNA for clinical use.
Citation Format: Zheng Li, Haoran Tang, Tiantian Zhang, Chunxiao Liu, Shengnan Zhu, Ying Zhang, Binggang Xiang, Zhixin Zhao. Development and validation of urine cfDNA preservative kit for detection of genomic alterations in 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 2236.
Abstract 2237: Detection of CK-19 mRNA positive CTCs, isolated with a size-based microfluidics platform, in NSCLC patients under osimertinib therapy
Authors: Ntzifa Aliki , Kotsakis Athanasios , Georgoulias Vassilis , Lianidou Evi 
Published: August 2019

Abstract
Background: Patients with EGFRmt non-small cell lung cancer (NSCLC) and resistant to first and second generation EGFR tyrosine kinase inhibitors (EGFR TKIs), receive therapy with osimertinib (third generation EGFR TKI). However, some patients experience resistance to osimertinib and disease progression. Molecular characterization of circulating tumor cells (CTCs) could offer great advantages as a non-invasive approach for disease monitoring. In this study, we isolated CTCs using a label-independent microfluidic-based platform to elucidate resistance mechanisms in these NSCLC patients.
Materials and methods: Peripheral blood (PB) (15mL) was obtained at different time points from 27 patients with advanced NSCLC under osimertinib therapy. CTCs were isolated using the ParsortixTM system (ANGLE, Plc) and further harvested in Trizol reagent, followed by extraction of total RNA and cDNA synthesis. RT-qPCR was performed for CK-19 and B2M (used as a reference gene) mRNA in the COBAS z480 system (Roche Diagnostics).
Results: PB samples were obtained at baseline (n=25), after one cycle of treatment with osimertinib (n=23), every 3 months (n=83) and at disease progression (PD) (n=16). CK-19 positive CTCs were detected in 3/25(12%) baseline samples, 24/83(28.9%) during treatment at different time points; 5/23(21.7%) after one cycle of treatment, 8/23(34.8%) after 3 months, 3/17(17.6%) after 6 months, 4/12(33.3%) after 9 months, 1/2(50%) after 12 months, 3/5(60%) after 15 months; and 5/16(31.2%) at PD.
Conclusions: CK-19 mRNA-positive CTCs were isolated using an epitope-independent enrichment microfluidic device. Further molecular characterization of these cells at the gene expression, DNA mutation, DNA methylation and miRNA level will provide biomarkers for the elucidation of resistance mechanisms in NSCLC patients treated with osimertinib.
Citation Format: Aliki Ntzifa, Athanasios Kotsakis, Vassilis Georgoulias, Evi Lianidou. Detection of CK-19 mRNA positive CTCs, isolated with a size-based microfluidics platform, in NSCLC patients under osimertinib therapy [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 2237.