bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2921: A dual role of genomic instability on radiosensitivity in cancer cells
Authors: Seo Yuji , Tamari Keisuke , Takahashi Yutaka , Minami Kazumasa , Otani Keisuke , Isohashi Fumiaki , Ogawa Kazuhiko 
Published: August 2019

Abstract
Background: Genomic instability is a hallmark of cancer, which may lead to heterogeneity and provide an advantage on tumor survival and proliferation. However, we previously found that a greater number of genomic mutations were associated with reduced tolerance to radiation. The aim of this study is to elucidate a role of genomic instability on cellular radiosensitivity.
Materials and Methods: We used 59 cancer cell lines derived from various types of solid tumors. Radiation-induced cell death was measured by the standard colony-forming assay at the dose range of 0 to 10 Gy. Based on the resulting survival curves, the mean inactivation dose (MID) was calculated as a single value representing cellular radiosensitivity. Somatic gene aberration data for the 59 cell lines were obtained from the Catalogue Of Somatic Mutations In Cancer cell line project v.80. The genomic analysis focused on cancer-related pathways defined by Kyoto Encyclopedia Genes and Genomes. The genomic mutations included nucleotide variations (substitutions, insertions, or deletions) and copy number variations (CNV). Only pathogenic mutations were selected and neutral mutations were disregarded according to the functional analysis through hidden Markov model. Both gain and loss in CNVs were included.
Results: There were either nucleotide variations or copy number variations in 598 genes in the 59 cancer cell lines. The mutations were found in 16 caretakers, 51 gatekeepers, 105 oncogenes, and 449 passengers. There were significant positive correlations between the MIDs and the proportions of mutations in the gatekeepers or the oncogenes to the whole mutations. Namely, radioresistant cell lines harbored gatekeeper mutations or oncogene mutations at higher proportions. Conversely, radiosensitive cell lines showed significantly higher proportions of passenger mutations. No correlation was found in between the MIDs and the proportions of caretaker mutations.
Conclusions: Genomic instability caused by caretaker mutations may result in not only increased tolerance to radiation through mutations in gatekeeper genes and oncogenes but also reduced tolerance to radiation through accumulating passenger mutations. A balance between the two opposing phenomena is a significant determinant of cancer cell radiosensitivity.
Citation Format: Yuji Seo, Keisuke Tamari, Yutaka Takahashi, Kazumasa Minami, Keisuke Otani, Fumiaki Isohashi, Kazuhiko Ogawa. A dual role of genomic instability on radiosensitivity in 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 2921.
Abstract 2929: Radiosensitization of head and neck cancer by FGFR inhibition
Authors: SenthilKumar Gopika , Miller Margot , Fisher Michael , Brennan Sean , Kaushik Saakshi , Able Lindsey , Harari Paul M. , Iyer Gopal , Kimple Randall J. , Baschnagel Andrew M. 
Published: August 2019

Abstract
Objective:
Fibroblast growth factor receptors are frequently amplified or overexpressed in head and neck squamous cell carcinomas (HNSCC). We assessed the potential of a selective FGFR-kinase inhibitor, AZD4547, to act as a radiosensitizer in head and neck cancer cell lines and xenografts.
Methods:
A panel of head and neck cancer (n=10) and normal oral mucosa (HTE) cell lines were screened for FGFR1, 2, and 3 gene copy number, RNA expression, and protein. Sensitivity to the FGFR inhibitor AZD4547, alone or in combination with radiation, was assessed using proliferation and clonogenic survival assays. Putative mechanisms of radiosensitization were investigated by immunoblot and by assessing for DNA repair capacity, cell cycle effects, apoptosis, senescence, and autophagy. Tumor response of cell line xenografts and patient derived xenografts was assessed in vivo.
Results:
Cells demonstrated varying responses to FGFR inhibition but this did not correlate with FGFR gene copy number, mRNA expression, or protein expression. Three cell lines which responded to AZD4547 alone (CCL30, Tu-138, and SCC6) were selected for further investigation. TU-138 and CCL30 featured high FGFR expression and were radiosensitized by AZD4547 in vitro. SCC6 was not. Cell lines which were insensitive to FGFR inhibition (including HTE) did not demonstrate radiosensitization by AZD4547. In the sensitive cell lines, enhanced p-MAPK inhibition was seen in a time-dependent manner following drug treatment. When added to radiation, AZD4547 resulted in increased apoptosis, autophagy, and senescence but did not alter the kinetics of DNA repair as assessed by resolution of gH2AX foci. No difference in the cell cycle distribution for irradiated cells treated with or without the addition of AZD4547 was seen. Treatment of two in vivo tumor xenografts with AZD4547 and radiation showed significant delay in tumor growth compared to treatment with radiation or drug alone.
Conclusion:
Our findings indicate that AZD4547 can augment the response of FGFR expressing HNSCC to radiation both in vitro and in vivo. Improved approaches to identify tumors most likely to benefit from FGFR inhibition could enable the selection of patients for combination therapy and has the potential to improve outcomes in these difficult to treat cancers.
Citation Format: Gopika SenthilKumar, Margot Miller, Michael Fisher, Sean Brennan, Saakshi Kaushik, Lindsey Able, Paul M. Harari, Gopal Iyer, Randall J. Kimple, Andrew M. Baschnagel. Radiosensitization of head and neck cancer by FGFR inhibition [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 2929.
Abstract 2935: Novel combination of repurposed drugs induces complete cell invasion arrest of glioblastoma in vitro
Authors: Oancea-Castillo Liliana , Bahr Kerstin , Régnier-Vigouroux Anne , Ackermann Maximilian , Gabriel Isaac R. , Pereles Samuel T. , Li Madeleine M. , Lowitt Dana W. , Li William W. , Li Vincent W. 
Published: August 2019

Abstract
Introduction: Glioblastoma multiforme (GBM) is an aggressive and lethal cancer with a poor prognosis even after conventional treatment (surgery, radiation, chemotherapy). Temozolomide (TMZ) is a standard cyotoxic agent used, despite resistance leading to recurrence. Therefore, additional strategies for targeting the tumor environment are needed. We demonstrate a combination of approved drugs (CAD) repurposed to target GBM leads to complete arrest of GBM cell invasion. Each drug in the combination individually targets diverse tumor pathways: 1) invasion via MMP2 (doxycycline); 2) angiogenesis, inflammation, and proliferation via p53-dependent G1 cell-cycle arrest (celecoxib); 3) autophagy (tamoxifen); 4) tumor metabolism and angiogenesis (metformin).
Material and Methods: Multicellular Tumor Cell Spheroids (MTCS) were generated from two GBM cell lines (LN18, U87MG) and embedded in collagen (three-dimensional in vitro assay) and mixed with the drug combination at 2 doses + TMZ. GBM cell invasion was monitored and quantified over 96h. Flow cytometry analysis using Propidium-Iodine was performed (24h, 48h, 7h2 and 96h) to quantify the effect of the drug cocktail. Scanning Electron Microscopy (SEM) of MTCS was used to evaluate cell death at the ultrastructural level (96h after treatment).
Results: The CAD induced complete cell invasion arrest in both U87MG and LN18 MTCS regardless of drug dose or presence of TMZ. GBM cell death was observed after 96h. TMZ in combination with CAD showed a significant increase in cell death, suggesting synergism. SEM images demonstrated large-scale changes in the tumor spheroid morphology showing GBM cell death.
Conclusions: The combination of approved drugs (CAD) with TMZ can effectively halt GBM cell invasion and induce cell death in vitro. These results suggest a sensitizing effect of CAD to potentiate TMZ’s effects. Because CAD components have well established safety profiles, further investigation to define the anti-GBM mechanisms and effects on the tumor microenvironment are warranted. This CAD has potential for future therapeutic approaches. The generic nature of the drugs makes CAD an intriguing cost-effective GBM adjunctive therapy.
Citation Format: Liliana Oancea-Castillo, Kerstin Bahr, Anne Régnier-Vigouroux, Maximilian Ackermann, Isaac R. Gabriel, Samuel T. Pereles, Madeleine M. Li, Dana W. Lowitt, William W. Li, Vincent W. Li. Novel combination of repurposed drugs induces complete cell invasion arrest of glioblastoma 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 2935.
Abstract 2936: Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity
Authors: Chen Hua-Dong , Chen Chuan-Huizi , Wang Yu-Ting , Guo Ne , Tian Yu-Nan , Huan Xia-Juan , Song Shan-Shan , He Jin-Xue , Miao Ze-Hong 
Published: August 2019

Abstract
PARP1 inhibitors (PARPis) have been successfully used in the clinic for cancer therapy. The mechanisms by which they elicit cytotoxicity in cancer cells remain to be clarified. Initially, inhibition of cellular polymerase activity of PARP1 (reflected as inhibition of cellular poly (ADP-ribose) (PAR) formation or PARylation) was proposed as their primary mechanism. However, either cell-free histone-based or cellular PARylation inhibition displays very low correlation with PARPis’ cytotoxicity or clinical anticancer effects. Subsequently, the Pommier’s group proposed the mechanism of PARP1-DNA trapping and demonstrated that this mechanism showed much higher correlation with PARPis’ cytotoxicity. Nevertheless, contradictory results have been reported since then. Here, we showed no significant correlation between PARP1-DNA trapping and cytotoxicity induced by PARPis. We complemented PARP1-knockout sublines with wild-type PARP1 and 11 mutants with different point mutations that affect the polymerase activity. When examining the PARPi talazoparib, the induced cytotoxicity was highly significantly correlated with cellular PARP1 polymerase activity, but not with its PARP1-DNA trapping or polymerase inhibition. Similarly, talazoparib’s PARP1-DNA trapping revealed significant correlation with the polymerase activity rather than its inhibition. Differently, however, when evaluating purified wild-type and mutated PARP1, we identified an almost linear relationship between PARPis’ inhibiting PARP1 dissociation from DNA and their cytotoxicity in 17 cancer cell lines. In contrast, no significant correlation existed between PARP1 polymerase inhibition in the histone-based systems and the cytotoxicity. After careful comparisons on different methods and detection targets, we conclude that the PARPi-mediated increase in PARP1-DNA binding by inhibiting autoPARylation of PARP1 on DNA rather than in PARP1-DNA trapping is correlated with PARPi’s cytotoxicity. Based on this conclusion, we established a new PARPi screening model that more closely predicts cytotoxicity (r=0.9984; p&lt;0.0001).
Citation Format: Hua-Dong Chen, Chuan-Huizi Chen, Yu-Ting Wang, Ne Guo, Yu-Nan Tian, Xia-Juan Huan, Shan-Shan Song, Jin-Xue He, Ze-Hong Miao. Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity [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 2936.
Abstract 2938: Transmembrane chloride intracellular channel 1 (tmCLIC1) correlates with metastatic potential of colorectal cancer cells
Authors: Carlini Valentina , Cianci Francesca , Verduci Ivan , Mazzanti Michele 
Published: August 2019

Abstract
Colorectal cancer (CRC) is the third most common and lethal tumor worldwide. Although CRC can be efficiently eradicated when diagnosed in the early stage, no effective therapies are currently available for advanced metastatic disease. Therefore, targeting metastasis represents a critical challenge for the successful treatment of CRC. To achieve this purpose, our laboratory has found a promising candidate inthe transmembrane localized Chloride Intracellular Channel 1 (tmCLIC1) protein. Growing scientific evidence have suggested an involvement of tmCLIC1 in different human malignancies, including CRC, with an unknown mechanism. CLIC1 is a metamorphic protein able to shuttle between a soluble cytoplasmic and a membrane integrated form, the latter characterized by ionic channel function. In normal cells, it is mostly cytoplasmic and cooperates to the maintenance of several physiological processes. Otherwise, in cancer cells CLIC1 undergoes to chronic membrane insertion, where contributes to the abnormal cellular hyperproliferative rate.In the present investigation, using CRC human cell lines at different stage of tumor development, we demonstrate that tmCLIC1 functional expression correlates with CRC cells increasing aggressiveness, while it is almost absent in normal colon cells. We also show that CLIC1 enrichment in plasma membrane is involved in promotion of CRC metastasis. CLIC1 inhibition using different pharmacological treatments led to drastic reduction of cell proliferation, migration and invasiveness.tmCLIC1 function permits to discriminate between normal and malignant cells and its downregulation is able to arrest metastatic cells. This is not the case of other upregulated proteins not only involved in tumorigenesis but also in physiological cell functions. Since metastasis are considered the leading cause of treatment failure and tumor relapse, CLIC1 inhibition coupled to conventional therapies can represent a novel strategy to successfully treat CRC with reduced side effects. (This work is supported by a GRANT from AIRC to MM)
Citation Format: Valentina Carlini, Francesca Cianci, Ivan Verduci, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) correlates with metastatic potential of colorectal 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 2938.
Abstract 2949: The impact of drug perturbations on neuroblastoma disease pathways: A pharmaco-transcriptomics approach
Authors: Elgendy Ramy , Almstedt Elin , Vanlandewijck Michael , Nelander Sven 
Published: August 2019

Abstract
Neuroblastoma (NB) cells exhibit a complex spectrum of pathway changes associated with oncogene activation, chromosome events, tumor micro-environment and super-enhancer states. So far, elucidating which pharmaceutical compounds could modulate the activation level of each known pathway in NB cells has not been feasible. To solve this problem, we have combined transcriptome profiling of drug-perturbed NB cells with mathematical modeling of public data to create a first map of drug- and NB-specific transcriptional signatures for more than 7000 pharmaceutical compounds. We treated 2 patient-derived xenograft (PDX) NB cell lines with different chemical compounds, at 3 different doses (IC50, IC20, and IC10) and 2 time-points (6 and 24h). The whole-transcriptome of the treated cells was analyzed by a cost-effective hybrid ‘PLATE-Seq/SMART-Seq2’ method. Using factor analysis and supervised machine learning, the data was used to build a model that predicts the NB-specific outcome of 7035 drugs studied in other (non-NB) cell lines in the L1000/LINCS project. Analysis of 768 NB-specific transcriptome profiles, showed that our method accurately detects dose-dependent drug-induced pathway changes in the NB cells, including alteration of characteristic pathways and risk signatures. From the 768 profiles, our best-fitted machine learning model was then extended to 7035 compounds by in silico extrapolation, providing a first panel of estimated drug effects in NB cells. Our constructed NB pharmacological map provides a detailed view of both predicted and in vitro-validated drug-NB interactions. Effective treatments for high-risk NB are currently lacking. Using a new and cost-effective strategy, we could build an accurate map of drug-induced pathway alterations, for network pharmacology and drug repositioning for NB patients.
Citation Format: Ramy Elgendy, Elin Almstedt, Michael Vanlandewijck, Sven Nelander. The impact of drug perturbations on neuroblastoma disease pathways: A pharmaco-transcriptomics approach [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 2949.
Abstract 2951: A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity
Authors: Udagawa Chihiro , Hara Mari , Shimo Arata , Kojima Yasuyuki , Yoshie Reiko , Zaha Hisamitsu , Abe Norie , Motonari Tokiwa , Unesoko Mikiko , Tamura Kenji , Shimoi Tatsunori , Yoshida Masayuki , Yoshida Teruhiko , Okamura Hiroshi , Mushiroda Taisei , Tsugawa Koichiro , Zembutsu Hitoshi 
Published: August 2019

Abstract
Purpose: Trastuzumab has been administered to HER2-positive breast or gastric cancer patients as an effective treatment, however, the cardiotoxicity is identified as one of the life-threatening side effects. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a genome-wide association study (GWAS).
Experimental Design: We carried out a GWAS using 11 cases (with trastuzumab-induced cardiotoxicity) and 257 controls (showing no sign of trastuzumab-induced cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed smallest P value in GWAS (P = 1.61 x 10-7 -1.97 x 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. Results: The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (chromosome 13q14.3, 4q25, 15q26.3, 17q25.3 and another 15q26.3, Pcombined = 6.00 x 10-6, 8.60 x 10-5, 1.01 x 10-4, 1.07 x 10-4, 1.60 x 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity, using five SNPs which revealed smallest P value at each locus. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was 42.5% (P =8.69 x 10-15) . This scoring system using five candidate loci could be used to predict the risk of the adverse event before administration of trastuzumab.
Conclusion: We identified five novel loci, which could be associated with trastuzumab-induced cardiotoxicity. These findings provide new insights into personalized trastuzumab therapy for patients with HER2-positive cancer.
Citation Format: Chihiro Udagawa, Mari Hara, Arata Shimo, Yasuyuki Kojima, Reiko Yoshie, Hisamitsu Zaha, Norie Abe, Tokiwa Motonari, Mikiko Unesoko, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Hiroshi Okamura, Taisei Mushiroda, Koichiro Tsugawa, Hitoshi Zembutsu. A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity [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 2951.
Abstract 2956: Inhibition of CHK1 sensitizes Ewing sarcoma cells to CDK1-dependent cell death in S-phase
Authors: Gordon David , Goss Kelli , Koppenhafer Stacia 
Published: August 2019

Abstract
Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. The treatment of Ewing sarcoma has changed very little in the past two decades and novel treatment approaches are needed. We recently identified that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), the rate limiting enzyme in the synthesis of deoxyribonucleotides. We subsequently found that the inhibition of checkpoint kinase 1 (CHK1) increases the sensitivity of Ewing sarcoma cells to inhibitors of RNR, such as gemcitabine. The ATR-CHK1 pathway, from a mechanistic standpoint, regulates multiple stages of the cell cycle, including S-phase, the G2/M transition, and M phase. In the current work, we used cell synchronization to identify that the inhibition of CHK1 in S-phase cells results in premature entry into mitosis and cell death. Similarly, the inhibition of ATR serine/threonine kinase (ATR), the upstream activator of CHK1, also causes Ewing sarcoma cells to inappropriately enter mitosis. Moreover, we have found in Ewing sarcoma cells that this aberrant entry into mitosis is mediated, in part, by cyclin dependent kinase 1 (CDK1). In addition, activation of CDK1 by inhibiting the WEE1 kinase with AZD1775 also results in entry into mitosis and cell death in Ewing sarcoma cells. Currently, ongoing work is focused on the in vivo testing of gemcitabine in combination with CHK1 and WEE1 inhibitors as a novel therapeutic approach for the treatment of Ewing sarcoma.
Citation Format: David Gordon, Kelli Goss, Stacia Koppenhafer. Inhibition of CHK1 sensitizes Ewing sarcoma cells to CDK1-dependent cell death in S-phase [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 2956.
Abstract 2957: Nasopharyngeal cancer
Authors: Kam Ngar Woon , Chan See Wing , Tsao George Sai-Wah , Guan Xin-Yuan , Kwong Dora Lai Wan 
Published: August 2019

Abstract
Background:
Nasopharyngeal cancer (NPC) is associated with a poor survival rate. The ability of cancer cells to evade apoptosis and exhibit limitless replication potential allows for the progression of cancer. The aim of this study was to investigate in vitro the effect of the isoflavone phenoxodiol on human NPC cell line and T cells, which has previously been shown to inhibit cell proliferation and promote apoptosis in a range of cancer cell lines and in anti-CD3/anti-CD28-activated murine splenocytes.
Methods:
Four NPC cancer cell lines-C666, C17, and paired NPC43 EBV-positive and its respective EBV-negative cell lines were cultured in vitro, and then treated with phenoxodiol for 72h or 5 days. The migration and proliferation was investigated by transwell and XTT, respectively. Conditioned medium of treated NPC cell lines were collected and incubated with human PBMC for 5 days. CD4 and CD8 surface staining were analyzed by flow cytometry.
Result:
We demonstrated that phenoxodiol inhibited NPC migration and cell proliferation (IC50 4µM). Among all the NPC cell lines, the proliferation effect on EBV-negative cell line (NPC43-ve) is least responsive to phenoxodiol. A dose-dependent of apoptosis in NPC cell lines by phenoxodiol [early apoptotic cells (Annexin V+/PI- at 1µM); late apoptotic cells (Annexin V+/PI+ at 2µM), and necrotic cells (Annexin V-/PI+, at 4µM) were distinguished. Interestingly, phenoxodiol reduced frequency of CD4 T cells while promoting the number of CD8 T cells.
Conclusions:
Phenoxodiol demonstrates an ability in NPC cancer cells to induce its apoptosis while inhibit its migration and proliferation. Moreover, the ability of phenoxodiol to modulate T cells population indicates that phenoxodiol would be effective as a potential future treatment for NPC.
Note: This abstract was not presented at the meeting.
Citation Format: Ngar Woon Kam, See Wing Chan, George Sai-Wah Tsao, Xin-Yuan Guan, Dora Lai Wan Kwong. Nasopharyngeal 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 2957.