bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2851: The evolution of tumor cells under AsiDNA treatment results in “autosensitization”
Authors: Kozlac Maria , Jdey Wael , Girard Pierre-Marie , Bono Françoise , Dutreix Marie 
Published: August 2018

Abstract
Purpose: The Achilles' heel of all conventional and targeted anticancer treatments is intrinsic or acquired resistance. The era of precision medicine where tumors are selected for specific treatments based on their genetic alterations is revolutionary, but unfortunately prolonged responses are rarely observed due to rapid emergence of resistant clones. We recently developed a new concept of DNA repair inhibitor (Dbait) acting by activating enzymes involved in DNA damage signaling. We tested how such agonist activity would be prone to induce resistance to Dbait treatment.
Experimental design: We performed repeated cycles of treatment with various targeted therapy agents (Imatinib, Olaparib, 6-thioguanine and the clinical form of Dbait, AsiDNATM). We analyzed the specific sensitivity of independent cultures after each treatment cycle. The study was performed in different tumor cell lines ((MDAMB231, MDAMB468, HCC1143, THP1, U937, KBM7) and in two non-malignant breast cell lines (MCF10A, MCF12A). Extensive transcriptome and genome studies were performed on MDAMB231 breast cancer cell lines.
Results: Resistant clones appeared at a frequency of 1.45% for Olaparib, 0.62% for imatinib, and 1.66% for 6-thioguanine. Similar protocol did not select for resistance to AsiDNA. Unexpectendly, tumor cells became more sensitive to AsiDNA after each cycle of treatment. This behavior was specific of AsiDNA and was not observed with other treatments. The six tumor cell lines tested developed AsiDNA autosensitisation and no resistance. Non tumoral cells were not affected by repeated treatments. The acquired sensitivity of the treated tumor populations was conserved for months after end of treatment Transcriptional and genetic analysis of independently treated MDAMB-231 populations reveals that all evolved similarly. They display a few conserved genome modifications and a large deregulation of 1160 genes resulting in an overexpression of luminal associated genes and a decrease in mesenchymal associated genes.
Conclusion: Our results indicate a phenomenon of “autosensitisation”, along treatment which has never been described for anticancer treatment and could prevent development of resistance during treatment.
Citation Format: Maria Kozlac, Wael Jdey, Pierre-Marie Girard, Françoise Bono, Marie Dutreix. The evolution of tumor cells under AsiDNA treatment results in “autosensitization” [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 2851.
Abstract 288: Genomic profiling of metastatic gastric adenocarcinoma
Authors: Harada Kazuto , Song Shumei , Xu Yan , Bagewell Brain D. , Pizzi Melissa P. , Jin Jiankang , Wang Ying , Scott Ailing W. , Ma Lang , Amlashi Fatemeh G. , Kobayashi Makoto , Vykoukal Jody V. , Ivan Cristina , Estrella Jeannelyn S. , Chowdhuri Sinchita R. , Calin George A. , Hanash Samir , Lee Ju-Seog , Liu Bin , Ajani Jaffer A. 
Published: August 2018

Abstract
Objectives: Metastatic gastric adenocarcinoma (mGAC) is highly resistant to therapy and is incurable. Particularly, peritoneal carcinomatosis leads to severe morbidities and short survival. The genome wide approaches have been conducted in primary GAC and have uncovered useful information. However, detailed understanding of mGAC is limited. Thus, we aimed to characterize the genomic landscape of mGAC.
Methods: Thirty-four malignant ascites specimens were prospectively collected from at The University of Texas MD Anderson Cancer Center (Houston, USA) from February 2016. 25 specimens had whole exome sequencing and 30 specimens had RNA sequencing.
Results: The top highly mutated genes in mGAC were TP53, ATM, SYNE2, TTN, CDH11, FAT4/3, KMT2C, FGF23, NCOR1, RP1, CYP2A, and ADAMTS8/9. Compared with mutations in primary GAC (TCGA and TMUCIH), mutations in mGAC shared only 13.7% with TCGA and 10.9% with TMUCIH data. The commonly shared mutations in all three sets were TP53, ATM, FAT4, CDH1, SYNE1, PLEC, PRKDC, and ZFHX3, while unique mutations in mGAC were TTN, SYNE2, ZNF503, PUS7L, PPP2R5C, NBPF12, MROH1, IFNL1, and COL18A1. Furthermore, RNA- sequencing revealed two frequent fusions; 36.7% of samples with C15orf57-CBX3 (t(15;7)) fusion and 10% with SLC35A1-TSHZ2 (t(6;20)). We explored gene signatures in C15orf57-CBX3 fusion subgroup and C15orf57-CBX3 non-fusion subgroup. Gene set enrichment analysis revealed that C15orf57-CBX3 fusion group had enrichment of immune-response related genes, while non-fusion subgroup had enrichment of genes related to the segregation of chromatid, DNA replication, and histone exchange. The clustering analysis of RNA expression using the top 2000 genes with most median absolute deviation identified two subgroups that correlated either with C15orf57-CBX3 fusion or mutations.
Conclusions: We have identified a novel genomic landscape of mGAC, such as unique mutation and fusions. Further studies are needed to gain insights into the mechanism of progression and resistance phenotype of mGAC.
Citation Format: Kazuto Harada, Shumei Song, Yan Xu, Brain D. Bagewell, Melissa P. Pizzi, Jiankang Jin, Ying Wang, Ailing W. Scott, Lang Ma, Fatemeh G. Amlashi, Makoto Kobayashi, Jody V. Vykoukal, Cristina Ivan, Jeannelyn S. Estrella, Sinchita R. Chowdhuri, George A. Calin, Samir Hanash, Ju-Seog Lee, Bin Liu, Jaffer A. Ajani. Genomic profiling of metastatic gastric adenocarcinoma [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 288.
Abstract 2883: Repurposing atovaquone, an antiprotozoal drug for management of breast cancer by inhibiting HER2/β-catenin signaling
Authors: Gupta Nehal , Srivastava Sanjay 
Published: August 2018

Abstract
Breast cancer is the second highest cause of cancer-related mortality in women. HER2 is an oncogene overexpressed in about 30% of breast cancer patients and β-catenin, a proto-oncogene plays a pivotal role in breast cancer metastasis and drug resistance leading to poor prognosis. In the current study, we evaluated the anti-cancer effects of an anti-protozoal drug, atovaquone against several breast cancer cell lines such as MCF-7, 4T1, HCC1806, CI66, SKBR3 and T47D. Our results showed that atovaquone treatment induced apoptosis as evaluated by PI/Annexin assay and cleavage of caspase-3 and PARP, and inhibited the growth of all the breast cancer cell lines tested. Similar observations were made in patient-derived cancer cell lines. In addition, atovaquone treatment significantly reduced the expression of HER2, β-catenin and its downstream molecules such as pGSK-3β, TCF-4, cyclin D1 and c-Myc in these cell lines. Treatment of HCC1806 cells with 5 µM atovaquone resulted in significant reduction in mammosphere forming efficiency (MFE) of breast cancer cells. Mammosphere-forming cells are known to exhibit cancer stem cell (CSC)-like properties together with drug resistance. Efficacy of atovaquone was evaluated in the in-vivo tumor model by orthotopic implantation of two highly aggressive 4T1 and CI66, triple negative breast cancer cells in the mammary fats of female mice. Our results demonstrate that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60% respectively. Atovaquone treated tumors exhibited reduced HER2, β-catenin and increased apoptosis when analyzed by western blot. We also developed resistance in 4T1 breast cancer cells towards paclitaxel, a first line chemotherapeutic agent for treatment of metastatic breast cancer. 4T1 paclitaxel resistant cells were orthotopically implanted in female balb/c mice and mice were treated with atovaquone for 20 days. Our results showed that atovaquone was able to suppress the growth of paclitaxel resistant tumors by 42%. Conclusively, our results indicate that atovaquone effectively reduces the growth of primary breast tumors as well as paclitaxel resistant tumors by inhibiting HER2/β-catenin signaling. Most importantly, atovaquone is already in clinical use with an established safety record therefore, any positive findings from our studies will prompt further clinical investigation into repurposing atovaquone for the treatment of advanced breast cancer patients. [Supported in part by R01 grant CA 129038 awarded by National Cancer Institute, NIH].
Citation Format: Nehal Gupta, Sanjay Srivastava. Repurposing atovaquone, an antiprotozoal drug for management of breast cancer by inhibiting HER2/β-catenin signaling [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 2883.
Abstract 2890: Trifluridine efficacy in cancer stem cell
Authors: Tsunekuni Kenta , Konno Masamitsu , Koseki Jun , Asai Ayumu , Doki Yuichiro , Mori Masaki , Ishii Hideshi 
Published: August 2018

Abstract
Background: Cancer stem cells (CSC) have been involved in disease recurrence, metastasis, and therapeutic resistance, but effective anti-cancer agent for these cells is not still currently available. Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which was approved for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine, oxaliplatin and irinotecan based chemotherapy etc. and improved overall survival. Here we showed the efficacy of FTD in CD44 and CD133 high expressing (CD44high/CD133high) cancer cells which has CSC like property.
Method: CD44high /CD133high and CD44low /CD133low DLD-1 cells were separated by Fluorescence-Activated Cell Sorting (FACS) and subjected to sphere formation assay. Anti-proliferative and anti-sphere forming effects of FTD in CD44high /CD133high cells were measured. Then, 150 days FTD long exposed colorectal cell line's CSC markers CD44 and CD133 were measured by flow cytometry and its tumor initiating property in in vitro and in vivo were evaluated.
Results: CD44 high /CD133 high DLD-1 cells formed much more sphere than CD44low /CD133low cells significantly. Compared to unsorted cells, CD44high /CD133high cells displayed 5-FU resistance (IC50 value of 5-FU for unsorted and CD44 high /CD133 high cells were 2.5 μM and 5.5 μM respectively) but not FTD resistance (IC50 value of FTD for unsorted and CD44 high /CD133 high cells were 8.9 μM and 10.7 μM, respectively) in in vitro proliferation assay. In addition, FTD treatment in a subtoxic concentration 1 μM for DLD-1 cells disrupted sphere formation. FTD-long exposed DLD-1 cell lines showed decreased CD44high /CD133high population compared to its parental cell line from 11.3% to 0.7%, and showed decreased sphere-forming efficacy. In addition, FTD-long exposed DLD-1 cell lines decreased tumor forming potential in in vivo. These results suggest that FTD is effective for CSC like cells and that long exposure to FTD might lead CSC depletion.
Conclusion: FTD was proved to be effective for CSC like CD44high /CD133high cells. It suggests that FTD might be useful for CSC targeted chemotherapy in case of CD44 and CD133 are highly expressed subtype of tumors.
Citation Format: Kenta Tsunekuni, Masamitsu Konno, Jun Koseki, Ayumu Asai, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Trifluridine efficacy in cancer stem cell [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 2890.
Abstract 2893: Balancing the efficacy and toxicity of anti-CD47 antibodies by direct screening in humanized mouse models
Authors: Guo Yanan , Guo Chaoshe , Shen Yuelei , Yang Benny 
Published: August 2018

Abstract
CD47 is a transmembrane protein found on the surface of many cells in the body. Its expression is often up-regulated in many cancer cells. The receptor of CD47 was identified as SIRPa, which is expressed on phagocytic cells. Engagement of SIRPa by CD47 serves as “do not eat me” signal, thus inhibiting the phagocytic activity of macrophages. Cancer cells often hijack this pathway by boosting CD47 expression on their surface, in order to prevent innate cell-mediated phagocytosis. Molecules blocking the CD47-SIRPa interaction will unleash such inhibition and promote tumor destruction. Accordingly, anti-CD47 antibodies offer new hope to successful cancer treatment. Despite people are enthusiastic about CD47 as a potential target, the side effects associated with CD47 blockade have emerged as a major concern. For example, treatment with anti-CD47 antibody greatly reduced the number of circulating red blood cells and platelets that also express CD47. Thus, the class of CD47 antibodies that stimulate tumor cell killing while sparing normal cells in vivois desirable for the cancer patients. We are interested in understanding whether humanized mouse models could aid the evaluation of a variety of monoclonal CD47 antibodies we generated. We first screened them using the CDX platformestablished at Biocytogen. Indeed, most antibodies were able to clear human tumor cells in B-NDG mice. However, when we screened the toxicity of these antibodies using humanized CD47 mice (B-hCD47), many antibodies caused rapid death of animals upon the first administration. Interestingly, we found two clonal antibodies bearing the least toxicity since the treated animals exhibited minimal weight loss. Thus, we concluded that humanized mice could expedite the development of safer CD47 antibodies that can be advanced to human clinical trials.
Citation Format: Yanan Guo, Chaoshe Guo, Yuelei Shen, Benny Yang. Balancing the efficacy and toxicity of anti-CD47 antibodies by direct screening in humanized mouse 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 2893.
Abstract 2902: Targeting the tight junction protein claudin-1 in colorectal cancer
Authors: Cherradi Sara , Ayrolles-Torro Adeline , Vezzo-Vié Nadia , Combes Eve , Canterel-Thouennon Lucile , Gava Fabien , Lobjois Valérie , Ducommun Bernard , Gongora Celine , Rio Maguy Del 
Published: August 2018

Abstract
Colorectal cancer (CRC) is one of the major causes of cancer-related deaths in the Western world. When localized, CRC is often curable by surgery, but the prognosis of patients with metastatic disease remains very poor. The current treatment of metastatic CRC (mCRC) relies on therapy combining chemotherapy and targeted therapies. However, relapses are observed in most cases due to the occurrence of drug resistance. Therefore, more therapeutic options are required particularly by identifying new molecular targets that can be reached by antibodies.
We previously showed that Claudin-1 (CLDN1), a major constituent of tight junctions, is overexpressed at the membrane of CRC cells which makes it a good target for antibodies. Besides, CLDN1 is differentially expressed in the new CRC molecular subtypes. We have then developed a monoclonal antibody (mAb) against CLDN1, called 6F6, which targets the extracellular part of CLDN1. Results showed that the 6F6 mAb significantly decreased cell growth, survival, and migration in vitro as well as in vivo. Furthermore, we demonstrated the cytostatic effect of the 6F6 mAb through proliferation assays.
We are now deciphering the role of CLDN1 on 3D spheroids, a model that reflects the physiopathology. Using immunofluorescence staining on frozen sections we are exploring the impact of CLDN1 on spheroids proliferation. We are also investigating on the distribution of tight junction proteins implicated on cell proliferation in the presence or absence of CLDN1.
CLDN1 is a new promising therapeutic target in CRC, it is now interesting to elucidate its role in colorectal cancer cell proliferation.
Keywords: Colorectal, Cancer, Claudin-1, monoclonal antibodies, spheroids, proliferation
Citation Format: Sara Cherradi, Adeline Ayrolles-Torro, Nadia Vezzo-Vié, Eve Combes, Lucile Canterel-Thouennon, Fabien Gava, Valérie Lobjois, Bernard Ducommun, Celine Gongora, Maguy Del Rio. Targeting the tight junction protein claudin-1 in colorectal 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 2902.
Abstract 2904: Awakening metastatic breast cancer cells to chemotherapy
Authors: Lourenco Ana Rita , Lopez Jay , Crowley Michael , Mittal Vivek , Gao Dingcheng 
Published: August 2018

Abstract
Breast cancer is the most common cancer in women with more than 316,000 new cases and expected 40,610 deaths in the US in 2017. Despite vast improvement in cancer management and treatment in the past years, not all subtypes of breast cancer have benefited equally. This includes the most aggressive form of invasive breast cancer, triple negative breast cancer (TNBC) subtype (ER-, PR- and HER2-), which accounts for about 20-25% of all breast cancer cases and presents a higher breast cancer-related mortality compared to other breast cancer subtypes. The poor survival rates attributed to TNBC is due to the lack of available biological targets and high rates of metastatic recurrence. Therefore, chemotherapy is the only therapeutic option for patients with metastatic TNBC. However, development of chemotherapy resistance is observed in the great majority of the cases and patients relapse within 5 years of a diagnosis. Given the unmet clinical needs, the discovery of novel therapeutic options that overcome chemoresistance of metastatic breast cancer is required. We have identified a group of genes which expression was enriched in chemotherapy resistant tumors cells, suggesting that these are potential therapeutic candidates to overcome chemotherapy resistance. Of these, CDKN1A (p21) was included. Furthermore, Immunostaining of metastatic lung tissue confirmed that surviving tumor cells under CTX treatment highly express p21. The enrichment of p21 in surviving tumor cells under chemotherapy, together with its well documented functions in cell-cycle arrest and regulation of apoptosis, provides a rationale to explore the underlying mechanisms that govern p21-induced chemoresistance and whether targeting p21 will re-sensitize the chemoresistant tumor cells in vivo.
Citation Format: Ana Rita Lourenco, Jay Lopez, Michael Crowley, Vivek Mittal, Dingcheng Gao. Awakening metastatic breast cancer cells to chemotherapy [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 2904.
Abstract 2907: Targeting the epigenetic regulator KAT2a in cancer
Authors: Gunnell Andrea , Downs Jessica , Pennicott Lewis , Osborn Kay , Grand Darren Le , Duffell Katie , Patel Hitesh , Hudson Jessica , Booth Jessica R. , Ward Simon 
Published: August 2018

Abstract
Gene expression frequently requires the dynamic remodelling of the chromatin architecture to orchestrate the assembly of transcriptional protein complexes at the promoter sites of DNA. Chromatin remodelling complexes are multicomponent proteins that facilitate reorganisation of chromatin structure using the energy derived from ATP hydrolysis, and as a result play a pivotal role in controlling gene expression. Mammalian SWI/SNF complexes are examples of chromatin remodelling complexes with multiple roles in maintaining genome stability. It is estimated that 19.6% of all human tumours have mutations in SWI/SNF complexes, leading to the deregulation of gene expression as an early driver of carcinogenesis. Our interest in developing novel treatments for renal cancer focused on the role of the chromatin remodelling complex, PBAF. The BAF180 component of PBAF is mutated in 40 % of clear cell renal carcinomas and its loss is an early event in renal cell tumorigenesis. We performed an siRNA based high throughput screen to identify genes associated with genome stability that were synthetically lethal with the loss of BAF180 and identified KAT2a as a potential druggable target. KAT2a is a protein that also functions in the regulation of gene expression as a component of the SAGA histone modifying complex. It is a multifunctional protein that can both ‘read' and ‘write' acetylation marks on histone proteins through its bromodomain and a histone acetyltransferase domain respectively. We will describe our efforts to establish suitable assays to support the discovery of selective inhibitors of the bromodomain of KAT2a. The work will include the establishment of a high throughput assay to measure compound binding, crystallographic characterisation of small molecule inhibitors of the bromodomain, and our initial studies towards the target validation of the bromodomain to recapitulate the synthetic lethality observed with depletion of BAF180.
Citation Format: Andrea Gunnell, Jessica Downs, Lewis Pennicott, Kay Osborn, Darren Le Grand, Katie Duffell, Hitesh Patel, Jessica Hudson, Jessica R. Booth, Simon Ward. Targeting the epigenetic regulator KAT2a in 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 2907.