bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5005: Impact of H3.3K27M mutation on diffuse intrinsic pontine glioma's resistance to treatment
Authors: Bailleul Quentin , Arcicasa Mélanie , Hochart Audrey , Rakotomalala Andria , Castets Marie , Pasquier Eddy , Angrand Pierre-Olivier , Adriaenssens Eric , Bourhis Xuefen Le , Leblond Pierre , Meignan Samuel 
Published: September 2020

Abstract
Diffuse Intrinsic Pontine Glioma is one of the worst pediatric brain tumors regarding prognosis due notably to intrinsic cell resistance to radio and chemotherapy. One of the main characteristics of DIPG cells is the presence of a mono-allelic mutation on the lysine 27 of histone H3 (H3K27M). This mutation inhibits the trimethylation of this lysine that leads to strong modifications of gene expression. Until now, even though this mutation seems to be a driver event in tumorigenesis, its role in cell resistance to treatment has not been deciphered, due to a lack of relevant cellular models. This way, in order to evaluate the role of the mutation on resistance to treatment, we first induced the mutation in three H3K27-unmutated pediatric glioma cell lines. In parallel, using the CRISPR/Cas9 technology, we are establishing DIPG cellular models in which the mutation will be reversed. By gene trapping approach, we aim to restore an H3F3Awt/wt genotype. After validation, these models would result in original tools to study the impact of H3K27M mutation in DIPG cells resistance to treatment. For the model of induction, the transfected cell lines exhibit the mutation accompanied by a loss of H3K27me3 mark and H3.3 overexpression. For now, we showed an increased cell growth due to the mutation in two cell lines, under normoxia as well as under hypoxia. On contrary there was no impact on resistance to chemotherapy or ionizing radiation. In the third cell line, we didn't observe any impact on cell growth, but an increase of cell radioresistance. Concerning the mutation reversion, our preliminary results show homologous recombination at the right locus in the genome, and some clones present a loss of the mutation confirmed by sequencing. After the removal of resistance cassette by action of a recombinase protein, we will be able to evaluate the biological effects of mutation reversion. To sum up, these different models would allow us to decipher cellular and molecular mechanism induced by the H3.3K27M mutation in DIPG cells including resistance to treatment, and thus, to possibly identify putative therapeutic targets.
Citation Format: Quentin Bailleul, Mélanie Arcicasa, Audrey Hochart, Andria Rakotomalala, Marie Castets, Eddy Pasquier, Pierre-Olivier Angrand, Eric Adriaenssens, Xuefen Le Bourhis, Pierre Leblond, Samuel Meignan. Impact of H3.3K27M mutation on diffuse intrinsic pontine glioma's resistance to treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5005.
Abstract 5042: Targeting the ERK5 and ERK1/2 pathways simultaneously induces mesenchymal to epithelial transition in TNBC
Authors: Bhatt Akshita , Wright Thomas , Barnes Van , Chakrabarty Suravi , Flaherty Patrick , Burow Matthew , Cavanaugh Jane 
Published: September 2020

Abstract
Extracellular signal-regulated kinase (ERK) 5, a member of mitogen activated protein kinase (MAPK) family, is an emerging target in cancer therapeutics. Activation of ERK5 via overexpression induces EMT and hormone-independent growth of breast cancer. EMT leads to the loss of cell polarity, downregulation of E-cadherin, and upregulation of mesenchymal markers snail, zinc-finger E-box binding homeobox (ZEB1), and vimentin. EMT is also associated with drug resistance. Although ERK1/2 and ERK5 activation is known to mediate EMT, the effect of ERK1/2 and ERK5 inhibition on mesenchymal to epithelial transition (MET), the reverse of EMT, is poorly understood in cancer.Triple negative breast cancer (TNBC) cells have a mesenchymal phenotype and show poor sensitivity to chemotherapy agents. The loss of estrogen, progesterone hormone receptors and human epidermal growth factor receptors (HER2) contributes to the aggressive state of the disease and lack of targeted therapy. Activation of the intracellular signaling pathways such as the MAPK pathway mediates tumorigenesis in TNBCs. MEK1/2 inhibitors have been successful clinical drug candidates; however, there is emerging evidence that the activation of the MEK5-ERK5 pathway mediates resistance to the MEK1/2 inhibitors in several BRAF and KRAS-mutant cancers. The effect of MEK1/2 inhibition on MEK5-mediated EMT, cell survival, and migration in TNBC is less well understood. Therefore, we hypothesize that dual inhibition of the ERK1/2 and ERK5 pathways is a relevant strategy to target TNBCs.In the present study, the effect of dual ERK1/2 and ERK5 inhibition on MET, cell viability, migration, and anchorage-independent growth was evaluated in TNBC. ERK1/2 and ERK5 activities were modulated via pharmacological inhibitors and molecular tools. Cell morphology and protein expression of EMT markers E-cadherin, ZEB1, snail, and vimentin were evaluated. XMD8-92, an ERK5 inhibitor was found to synergize with doxorubicin in lung and cervical cancer cells. Therefore, the effect of dual ERK1/2 and ERK5 on doxorubicin sensitivity was evaluated.
Citation Format: Akshita Bhatt, Thomas Wright, Van Barnes, Suravi Chakrabarty, Patrick Flaherty, Matthew Burow, Jane Cavanaugh. Targeting the ERK5 and ERK1/2 pathways simultaneously induces mesenchymal to epithelial transition in TNBC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5042.
Abstract 5044: Integrin-linked kinase gene knockdown results in decreased growth of ovarian cancer xenograft models
Authors: Redfern Tiffany , Wilson Benjamin , Ulm Michael , ElNaggar Adam , Ponnusamy Suriyan , Wang Yinan , Asemota Sarah , Narayanan Ramesh 
Published: September 2020

Abstract
Integrin-linked kinase (ILK) is overexpressed in ovarian cancer cells. In the present study, we sought to assess the effect of ILK silencing on ovarian cancer cell proliferation using shRNA. Our lab previously demonstrated that phosphorylation of ILK acts as a proliferative signal in a variety of ovarian cancer cell lines. Cytotoxicity of ILK knockdown using shRNA was analyzed in vitro using SKOV3 cell lines. Transfected cells were incubated in Incucyte®, which allowed for simultaneous assessment of viable cells at the end of the incubation period using CellTiter glo assay. Knockdown of ILK using shRNA significantly inhibited the proliferation of SKOV3 cells. SKOV3 cells were then infected with lentivirus expressing ILK shRNA to obtain stable knockdown of ILK, which was confirmed with Western blot. Both parental and ILK shRNA infected cells were injected subcutaneously in NOD SCID Gamma immunocompromised mice. Tumor growth was assessed by sequential tumor measurements and final weights. Xenograft data indicated significantly decreased tumor volume over multiple time points in the transfected cells (p &lt;0.0001) (Figure 1). Average final volume for the ILK-shRNA group (n = 15) and control group (n = 13) was 660mm3 (SD = 366.7, range 271 - 1667 mm3) and 1165 mm3 (SD = 668.7, range 506 - 2664 mm3), respectively. Similarly, average tumor weight was less for the ILK-shRNA group (404.4mg [range 226.1 - 801mg]) relative to control (584.3mg [range 293.2 - 1033.4mg]). Our findings demonstrate that knockdown of ILK in ovarian cancer cell lines results in decreased cell proliferation, as well as decreased tumor growth in xenograft models. This supports the role for further investigation into ILK as a potential therapeutic target in ovarian cancer.
Days From Tumor Implantation1214161921232628313438VectorAverage Tumor Volume (mm^3)142.4151.6203274.7379.3482.1671.4741.2845.11083.81164.6Standard Error26.983.430.835.759.682112.3110.7133.9172.2185.5ILK-shRNAAverage Tumor Volume (mm^3)45.9107.282.4113150.9177263.4345.2397.3568.8659.9Standard Error6.39.99.915.225.822.841.558.455.19994.7
Citation Format: Tiffany Redfern, Benjamin Wilson, Michael Ulm, Adam ElNaggar, Suriyan Ponnusamy, Yinan Wang, Sarah Asemota, Ramesh Narayanan. Integrin-linked kinase gene knockdown results in decreased growth of ovarian cancer xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5044.
Abstract 5051: RenMab Mouse: A leading platform for fully human antibody generation
Authors: Ng Gary , Zhao Huizhen , Zhang Yabo , Liu Lili , Lu Hui , Huang Shuwen , Shen Yuelei 
Published: September 2020

Abstract
With the development of immune-oncology, therapeutic antibodies have been proven to be extraordinarily effective for cancer treatment. Conventional human antibody discovery process can be divided into steps including target selection, target validation, screening preparation, hits generation, leads selection, lead optimization, and clinical candidate selection. To accelerate antibody development process, Biocytogen has developed RenMab Mouse, a fully human antibody mouse whose entire variable regions were replaced by human Ig heavy chain and κ light chain through Biocytogen's unique Mb-scale chromosome engineering technology. RenMab Mouse provides a remarkably efficient therapeutic antibody discovery platform for fully human antibody generation, characterization, and rapid in vivo efficacy screening. We have characterized RenMab Mouse with the following features.
1. The entire mouse variable regions were replaced with complete human genome DNA in situ for complete human & mouse regulatory elements. The gene regulation of RenMab mouse is highly consistent with that of human.
2. Mouse constant region remains to ensure normal immune cell population, development and maturation. Immune system of RenMab Mouse has been proven to be almost identical to that of wild type mice. RenMab Mouse showed normal antibody immune responses to antigens.
3. RenMab Mouse generates a highly diverse repertoire of fully human antibody variable regions through V(D)J recombination. This capability can lead to improved hit rates in antibody drug discovery.
In conclusion, RenMab Mouse, a fully human antibody mouse developed by Biocytogen's chromosome engineering technology, has been proven to exhibit normal immune cell profile and rapid immune response. Combined with existing inventory of single, double or triple target humanized mouse models and a world-leading proprietary gene editing platform, Biocytogen is dedicated to providing a one-stop solution for antibody discovery and development from target validation to IND application.
Citation Format: Gary Ng, Huizhen Zhao, Yabo Zhang, Lili Liu, Hui Lu, Shuwen Huang, Yuelei Shen. RenMab Mouse: A leading platform for fully human antibody generation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5051.
Abstract 5089: The origin and contribution of the tumor stroma in colorectal cancer
Authors: Kobayashi Hiroki , Gieniec Krystyna A. , Lannagan Tamsin RM , Wang Tongtong , Asfaha Samuel , Hayakawa Yoku , Leedham Simon J. , Arpaia Nicholas , Mukherjee Siddhartha , Wang Timothy C. , Enomoto Atsushi , Takahashi Masahide , Woods Susan L. , Worthley Daniel L. 
Published: September 2020

Abstract
Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment and play a critical part in cancer progression. However, the precise origin of the tumor stroma remains unknown, making it challenging to effectively target the cancer mesenchyme. Here, employing 4 different genetic fate mapping mouse models and a bone marrow transplantation model in combination with BrdU labeling, we uncovered a key contributor to the tumor stroma in colorectal cancer (CRC). We found that approximately half of a-smooth muscle actin (aSMA)+ CAFs emerge through proliferation in an AOM/DSS mouse model of CRC. Lineage tracing experiments revealed that intestinal leptin receptor (Lepr)-lineage stromal cells expanded and contributed to 75% of the aSMA+ proliferating CAFs. Notably, no aSMA+ CAFs in the tumor were derived from Krt19-lineage epithelial cells or bone marrow-transplanted cells, indicating no involvement of epithelial-mesenchymal transition and bone marrow recruitment to the tumor in this model. Moreover, RNA-sequencing of FACS-purified CRC mesenchymal cells identified MCAM (also known as CD146) as a CRC stroma-specific marker, which is expressed by Lepr-lineage cells. Analysis of human CRC samples showed that high MCAM expression was associated with a mesenchymal subtype of CRC and was independently prognostic of poor overall survival. Our data identify Lepr-lineage cells as a major source of the tumor stroma in CRC and suggest that targeting MCAM+ cells may serve as a novel therapeutic approach to restrain CRC progression.
Citation Format: Hiroki Kobayashi, Krystyna A. Gieniec, Tamsin RM Lannagan, Tongtong Wang, Samuel Asfaha, Yoku Hayakawa, Simon J. Leedham, Nicholas Arpaia, Siddhartha Mukherjee, Timothy C. Wang, Atsushi Enomoto, Masahide Takahashi, Susan L. Woods, Daniel L. Worthley. The origin and contribution of the tumor stroma in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5089.
Abstract 5142: Proteome-wide analysis identifies three subgroups of diffuse-type gastric cancer
Authors: Huang Wenwen , Xia Xia , Zhan Dongdong , Shen Lin , Qin Jun 
Published: September 2020

Abstract
Background: Gastric cancer (GC) is highly heterogeneous and the leading cause of cancer death. Diffuse-type gastric cancer (DGC) is one of poor-prognosis GC subtypes with few treatment options. Genomic subtyping classifies overall gastric cancers into different subgroups that associate with prognosis and therapeutic targets, but it has not translated into clinical benefit. Proteomic subtyping with DGC may offer the potential for personalized risk stratification and treatment recommendation.
Methods: We developed a workflow using fast mass spectrometry and ConsensusClusterPlus (CCP) consensus clustering for proteomic subtyping and applied it to 99 DGC formalin-fixed, paraffin-embedded (FFPE) samples.
Results: In this study, 99 FFPE tumor samples were analyzed and classified into three proteomic subtypes (DGCP1-3) based on proteome-wide data, which were significantly associated with prognosis and response to chemotherapy. DGCP1 is with the best survival and DGCP3 is with the worst survival. DGCP2 derives benefit from chemotherapy. The rest of the subtypes do not receive benefit from chemotherapy. Specific signaling pathways are enriched in the subtypes: DGCP1/innate immune system; DGCP2/metabolism of RNA plus cell cycle; DGCP3/Extracellular Matrix (ECM). The classification with subtype-specific proteins provides a roadmap for stratifying patients into subgroups in trials of chemotherapy, targeted, and immune therapies.
Conclusions: Proteomic subtyping of DGC identified three subgroups that have significant associations with distinct clinical characteristics. The DGCP subtyping can be further verified in more clinical cohorts and used to predict prognosis and recommend clinical actions in DGC treatment.
Citation Format: Wenwen Huang, Xia Xia, Dongdong Zhan, Lin Shen, Jun Qin. Proteome-wide analysis identifies three subgroups of diffuse-type gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5142.
Abstract 5173: Identification of new targets in SMAD4-deficient cancers by whole genome CRISPR screening
Authors: Marcireau Christophe , Erasimus Hélène , Kolnik Vanessa , Lacroix Frederic , D'agostino Stéphane , Lemaitre Olivier , Rohaut Alexandre , Sanchez Isabelle , Sidhu Sukhvinder , Thill Gilbert , Didier Michel , Debussche Laurent 
Published: September 2020

Abstract
The TGF-β signaling mediator SMAD4 is frequently mutated or deleted in colorectal cancer (CRC) and pancreatic cancers (PC) and is associated with poorer prognosis. This makes SMAD4 loss interesting to harness for synthetic lethality-based therapy. In this study, we first restored SMAD4 in SMAD4-deficient cell lines (HT29 and SW620) and showed that SMAD4 restoration reestablished the TGF-β-induced growth inhibition in vitro and in vivo, thereby confirming the tumor suppressive role of SMAD4 in these cell lines. In order to identify genetic vulnerabilities of SMAD4-deficient cells, we conducted pooled genome-wide loss-of-function CRISPR/Cas9 screens across four non-isogenic cell lines harboring altered (HT29 and SW620) or wild-type (DLD1 and MIAPACA2) SMAD4. We identified candidate genes, including the Krüppel-like factor 5 (KLF5), which has already been suggested as a potentially interesting target for drug therapy in SMAD4-deficient cancers. Novel candidates that might be interesting synthetic lethal targets in SMAD4-negative cancers will be presented.
Citation Format: Christophe Marcireau, Hélène Erasimus, Vanessa Kolnik, Frederic Lacroix, Stéphane D'agostino, Olivier Lemaitre, Alexandre Rohaut, Isabelle Sanchez, Sukhvinder Sidhu, Gilbert Thill, Michel Didier, Laurent Debussche. Identification of new targets in SMAD4-deficient cancers by whole genome CRISPR screening [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5173.
Abstract 5180: Nuclear receptor tyrosine kinase c-MET restrains efficacy of PARP inhibitor in pancreatic cancer cells
Authors: Gao Yuan , Chen Mei-Kuang , Yu Dihua , Hung Mien-Chie 
Published: September 2020

Abstract
Pancreatic tumors commonly have intra-tumor hypoxia and high reactive oxygen species (ROS) production and have become the fourth leading cause of death in the United States. Although ROS leads to oxidation of macromolecules such as DNA, protein, and lipids, pancreatic cancer cells are capable of surviving from the ROS-induced stress at relatively high tolerable levels. Therefore, identifying potential molecular mechanisms for pancreatic cancer cells to overcome ROS-induced cellular stress is important for develop therapeutic strategies in treating pancreatic cancer patients. While poly (ADP-ribose) polymerase 1 (PARP1) is a key protein for repairing ROS-induced DNA damages, we intended to include PARP inhibitors in targeted therapy strategy. Recent clinical trial showed that PARP inhibitor benefits pancreatic patients with BRCA mutation. However, our goal is to expand PARP inhibitor targeted therapy to pancreatic cancer patients without BRCA mutation with PARP inhibitor using strategies of combining kinase inhibitors as we demonstrated in breast cancer in our previous publications. Here, we used hydrogen peroxide (H2O2) as ROS stimuli and demonstrated that H2O2 induces nuclear transport of the receptor tyrosine kinase c-MET in AsPC-1 and BxPC-3 pancreatic cancer cells. We further showed that nuclear-located c-MET interacts with PARP1, and the interaction can be partially interrupted by crizotinib, a kinase inhibitor targeting c-MET. Moreover, combination of crizotinib and PARP inhibitor, olaparib, has synergistic anti-tumor effect in eliminating pancreatic cancer cells. Our data suggest that the intra-tumor hypoxia micro-environment of pancreatic cancer may promote nuclear localization of c-MET, which results in resistance to PARP inhibitor therapy. We further proposed a new therapeutic strategy of combining c-MET inhibitors and PARP inhibitors for advanced pancreatic cancer patients.
Citation Format: Yuan Gao, Mei-Kuang Chen, Dihua Yu, Mien-Chie Hung. Nuclear receptor tyrosine kinase c-MET restrains efficacy of PARP inhibitor in pancreatic cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5180.
Abstract 5183: The preclinical characterization of TST001, a novel humanized anti-claudin18.2 mAb with enhanced binding affinity and anti-tumor activity
Authors: Teng Fei , Gu Yi , Chai Hui , Guo Huanhuan , Li Hongjun , Wu Xiwen , Yao Xinlai , Xu Fei , Shi Lei , Yan Zhenzhi , Zi Xiaoli , Dai Zheng , Liao Timethy , Zheng Lisa , Fan Francis , Li Zhen , Yang Jerry , Qian Xueming 
Published: September 2020

Abstract
Claudin-18 isoform 2 (CLDN18.2) is a member of the human claudin family of tetraspan membrane proteins that are crucial structural and functional components of tight junctions. Unlike other family members, CLDN18.2 expression is strictly limited to differentiated epithelial cells of gastric mucosa. Interestingly CLDN18.2 was ectopically expressed at a significant level in multiple tumor types including gastric, esophageal, pancreatic and lung cancers, which makes it as an attractive anti-cancer target. TST001 is a novel humanized IgG1 monoclonal antibody, which specifically binds to cells expressing human CLDN18.2 with high affinity but not to the closely related Claudin 18.1. TST001 can compete with IMAB362, the clinical stage anti-CLDN18.2 mAb, for its binding to CLDN18.2 yet engages distinct epitope for binding. By reducing fucosylation during cell culture process, TST001 has further enhanced binding affinity to FcγRIIIa, which translates into more potent ADCC activity. Indeed, TST001 showed sub-nanomolar ADCC activity against gastric cancer cells expressing medium to low CLDN18.2 in the presence of human PBMC and NK cells, which is significantly more potent than IMAB362. TST001 also showed more potent CDC and ADCP activities against CLDN18.2 expressing cells than IMAB362. In both Sprague Dawley Rat and Cynomolgus Monkey, the systemic exposure of TST001 increased proportionally in a dose-dependent manner. In gastric cancer cell line and patient derived xenograft tumor models, TST001 showed more potent anti-tumor activity as compared with IMAB362. Furthermore, the combination of TST001 with chemo agents resulted in synergistic anti-tumor effect in these tumor models. In addition, we have also generated and characterized an antibody that is suitable for IHC based detection and is selective to CLDN18.2 over CLDN18.1. Altogether, these preclinical findings warrant further clinical evaluation of TST001 in patients with CLDN18.2 positive tumors.
Citation Format: Fei Teng, Yi Gu, Hui Chai, Huanhuan Guo, Hongjun Li, Xiwen Wu, Xinlai Yao, Fei Xu, Lei Shi, Zhenzhi Yan, Xiaoli Zi, Zheng Dai, Timethy Liao, Lisa Zheng, Francis Fan, Zhen Li, Jerry Yang, Xueming Qian. The preclinical characterization of TST001, a novel humanized anti-claudin18.2 mAb with enhanced binding affinity and anti-tumor activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5183.