bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 782: Development of a high throughput in vitro screening platform to identify novel inducers of immunological cell death
Authors: Grillot Didier , Gangar Akanksha , Guillard-Huet Raphaelle , Boursier Eric , Potvain Florent , Serin Guillaume , Mirjolet Jean-François 
Published: August 2018

Abstract
Immunological cell death (ICD) is a form of cancer cell death induced by radiotherapy, photodynamic therapy and a few chemotherapeutic agents such as Doxorubicin, Mitoxantrone, and Oxaliplatin. Unlike apoptosis or necrosis, ICD can induce an effective immune response directed against the tumor whereby both dendritic cells and T lymphocytes are mediators of this response. Dying cancer cells recruit and activate immune cells by releasing damage-associated molecular patterns (DAMPS) that help and promote the immune response to antigenic tumor neo-epitopes. Three key DAMPS are associated with the ICD process: calreticulin exposition on the cell surface, ATP secretion and high-mobility group box 1 (HMGB1) release. In order to identify new therapeutic agents that promote ICD in malignant cells, we developed a screening strategy facilitated by an automated in vitro platform with four assays on three different tumor cell lines (human osteosarcoma U-2 OS, human breast MDA-MB-231 and murine liver Hepa 1-6). ICD inducers Doxorubicin and Mitoxantrone used as positive controls increased ATP secretion by 2 to 10-fold at a non-cytotoxic dose after 72 hours incubation on the three cell lines. Both compounds also increased calreticulin exposition by 2 to 4-fold (determined by immunofluorescence using the Operetta High-Content Imaging System) and HMGB1 release by two-fold on the three cell lines. Here we will present recent data from the screening of Oncodesign's Nanocyclix® library using this platform to identify novel ICD inducers.
Citation Format: Didier Grillot, Akanksha Gangar, Raphaelle Guillard-Huet, Eric Boursier, Florent Potvain, Guillaume Serin, Jean-François Mirjolet. Development of a high throughput in vitro screening platform to identify novel inducers of immunological cell death [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 782.
Abstract 785: Application of CRISPR/Cas9 gene editing to primary T cells
Authors: Li Xi , Tang Wanbing , Zhou Chenjie , Yang Yulin , Peng Zhengang , Zhou Wenrong , Ji Qunsheng , Cang Yong 
Published: August 2018

Abstract
T cells mediate a broad range of immune responses, especially generation of adaptive immunity for cancer cell clearance. Identification of genetic components that modulate T cell proliferation, differentiation, migration and cytotoxicity would facilitate development of more effective cancer immunotherapy. CRISPR/Cas9, as a tool, could generate gene knockout with high specificity and efficiency and has been widely used in genome-wide screening for therapeutic targets in many tumor cell models. However, its application to primary cells especially T cell has not been extensively investigated. Here, we described how to employ the CRISPR/Cas9 tools for immune-oncology target identification in primary mouse T cells. Cas9/sgRNA could be transduced into T cells with high efficiency and low toxicity using a lentivirus based delivery system. The transduced T cells acquired Cas9 expression but no DNA editing was observed. However, we achieved gene editing in primary T cells isolated from a Cas9 transgenic mouse strain after lentiviral delivery of guide RNA's. In summary, we provide a new method to generate DNA editing in primary T cell using CRISPR/Cas9 technology. It could be used for gene knockout, knockin and even genome-wide screening in primary T cell for immune checkpoint regulators.
Citation Format: Xi Li, Wanbing Tang, Chenjie Zhou, Yulin Yang, Zhengang Peng, Wenrong Zhou, Qunsheng Ji, Yong Cang. Application of CRISPR/Cas9 gene editing to primary T cells [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 785.
Abstract 80: Glucocorticoids mediate DCIS transition to IDC through myoepithelial cell apoptosis
Authors: Zubeldia-Plazaola Arantzazu , Recalde-Percaz Leire , Moragas Núria , Mancino Mario , Noguera Aleix , Puig Miquel Prats de , Guzman Flavia , Gascón Pedro , Bragado Paloma , Fuster Gemma 
Published: August 2018

Abstract
The most accepted theory in breast cancer evolution is the linear progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). DCIS is defined by a clonal proliferation of epithelial cells that accumulate within the lumen of a duct and surrounded by the myoepithelial cells layer and the basement membrane. The challenge is to predict which of the DCIS lesions will eventually progress to IDC and which will remain stable for a long time. Understanding the progression from DCIS to IDC is crucial to properly treat DCIS patients and to develop new and more approachable therapeutic strategies in this stage. The microenvironment, as well as stress factors like glucocorticoids, exerts strong influences in DCIS to IDC transition. These factors have been previously implicated in breast cancer progression however its role in the first stages of breast cancer and particularly in myoepithelial cells regulation remains elusive. In order to clarify glucocorticoids role in this breast cancer stage, we evaluated the effects of corticosterone and cortisol in epithelial cells and myoepithelial cells using in vitro 2D and 3D and in vivo techniques. Glucocorticoids induced a decreased in laminin levels and favour the disruption of the myoepithelial cell layer through myoepithelial cells apoptosis promotion. In addition, increased corticosterone levels, in an in vivo stress murine model, fostered the transition from DCIS to IDC via myoepithelial cell apoptosis and basement membrane vanishing. Furthermore, myoepithelial cell apoptosis is a more frequent event in DCIS+IDC than in DCIS breast cancer patients. Our findings show that stress, through glucocorticoids, plays a role in the progression of DCIS to IDC, and particularly by promoting apoptosis of myoepithelial cells and the apoptosis in myoepithelial cells seems to be a requirement to achieve invasive features in breast cancer patients.
Citation Format: Arantzazu Zubeldia-Plazaola, Leire Recalde-Percaz, Núria Moragas, Mario Mancino, Aleix Noguera, Miquel Prats de Puig, Flavia Guzman, Pedro Gascón, Paloma Bragado, Gemma Fuster. Glucocorticoids mediate DCIS transition to IDC through myoepithelial cell apoptosis [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 80.
Abstract 809: Afatinib restrains K-RAS driven lung tumorigenesis
Authors: Moll Herwig P. , Pranz Klemens , Musteanu Monica , Brcic Luka , Popper Helmut , Moldvay Judit , Dome Balázs , Casanova Emilio 
Published: August 2018

Abstract
Lung cancer is still the leading cause of cancer deaths worldwide. While it is well documented that patients suffering from epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) benefit from (EGFR) inhibition, there are still no successful targeted therapies for oncogenic mutations in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene available. Indeed, based on clinical trials using first generation EGFR tyrosine kinase inhibitors (TKI) it became a doctrine that K-RAS mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC).
Conversely, we demonstrate here that EGFR signaling is engaged in K-RAS driven lung tumorigenesis both in human and in mice. Genetic mouse models revealed that deletion of Egfr quenches mutant K-ras activity and transiently reduces tumor growth. However, EGFR inhibition initiates a resistance mechanism which involves non-EGFR ERBB family members. This escape mechanism not only clarifies the disappointing outcome of first generation TKI in clinical trials, but also suggests therapeutic potential of pan-ERBB inhibitors. Indeed, by using several experimental models, including genetically engineered mouse models, (patient derived-) xenografts and in vitro experiments, we demonstrate that the FDA approved pan-ERBB inhibitor afatinib formidably reduces K-RAS driven lung tumorigenesis, whereas first generation TKI erlotinib and gefitinib remained ineffective in our models.
Altogether, our data strongly suggests revisiting the potential of EGFR TKI in clinical trials for the treatment of K-RAS mutated NSCLC, with a particular focus on pan-ERBB inhibitors, which are readily available.
Citation Format: Herwig P. Moll, Klemens Pranz, Monica Musteanu, Luka Brcic, Helmut Popper, Judit Moldvay, Balázs Dome, Emilio Casanova. Afatinib restrains K-RAS driven lung tumorigenesis [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 809.
Abstract 821: B7-H3 is a potential antibody drug conjugate target for the treatment of prostate cancer
Authors: Davies Gareth C. , Ryan Kelli , Smith Alison J. , Lloyd Chris , Tammali Ravinder , Monks Noel , Lewis Arthur , Wilkinson Robert W. 
Published: August 2018

Abstract
B7-H3 is a member of the B7 family of immune-regulatory ligands and has been reported to be overexpressed in a broad range of human cancers. In order to understand more comprehensively the expression of B7-H3 on both normal tissues and on tumors, we developed an immunohistochemistry (IHC) assay for the detection of human B7-H3. Using this, we confirmed a restricted normal tissue expression pattern and demonstrated expression of B7-H3 in a range of solid tumors. In particular, a high proportion of prostate cancer samples showed strong homogenous B7-H3 expression. This low normal tissue expression and upregulation in cancer makes B7-H3 an attractive target for an antibody drug conjugate (ADC). To evaluate this approach, antibodies to B7-H3 were isolated by screening a phage display library for binding to B7-H3. These antibodies specifically bind to and are internalised by B7-H3 expressing cancer cells. ADCs were generated by site-specific conjugation of either a DNA-damaging pyrrolobenzodiazepine dimer or a microtubule-disrupting tubulysin payload. These ADCs selectively inhibited the growth of B7-H3 expressing cell lines including androgen-insensitive prostate cancer cell lines such as LNCAP-AI in vitro. Furthermore, these ADCs caused durable tumour regression in human tumor xenograft models in vivo. Together, these data suggest that an ADC targeting B7-H3 may have potential to be used for the treatment of a range of solid tumors including prostate cancer.
Citation Format: Gareth C. Davies, Kelli Ryan, Alison J. Smith, Chris Lloyd, Ravinder Tammali, Noel Monks, Arthur Lewis, Robert W. Wilkinson. B7-H3 is a potential antibody drug conjugate target for the treatment of prostate 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 821.
Abstract 83: The role of Nrf2-Keap1 pathway in the survival of circulating metastatic cancer cells
Authors: Aljohani Hashim M. , Furgason John M. , Amaya Peter , Deeb Ayham , Chalmers Jeffery J. , Bahassi El Mustapha 
Published: August 2018

Abstract
Approximately 90% of all cancer deaths arise from the metastatic spread of primary tumors. Of all the processes involved in carcinogenesis, local invasion and the formation of metastases are clinically the most relevant, but they are the least well understood at the molecular level. As a barrier to metastasis, cells normally undergo an apoptotic process known as “anoikis,” in circulation. The recent technological advances in the isolation and characterization of rare circulating tumor cells (CTCs) will allow a better understanding of anoikis resistance. Detailed molecular and functional analyses of anoikis-resistant cells may provide insight into the biology of cancer metastasis and help identify novel targets for prevention of cancer dissemination. To uncover the molecular changes that govern the transition from a primary lung tumor to a secondary metastasis and specifically the mechanisms by which CTCs survive in circulation, we carried out whole-genome sequencing (WGS) of normal lung, primary tumors and the corresponding brain metastases from five patients with progressive metastatic NSCLC. We also isolated CTCs from patients with metastatic cancer and subjected them to whole-genome amplification and Sanger sequencing and quantitative digital PCR of genes of interest. While the primary tumors showed mutations in genes associated with cell adhesion and motility, brain metastases acquired mutations in adaptive and cytoprotective genes involved in the response to cellular stress such as Keap1, Nrf2 and E300, which are key players of the Keap1-Nrf2-ARE survival pathway. Nrf2 is a transcriptional factor that upon stress translocates into the nucleus, binds to the ARE (anti-oxidant response elements) and drives the expression of antioxidant genes. The identified mutations affect regulatory domains in all three proteins, suggesting a functional role in providing a survival advantage to CTCs in the peripheral blood, allowing their dissemination to distant organs.
Citation Format: Hashim M. Aljohani, John M. Furgason, Peter Amaya, Ayham Deeb, Jeffery J. Chalmers, El Mustapha Bahassi. The role of Nrf2-Keap1 pathway in the survival of circulating metastatic cancer cells [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 83.
Abstract 837: Antitumor effects of anti-EGF antibodies generated by vaccination in NSCLC tumor cells
Authors: Garcia-Roman Silvia , Codony-Servat Jordi , Molina-Vila Miguel Angel , Bertran-Alamillo Jordi , Gimenez-Capitán Ana , Karachaliou Niki , d'Hondt Erik , Rosell Rafael 
Published: August 2018

Abstract
Background: Immunization against Epidermal Growth Factor (EGF) has demonstrated clinical efficacy in a phase III trial including unselected NSCLC patients. We are currently analyzing if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) showed antitumor activity in EGFR-mutant, Kras-mutant (mut) and Anaplastic Lymphoma Kinase (ALK) translocated non-small cell lung cancer cells (NSCLC), alone or in combination with tyrosine kinase inhibitors (TKI). In an EGFR-mut and in an ALK translocated cell lines we are also studying if the anti-EGF VacABs can delay the emergence of resistance to TKIs.
Methods: Anti-EGF VacAbs were obtained by immunizing rabbits with recombinant EGF. Cell lines were treated with anti-EGF VacABs alone and in combination with TKIs in EGFR (PC9, H1975) and ALK translocated (H3122, H2228) cell lines. In KRAS-mut cells (A549, H23) the combination was with chemotherapy agents. Cell viability was analyzed by MTT and apoptosis and cell cycle by fluorescence-activates cell sorting analysis (FACS). Changes of total and phosphorylated proteins were determined by Western blot. Sera from advanced NSCLC patients immunized with anti-EGF vaccine were also tested
Results: Anti-EGF VacAbs suppressed EGF-induced cell proliferation and inhibited downstream EGFR signaling in all cell lines tested. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of gefitinib, erlotinib, osimertinib and afatinib in EGFR-mut cells, potentiated Erk ½ phosphorylation, arrested cell cycle progression and increased apoptosis. In addition, anti-EGF VacAbs blocked the activation of STAT3, downregulated the expression of proteins related to EGFR resistance, such as AXL, and significantly delayed the emergence in vitro of clones resistant to EGFR TKI. Sera from patients vaccinated against EGF also suppressed Erk ½ phosphorylation. Results for the combination of ALK TKIs and chemotherapy agents in ALK translocated and KRAS-mut cell lines will be presented at the meeting.
Conclusions: Anti-EGF VacAbs decreased cell proliferation and inhibited the activation of EGFR-pathway downstream proteins in EGFR-mut, KRAS-mut and ALK translocated cell lines. Also, they potentiate the effects of TKIs and prevent the emergence of resistance in EGFR-mut NSCLC cells. Two clinical trials are currently testing anti-EGF vaccination in EGFR-wt and EGFR-mut advanced NSCLC patients.
Citation Format: Silvia Garcia-Roman, Jordi Codony-Servat, Miguel Angel Molina-Vila, Jordi Bertran-Alamillo, Ana Gimenez-Capitán, Niki Karachaliou, Erik d'Hondt, Rafael Rosell. Antitumor effects of anti-EGF antibodies generated by vaccination in NSCLC tumor cells [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 837.
Abstract 839: Treatment and signaling contexts for the application of the imipridone ONC201 to prostate cancer cells
Authors: Amoroso Francesca , Pickard Adam , Glass Kimberly , Tarapore Rohinton , Allen J. E. , Mills Ian G. 
Published: August 2018

Abstract
Prostate cancer is the most common non-cutaneous cancer in men and a significant cause of cancer mortality. In the majority of the cases localised disease is treated with surgery or radiotherapy and whilst androgen deprivation therapy can extend survival in the subset of cases that progress, metastatic disease is incurable. We have previously reported that oncogenic drivers of prostate cancer (e.g. PTEN loss or mutation), as well as therapy, lead to changes in the activation of prostate cancer cell stress signalling pathways and in particular the unfolded protein response (UPR)1. Here we assess whether the activation of the UPR in response to radiation mirrors the immunogenic/inflammatory response, which is known to characterize the initially acute apoptotic phase before resolving to a chronic level. Further we have evaluated the impact of combining radiation with ONC201, a novel anti-cancer small molecule in clinical trials that is known to activate the pro-apoptotic stress response signalling2. We find that ONC201 has a delayed cytotoxic effect as a single agent in prostate cancer cells, with significant dose-dependent reductions in cell viability occurring 72 hours post-treatment. However activation of multiple arms of the UPR occurs earlier and is detectable at 24 hours for ATF4, ATF6 and IRE1-XBP1 at the protein/mRNA levels in the absence of impacts on cell viability. This delayed impact on viability offers a time window within which to evaluate short-term administration of ONC201 as a ‘primer' to enhance the cytotoxic response to radiation. We show that ‘priming' does indeed enhance radiotherapy response as assessed by cell viability and clonogenic assays. Since PTEN-loss is a high-incidence event in the development and progression of prostate cancer and has been linked to prognosis, we have also evaluated the impact of altering PTEN expression in our models as well as the effect of knocking down core regulators of the UPR. Cumulatively this work represents a further progression to positioning ONC201 in an appropriate molecular context to have durable effects when combined with other therapies to treat prostate cancer.
1.Sheng, X. et al., EMBO Molecular Medicine 7, 788-801 (2015).
2.Allen, J. et al. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget (2016). doi:10.18632/oncotarget.11814
Citation Format: Francesca Amoroso, Adam Pickard, Kimberly Glass, Rohinton Tarapore, J. E. Allen, Ian G. Mills. Treatment and signaling contexts for the application of the imipridone ONC201 to prostate cancer cells [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 839.
Abstract 84: Identification of HNRNPLL as a novel metastasis suppressor of colorectal cancer
Authors: Aoki Masahiro , Sasaki Eiichi , Kimura Kenya , Komori Koji , Shimizu Yasuhiro , Yatabe Yasushi , Sakuma Keiichiro 
Published: August 2018

Abstract
Despite the advances in surgery and chemotherapy for colorectal cancer patients, those with distant metastasis still suffer poor prognosis. Metastasis is a complex process regulated by a number of biomolecules, which can be conceptually divided into metastasis promoters and suppressors. To identify novel targets for prevention and/or therapy of colorectal cancer metastasis, we performed an in vivo shRNA library screen for colorectal cancer metastasis suppressor genes using an orthotopic transplantation model. CMT93 cells, a murine colorectal cancer cell line with poor metastasizing activity, were transduced with lentiviral shRNA library, and then transplanted into the rectum of C57/BL6 mice. Genomic DNA was collected from metastatic lesions, and the integrated shRNAs were retrieved by PCR for sequencing, followed by identification of the candidate genes targeted by the shRNAs. Among 47 candidate genes identified, we focused on Hnrnpll (heterogeneous nuclear ribonucleoprotein L-like) gene encoding a pre-mRNA binding protein involved in pre-mRNA splicing. Hnrnpll knockdown in CMT93 cells significantly increased their matrigel invasion in vitro and lung metastasis in vivo. An RNA-immunoprecipitation analysis identified Cd44 as a candidate target of Hnrnpll. The mRNA level of Cd44 variant 6 (Cd44v6), a splicing variant of Cd44 that had been shown to demarcate colon cancer stem cells driving colon cancer metastasis, was increased by knocking down Hnrnpll in colon cancer cells. Treatment with neutralizing anti-CD44v6 monoclonal antibodies suppressed matrigel invasion of colon cancer cells induced by Hnrnpll knockdown, suggesting that Hnrnpll may suppress invasion and metastasis, at least in part, by modulating the alternative splicing of Cd44. HNRNPLL expression level in colorectal cancer cells was drastically decreased upon induction of epithelial-mesenchymal transition (EMT), accompanied by increased expression of CD44v6. The link between HNRNPLL and EMT was further suggested by immunostaining analysis of clinical samples; colorectal cancer cells with low E-cadherin expression at the invasion front exhibited decreased HNRNPLL expression as compared with those in the tumor center. These results suggest that HNRNPLL is a novel metastasis suppressor in colorectal cancer. Possible mechanisms for regulation of HNRNPLL expression during EMT will also be discussed.
Citation Format: Masahiro Aoki, Eiichi Sasaki, Kenya Kimura, Koji Komori, Yasuhiro Shimizu, Yasushi Yatabe, Keiichiro Sakuma. Identification of HNRNPLL as a novel metastasis suppressor of 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 84.