bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3109: Protein stability screen to identify compounds destabilizing EWS-FLI1 in Ewing sarcoma
Authors: Pedot Gloria , Niggli Felix K. , Schaefer Beat W. 
Published: August 2019

Abstract
Ewing sarcoma is an aggressive pediatric bone and soft tissue tumor driven by the expression of a fusion oncoprotein named EWS-FLI1, which acts as an oncogenic transcription factor. Tumor cells are strictly dependent on continuous expression of the fusion protein, since downregulation of EWS-FLI1 inhibits tumor growth. Therefore, interference with the fusion oncoprotein turnover is critical for the modulation of tumor cell proliferation and survival. We demonstrated previously that EWS-FLI1 is predominantly a proteasomal substrate with high turnover mediated by poly-ubiquitination at one specific lysine. This study provided novel insights into the crucial importance of targeting EWS-FLI1 stability as novel strategy for the treatment of Ewing sarcoma. Hence, we aimed at identifying compounds that destabilize EWS-FLI1 with subsequent reduction of tumor cell growth by performing a screen of 2’486 FDA-Approved drugs and 204 novel targeted compounds in a Ewing sarcoma reporter cell line. To this, we adopted a Global Protein Stability approach as novel read-out (Global protein stability profiling in mammalian cells, Science, 2008), which relies on a reporter construct expressing two fluorescent dyes from one mRNA to monitor changes in stability of EWS-FLI1 by high-throughput flow cytometry. This drug screen identified two main enriched classes of inhibitors that significantly destabilize EWS-FLI1. Validation of these results and characterization of their mechanism of action is currently under way. We conclude that the study of EWS-FLI1 turnover represents a novel approach to identify new effective drugs that can be used as monotherapy or in combination with other drugs as novel treatment opportunities in Ewing sarcoma.
Citation Format: Gloria Pedot, Felix K. Niggli, Beat W. Schaefer. Protein stability screen to identify compounds destabilizing EWS-FLI1 in Ewing sarcoma [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 3109.
Abstract 312: Hypoxia induces EGFR inhibitor resistance in lung cancer cells via fibroblast growth factor receptor 1 (FGFR1) by promoting epithelial-mesenchymal transition (EMT)
Authors: Lu Yuhong , Zhang Gary J. , Glazer Peter M. 
Published: August 2019

Abstract
The development of small molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due in part to acquired resistance to conventional therapy. In this study, we show that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation. We also found that hypoxia induces resistance to the third generation EGFR TKI, osimernitib, in the NSCLC cell line, H1975, which developed resistance to first and second EGFR TKI resistance by harboring a second EGFR mutation, T790M. Following growth in hypoxia, HCC827 and H1975 cells show increased N-cadherin expression with downregulation of E-cadherin, characteristics of an epithelial-mesenchymal transition (EMT), which prior studies have linked to EGFR TKI resistance. Mechanistically, we show that hypoxia increases fibroblast growth factor receptor 1 (FGFR1) expression in both HCC827 and H1975 cells, accompanied by down regulated BIM expression. ZEB1, an EMT activator, was also increased by hypoxia in HCC827 H1975 cells. Knockdown of the FGFR1 by shRNA can attenuate gefitinib resistance in HCC827 cells and osimerinitib resistance in H1975 cells, respectively. Inhibition of FGFR1 function by the small molecular inhibitor, ponatinib, resensitizes hypoxia-induced resistant HCC827 clones to gefitinib treatment, and also attenuates osimerinitib resistance in hypoxic H1975 cells. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased FGFR1 expression and coordination of EMT in NSCLC. The combination of EGFR TKIs and FGFR1 inhibitors may offer an attractive therapeutic strategy for NSCLCs.
Citation Format: Yuhong Lu, Gary J. Zhang, Peter M. Glazer. Hypoxia induces EGFR inhibitor resistance in lung cancer cells via fibroblast growth factor receptor 1 (FGFR1) by promoting epithelial-mesenchymal transition (EMT) [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 312.
Abstract 3147A: The use of the sTRA glycan for predicting responses to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma
Authors: Staal Ben , Liu Ying , Hsueh Peter , Aldakkak Mohammed , Zeh Herbert , Evans Douglas , Brand Randall E. , Tsai Susan , Haab Brian B. 
Published: August 2019

Abstract
The sTRA glycan has been validated as a serological and cell-surface biomarker of pancreatic ductal adenocarcinoma (PDAC). In previous work, a biomarker panel using sTRA and CA19-9 performed significantly better than CA19-9 for distinguishing PDAC from benign diseases of the pancreas; here we explored whether the subgroup identified by sTRA has a different prognosis than other subgroups. We examined the plasma levels of sTRA and CA19-9 in two cohorts of patients with resectable or borderline-resectable PDAC. In each cohort, two samples per patient were collected: one prior to any therapy, and another after neoadjuvant therapy but before surgery. In the first cohort (n = 54), the ratio of post-therapy to pre-therapy plasma sTRA was statistically higher (p &lt; 0.05, student’s t-test using logged ratios) in patients with poor response, as assessed by surgical pathology. CA19-9 had higher ratios in a subset of the poor-response subjects but without statistical significance. In the second cohort (n = 75), the pre-treatment and post-treatment levels of sTRA were significantly higher (p &lt; 0.01, Wilcoxon Rank-Sum test) in patients with shorter survival (&lt;2 years). In contrast, CA19-9 did not show statistical significance in the pre-treatment or post-treatment levels, but the post:pre ratios were substantially higher in a subset of the short-survival group. In both cohorts, sTRA identified a subset of poor responders that was non-identical to the one identified by CA19-9. As a result, a biomarker panel combining the markers provided better accuracy for identifying poor responders than either marker alone. In an analysis of 24 cell line models of PDAC, the cell lines that secreted sTRA had a statistically higher resistance to chemotherapy than those not secreting sTRA, whereas the cell lines secreting CA19-9 showed no such association. Therefore, pancreatic cancers that produce sTRA may be a distinct subtype with higher resistance to chemotherapy, and sTRA in combination with CA19-9 could be a valuable serological predictor of responsiveness to chemotherapy.
Citation Format: Ben Staal, Ying Liu, Peter Hsueh, Mohammed Aldakkak, Herbert Zeh, Douglas Evans, Randall E. Brand, Susan Tsai, Brian B. Haab. The use of the sTRA glycan for predicting responses to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma [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 3147A.
Abstract 3176: Biomarker identification using xenograft mouse model based clinical trial simulation and artificial intelligence data analytics
Authors: Afshar M , Bichat Francis , Duchamp Olivier , Etcheto A , France Damien , Kindermans M , Mignard Caroline , Parmentier F , Ratsima Hery 
Published: August 2019

Abstract
The growing number of anti-cancer drugs available at different stages of clinical development combined with the broadening potential use of combination therapy further complexifies the early identification of companion markers, markers of synergy as well as novel indications for existing and new drug combinations. Well characterized patient derived xenograft mouse models (PDX), combined with Artificial Intelligence tools that can integrate and analyze the broad range of generated data can help address this challenge. PDX experiments can providing an opportunity to simulate a clinical assessment using multiple mice models.In this study, we developed a PDX platform combined with the KEM® Artificial Intelligence data analytics, that is based on Formal Concept Analysis, to simulate a clinical trial and identify biomarkers of response. The platform was tested on colon cancer patient derived PDX. Respectively mRECIST response and survival of respectively 21 and 26 PDXs against Oxalipaltin combined with 5-Fluorouracil and folinic acid (Folfox) was experimentally assessed against a placebo, simulating a clinical trial-like setting with 2 arms. Biomarkers of response (mRECIST) and survival were identified using KEM®, combined with statistical modelling (Cox survival-modelling). 24 candidate biomarker genes were identified including PGAP3, ERBB2, NOTCH2, WDR70, and ZNF227. Alone or combined, these biomarkers are significantly linked to an increase or decrease of the survival PDX (p ranging from 2.2e-10 to 0.048, odd-ratio ranging from 0.12 to 10.00), with the potential to be used as inclusion or exclusion biomarkers. This work demonstrates the ability of a combined PDX / Artificial Intelligence platform to simulate clinical trials and identify biomarkers of drug efficacy and synergy, thus fostering the design of precision medicine clinical trials.
Citation Format: M Afshar, Francis Bichat, Olivier Duchamp, A Etcheto, Damien France, M Kindermans, Caroline Mignard, F Parmentier, Hery Ratsima. Biomarker identification using xenograft mouse model based clinical trial simulation and artificial intelligence data analytics [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 3176.
Abstract 3178: Comparative study of methods and platforms for T-cell receptor repertoire
Authors: Dutta Mukta , Smit Mariya , Collins Heather , Malge Anjali , Anderson Steve , Braastad Corey 
Published: August 2019

Abstract
High-throughput sequencing technologies facilitate in-depth sequencing of T-cell receptor (TCR) repertoires to gain insights into human adaptive immunity. These studies can help decipher the diversity of T-cell receptors, relevant to physiological and disease conditions, and potential therapy responses. A variety of TCR kits and programs have been developed for the identification of V, D and J gene segments, complementarity-determining region 3 (CDR3) sequence extraction and clonality analysis. However, there is still a deficit of systematic comparative studies to assist in the selection of an optimal platform. Here, we present a detailed comparison of 4 state-of-the-art TCR platform on samples with different complexities (ranging from cancers to immune disorders) by taking into account aspects such as clonotype detection [unique V(D)J combination] and CDR3 identification. Our results provide new insights into the effect of method selection on analysis results, and will consequently inform users in the selection of an appropriate analysis method for the desired application(s).
Citation Format: Mukta Dutta, Mariya Smit, Heather Collins, Anjali Malge, Steve Anderson, Corey Braastad. Comparative study of methods and platforms for T-cell receptor repertoire [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 3178.
Abstract 3181: A novel, bioluminescent assay for the selective detection of target cell killing in mixed cultures
Authors: Binkowski Brock , Paguio Aileen , Eggers Christopher , Butler Braeden , Beck Michael , Fan Frank 
Published: August 2019

Abstract
Efforts to develop and commercialize T cell immunotherapies would benefit from sensitive and easy-to-use assays to monitor target cell killing. We have developed an approach to selectively measure the death of target cells mediated by CAR/TCR-T cells or other types of effector cells. The method relies on the release of a HiBiT-tagged protein from target cells following cell lysis. Once released, HiBiT, an 11 a.a. peptide tag, binds to cell-impermeable Large BiT (LgBiT), a 17.6 kDa protein, to reconstitute NanoBiT Luciferase. In the presence of furimazine substrate, the luminescent signal is proportional to the amount of target cell killing, and cell lysis can be quantified at a single time point using Maximum Release and Spontaneous Release controls. The assay is compatible with a wide range of target cells per well (e.g. 100-500,000 cells/well), and low levels of Spontaneous Release allow the sensitive detection of low levels of target cell lysis (e.g. 1-5%). Using a modified format, target cell killing can be measured continuously in a bench-top luminometer for 24 hours or more. We demonstrate these approaches using commercially available CAR-T cells and target cells stably expressing a HiBiT-tagged protein via random integration of plasmid DNA or viral transduction. We also demonstrate the use of a thaw-and-use format to facilitate MOA-based lot release assays. The approach provides simple, non-radioactive assay formats for selectively monitoring target cell killing in mixed culture experiments.
Citation Format: Brock Binkowski, Aileen Paguio, Christopher Eggers, Braeden Butler, Michael Beck, Frank Fan. A novel, bioluminescent assay for the selective detection of target cell killing in mixed cultures [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 3181.
Abstract 3182: Directed screening TCRs against Ras mutations in mCRC patients
Authors: Yuan Jijun 
Published: August 2019

Abstract
Ras gene is involved in many signaling pathway to regulate cell proliferation, metabolism and motility, for example MAPK and PI3K pathway. Ras mutation is constitutively active to drive uncontrolled cell proliferation that results in malignant transformation. Ras mutation frequently occurs in human malignancy, for example pancreatic cancer (98%), colorectal cancer (45%) and lung cancer (31%). Drug development targeting Ras mutation was not succeed despites decades of effort in small molecule fields.
T cell receptor (TCRs) can recognize processed and presented neoantigens on human leukocytes antigen (HLA). Ras G12D mutation was report as neoantigen and could be recognized by tumor infiltrating lymphocytes restricted by HLA-C0802 in mCRC patients. We assume that human TCR repertoire encompassing specific TCRs against Ras mutation restricted by other HLAs in Chinese patients.
We design a novel synthetic presentation mRNA construct which harboring all pathogenic Ras mutations. The construct significantly enhanced Ras mutation peptides presentation on HLAs (&gt;60%) compared with conventional used construct. We developed a directed screening method to identify T cell clone against Ras mutation restricted by Chinese pop HLAs in tumor infiltrating lymphocytes and sequenced TCRs by using 10xGenomics. We identified several TCRs that showed effector function against Ras mutation in China mCRC patients for further developing TCR-T cell therapy.
Citation Format: Jijun Yuan. Directed screening TCRs against Ras mutations in mCRC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3182.
Abstract 3184: Targeting multiple solid tumor types with anti-CD70 allogeneic CAR-T cells
Authors: Dequeant Mary Lee , Karnik Sushant , Padalia Zinkal , Tham Minh Thu , Ho Tony , Carson Julie , Terrett Jonathan A. 
Published: August 2019

Abstract
CD70 (CD27 ligand) is highly expressed in multiple hematologic malignancies, such as non-Hodgkin lymphoma, multiple myeloma, and chronic lymphocytic leukemia, and is uniquely highly expressed in the solid tumor type clear cell renal cell carcinoma (ccRCC). Malignancies showing high CD70 expression have been the subject of multiple clinical trials evaluating anti-CD70 agents, such as antibodies with enhanced antibody-dependent cell-mediated cytotoxicity and antibody drug conjugates (ADCs). The focus on high expression indications seems to be a requirement, particularly for ADCs. We have shown previously that CTX130, a CRISPR/Cas9 gene-edited allogeneic anti-CD70 CAR-T, is potently cytotoxic against even the lowest expressing RCC cells (e.g. ACHN). With this in mind, we evaluated CD70 expression in other solid tumor indications, including pancreatic, lung, and ovarian cancers, and assessed the cytotoxic activity of CTX130 against cell lines derived from these tumor types. These studies show that high expression is not a requirement for potent activity for CAR-T cells as it appears to be for CD70-targeted ADCs. Further, these data highlight a translational medicine route for CTX130 in many solid tumor indications.
Citation Format: Mary Lee Dequeant, Sushant Karnik, Zinkal Padalia, Minh Thu Tham, Tony Ho, Julie Carson, Jonathan A. Terrett. Targeting multiple solid tumor types with anti-CD70 allogeneic CAR-T 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 3184.
Abstract 3185: CAR-T cells can eradicate human uveal melanoma and immune-therapy resistant malignant melanoma in IL-2 transgenic NOD/SCID IL2 receptor gamma knockout mice
Authors: Forsberg Elin , Lindberg Mattias , Jespersen Henrik , Alsén Samuel , Bagge Roger Olofsson , Donia Marco , Svane Inge Marie , Nilsson Ola , Ny Lars , Nilsson Lisa , Nilsson Jonas 
Published: August 2019

Abstract
Immune therapies including checkpoint blockade and adoptive T cell transfer show great promise for the treatment of melanoma, with long-term effects in some patients. However, not all patients respond to current immune therapies and are in need of other treatment strategies. For example, around half of the patients with metastatic malignant melanoma will not be cured with available therapies today. For metastatic uveal melanoma (a rare melanoma of the eye) available immune therapies have less effect, and there is currently no approved therapy for these patients. Our objective is to find novel immune therapies with the potential to treat immune-therapy resistant melanoma, with the use of chimeric antigen receptor T cells (CAR-T). So far, no CAR-T therapy is approved for use in solid tumors. We have previously developed a humanized mouse model, where tumor cells and T cells from the same patient are grafted in IL-2 transgenic NOD/SCID IL2 receptor gamma knockout (NOG) mice, and found that responses in the mouse model correlated to responses in the corresponding patients in a clinical trial of adoptive T cell transfer (Jespersen et al, Nature Communications, 2017). In order to test the potential for CAR-T therapy in immune-therapy resistant melanoma in this mouse model, we used TCGA to determine the expression in melanoma biopsies of targets for commercially available CAR-T cells. Interestingly, we were able to use this model to treat immune-therapy resistant malignant melanoma and uveal melanoma patient-derived xenografts with human CAR-T cells and obtain curative responses, but only in IL-2 transgenic mice and not in regular NOG mice. These findings prove potential for the use of CAR-T cell therapy in immune-therapy resistant melanoma, and indicate the utility of this mouse model in the translation of CAR-T therapies. We are currently working on the development of CAR-T cells derived from patient-specific T cells.
Citation Format: Elin Forsberg, Mattias Lindberg, Henrik Jespersen, Samuel Alsén, Roger Olofsson Bagge, Marco Donia, Inge Marie Svane, Ola Nilsson, Lars Ny, Lisa Nilsson, Jonas Nilsson. CAR-T cells can eradicate human uveal melanoma and immune-therapy resistant malignant melanoma in IL-2 transgenic NOD/SCID IL2 receptor gamma knockout mice [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 3185.
Abstract 3193: Combining immunotherapies: A strategy for improving CD8 T cell-mediated antitumor responses
Authors: Fan Aaron E. , Sultan Hussein , Kumai Takumi , Celis Esteban 
Published: August 2019

Abstract
Adoptive cell therapy (ACT) of retrovirally transduced (RV) CD8 T cells is a powerful technique that has shown promise in tumor eradication in cancer patients. However, some major barriers to current methods are that ACT is expensive, time consuming, and requires harmful and toxic adjunct procedures. Our laboratory has demonstrated the use of TriVax, a potent peptide vaccination strategy that dramatically expands ACT cell populations and bypasses the necessity for adjunct procedures. The purpose of this project was to enhance current methods of ACT+TriVax by testing an antigen-specific antitumor response of RV CD8 T cells and if it could be improved with constitutively active STAT5 (CA-STAT5) expression, a protein activated downstream several cytokine pathways that have been shown to play a role in increasing CD8 T cell persistence and resistance to apoptosis. We tested the hypothesis that CA-STAT5 in CD8 T cells enhances an antitumor effect by increasing T cell persistence and efficacy.
Our results show that TriVax administration selectively expanded frequencies of the ACT cell population expressing gp100-TCR in both blood and spleen. When co-transduced with CA-STAT5, an even higher fold expansion of antigen-specific cells was observed. +CA-STAT5 T cells were able to expand more robustly than -CA-STAT5 T cells upon repeated antigen stimulation (vaccine boost), demonstrating nearly 4000-fold increases in antigen-specific CD8 T cells. +CA-STAT5 T cells also seemed to persist longer in vivo over time, and they expressed lower levels of surface PD-1. Using B16F10 melanoma, ACT+TriVax of these cell populations into tumor-bearing mice demonstrated a powerful antitumor effect, leading to tumor regression in treated groups. CA-STAT5 seemed to recapitulate similar antitumor effects our laboratory observed previously with combinatorial anti-PD-L1 treatment or IL2/anti-IL2 mAb complexes (IL2Cx), suggesting a potential role for STAT5 in resisting the PD-1/PD-L1 inhibitory pathway. When compared to tumor-bearing mice treated with ACT+TriVax with anti-PD-L1 antibody, our approach using +CA-STAT5 T cells generated a comparable antitumor response. Altogether, these results demonstrate that RV CD8 T cells expressing gp100-TCR and CA-STAT5 are capable of antigen-dependent expansion in response to TriVax. CA-STAT5 plays a role in increasing T cell proliferation and persistence, as well as increasing efficacy through mechanisms that seem to indicate resistance to PD-1/PD-L1 inhibition.
Citation Format: Aaron E. Fan, Hussein Sultan, Takumi Kumai, Esteban Celis. Combining immunotherapies: A strategy for improving CD8 T cell-mediated antitumor responses [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 3193.