tbuckley/cabot-search huggingface dataset:
Abstract 4155: ARID1A loss leads to chemotherapy resistance and is associated with a poor clinic outcome for patients with non-small cell lung cancer
Authors: Linlin Yang, Changxian Shen, Xiaokui Mo, Terence M. Williams
Journal: Cancer Research (2020)

Abstract Purpose: ARID1A (AT-rich interactive domain 1A) is a member of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, and plays important roles in the regulation of gene transcription and DNA damage responses. ARID1A mutations occur frequently in non-small cell lung cancer (NSCLC), but the functions of ARID1A loss in the initiation, progression and maintenance of NSCLC remains largely unknown. This study aimed to investigate the clinical, pathological, and functional significance of ARID1A in NSCLC. Experimental design: We first analyzed the prognostic value of ARID1A using a gene-expression microarray from the Director's Challenge Lung Study. Kaplan-Meier method and Log-rank tests were used to estimate the correlation between ARID1A expression and overall survival (OS). Univariate and multivariate Cox regression models were used to investigate the relationship between ARID1A and other clinical covariates. We further established stable ARID1A knockdown H1299 and H358 cell lines, and ARID1A exogenously expressing H460 and A549 cell lines. We performed functional assays to study the effects of ARID1A on proliferation, migration, invasion, cell cycle progression, sensitivity to chemotherapy, and in vivo tumor growth. Results: In the Director's Challenge Study, decreased expression of ARID1A was associated with lymph node dissemination, higher T-stage (T3/T4), and worse survival compared with high expression in patients in the whole group (n=440) and subgroup who received surgery alone and no adjuvant therapy (n=328). ARID1A ablation by shRNA suppressed cell proliferation, promoted cell mobility, increased G2/M phase cell cycle distribution, and protected NSCLC cells from chemotherapy; whereas overexpression of ARID1A showed the opposite biological effects. Consistent with in vitro findings, in vivo tumor xenografts demonstrated ARID1A depletion led to reductions in cell growth but resistance of NSCLC to chemotherapy. Conclusions: Our results suggest that loss of ARID1A suppresses NSCLC cell growth perhaps by inducing G2/M arrest, but promotes cell migration/invasion, and protect cells from chemotherapy. Further study of ARID1A is needed to better define its roles in the initiation and progression of NSCLC and response to chemotherapy. Citation Format: Linlin Yang, Changxian Shen, Xiaokui Mo, Terence M. Williams. ARID1A loss leads to chemotherapy resistance and is associated with a poor clinic outcome for patients with non-small cell lung 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 4155.
Abstract 470: High-dose TSLP decreases in vivo tumor burden in preclinical models of CRLF2 B-ALL
Authors: Caleb Ruiz-Jimenez, Jacqueline Coats, Cornelia Stoian, Ineavely Baez, Hossam Alkashgari, Andy Paz-Aldana, Hannah Choi, Roland Williams, Shadi Farzin Gohar, Sinisa Dovat, Kimberly Payne
Journal: Cancer Research (2020)

Abstract B cell acute lymphoblastic leukemia (B-ALL) is the most common cancer in pediatric patients and children of Hispanic ancestry experience higher incidence and mortality rates than others. While cure rates approach 90%, approximately 10% to 20% of patients still relapse. Genomic profiling has identified Ph-like B-ALL as the subtype at highest risk for relapse. Half of all Ph-like B-ALL overexpress the CRLF2 surface protein (CRLF2+ B-ALL). CRLF2 homodimerizes with the IL-7 receptor alpha (IL-7Ra) to comprise a receptor complex that is activated by the cytokine, Thymic Stromal Lymphopoietin (TSLP). TSLP activates the JAK/STAT and PI3/AKT/mTOR pathways which are known to promote cell survival and proliferation. In vitro studies of CRLF2 B-ALL in our laboratory showed that physiological levels (20 pg/ml) of TSLP could activate the TSLP receptor (indicated by STAT5 and ribosomal protein S6 phosphorylation) when stimulated over time. In contrast, we found that supra-physiological levels of TSLP (1 ng/ml or less) induced an initial activation event, but this was followed by a complete shutdown of CRLF2 downstream signaling events that was maintained in the presence of high TSLP. This signal shutdown was correlated with the loss of surface IL-7Ra. The work presented here evaluates the impact of high dose TSLP vs. physiological levels of TSLP on CRLF2 B-ALL in vivo. We make use of novel PDX/xenograft models that expresses human TSLP (hTSLP, mouse TSLP does not activate human CRFL2) created in our lab. Using in vivo bioluminescence analysis of xenografts produced from the MUTZ5 CRLF2 B-ALL cell line, we found that high dose hTSLP induced an 82% decrease in tumor burden (p &amp;lt; 0.0001) as compared to controls with physiological levels of hTSLP. Ongoing studies are evaluating the effect of high dose TSLP on leukemia burden and prolonged survival in a PDX model produced from a Hispanic pediatric patient with CRLF2 B-ALL. Results from these studies will be presented. Taken together, these data suggest that TSLP has promise as a biologic for the treatment of CRLF2 B-ALL. This work was supported by NIH NCI award R01 CA209829 (KJP &amp; SD). Citation Format: Caleb Ruiz-Jimenez, Jacqueline Coats, Cornelia Stoian, Ineavely Baez, Hossam Alkashgari, Andy Paz-Aldana, Hannah Choi, Roland Williams, Shadi Farzin Gohar, Sinisa Dovat, Kimberly Payne. High-dose TSLP decreases in vivo tumor burden in preclinical models of CRLF2 B-ALL [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 470.
Abstract 589: Immune biomarker profiling and safety evaluation response to 4-1BB antibody (Urelumab) in humanized 4-1BB mice
Authors: Jie Xiang, Dirui Li, Hao Yang, Gary Ng, Yuelei Shen
Journal: Cancer Research (2020)

Abstract 4-1BB (CD137) belongs to the TNFR superfamily and is expressed by activated CD4 helper T cells, B cells, natural killer cells, natural killer T cells, dendritic cells and Treg cells. 4-1BB is a potential therapeutic target as it enhances tumor rejection by upregulating T cells following activation and its engagement increases T cell proliferation and pro-inflammatory cytokine production. However, the liver toxicity associated with over immune activation has obstructed the clinical development of 4-1BB targeting therapies. To address the issue, Biocytogen has developed humanized B-h4-1BB mice as an efficient platform of both in vivo MOA and safety studies of 4-1BB antibody. In B-h4-1BB mice, murine colon cancer MC38 cells were subcutaneously implanted. Biomarkers, such as, mCD45, mCD3, mCD4, mCD8, mNK, mFoxp3, mCD11b, and etc., were profiled after the treatment with an 4-1BB antibody (Urelumab). FACS, IHC, and IF data showed that Urelumab have increased the ratio of CD8+ T cell, but on the other hand decreased Treg cell, the PD-1 and Tim3 (T cell exhausted marker) upon treatment. Toxicity have also been with the treatment of Urelumab using this model. The blood chemistry assays showed that the high dose Urelumab had toxicity effects compared with the control group and WT C57BL/6 mice. Based on these findings, we conclude that the B-h4-1BB humanized mouse model is a powerful platform for both MOA (biomarker) discovery and safety evaluation of 4-1BB antibody. Citation Format: Jie Xiang, Dirui Li, Hao Yang, Gary Ng, Yuelei Shen. Immune biomarker profiling and safety evaluation response to 4-1BB antibody (Urelumab) in humanized 4-1BB mice [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 589.
Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial
Authors: Remo H M Furtado, Otavio Berwanger, Henrique A Fonseca, Thiago D Corrêa, Leonardo R Ferraz, Maura G Lapa, Fernando G Zampieri, Viviane C Veiga, Luciano C P Azevedo, Regis G Rosa, Renato D Lopes, Alvaro Avezum, Airton L O Manoel, Felipe M T Piza, Priscilla A Martins, Thiago C Lisboa, Adriano J Pereira, Guilherme B Olivato, Vicente C S Dantas, Eveline P Milan, Otavio C E Gebara, Roberto B Amazonas, Monalisa B Oliveira, Ronaldo V P Soares, Diogo D F Moia, Luciana P A Piano, Kleber Castilho, Roberta G R A P Momesso, Guilherme P P Schettino, Luiz Vicente Rizzo, Ary Serpa Neto, Flávia R Machado, Alexandre B Cavalcanti
Journal: The Lancet (2020)
Abstract 1377: Identification and validation of WRN as a novel synthetic lethality target in context of microsatellite instability
Authors: Zhihu (Jeff) Ding, Jing Zhang, Chandra Sekhar Pedamallu, Steve Rowley, Jane Cheng, Shujia Dai, Bridget Zhou, Malvika Koundinya, Zhuyan Guo, Stephane Poirier, Joern Hopke, Amanda Lennon, Jennifer Buell, May Cindhuchao, Karen Wong, Emma Wang, Alexei Protopopov, Bailin Zhang, Dietmar Hoffmann, Fangxian Sun, Jack Pollard, Laurent Debussche, Monsif Bouaboula
Journal: Cancer Research (2020)

Abstract Despite the significant clinical success of the Immuno-Oncology treatment of microsatellite instability (MSI) patients, there remains huge unmet medical need because of mechanisms of resistance. Through an effort to analyze publicly available large-scale shRNA screening and CRISPR screening, we surprisingly found that WRN is a potent synthetic lethality target in the context of MSI. WRN is an enzyme known as the “Werner syndrome ATP-dependent helicase”. WRN is involved in multiple cellular functions, including DNA repair and telomere maintenance. Silencing of WRN by RNAi and CRISPRi in a panel of MSI-H cells lead to tumor cell growth inhibition in vitro and in vivo, thus demonstrated WRN is a novel synthetic lethality target in context of MSI. Our discovery has recently been cross-validated by multiple independent studies1-4. Furthermore, we also report here the first time that silencing of WRN by RNAi and CRISPRi in DLD1, a MSI-H cell, does not lead to tumor cell inhibition. Taken together, our data using independent genetic approach CRISPRi in vitro and in vivo, further highlight fundamental importance of WRN as a synthetic lethality target in some, but not all, MSI context. References: 1 Chan E.M. et al. (2019). Nature. 568(7753):551-556. 2 Behan F.M. et al (2019). Nature. 2019 568(7753):511-516. 3 Kategaya L. et al. (2019). iScience. 13:488-497. 4 Lieb S. et al. (2019). Elife. 8. pii: e43333. Citation Format: Zhihu (Jeff) Ding, Jing Zhang, Chandra Sekhar Pedamallu, Steve Rowley, Jane Cheng, Shujia Dai, Bridget Zhou, Malvika Koundinya, Zhuyan Guo, Stephane Poirier, Joern Hopke, Amanda Lennon, Jennifer Buell, May Cindhuchao, Karen Wong, Emma Wang, Alexei Protopopov, Bailin Zhang, Dietmar Hoffmann, Fangxian Sun, Jack Pollard, Laurent Debussche, Monsif Bouaboula. Identification and validation of WRN as a novel synthetic lethality target in context of microsatellite instability [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 1377.
The Close Link of Pancreatic Iron With Glucose Metabolism and With Cardiac Complications in Thalassemia Major: A Large, Multicenter Observational Study
Authors: Alessia Pepe, Laura Pistoia, Maria Rita Gamberini, Liana Cuccia, Angelo Peluso, Giuseppe Messina, Anna Spasiano, Massimo Allò, Maria Grazia Bisconte, Maria Caterina Putti, Tommaso Casini, Nicola Dello Iacono, Mauro Celli, Angelantonio Vitucci, Pietro Giuliano, Giuseppe Peritore, Stefania Renne, Riccardo Righi, Vincenzo Positano, Vincenzo De Sanctis, Antonella Meloni
Journal: Diabetes Care (2020)

We systematically explored the link of pancreatic iron with glucose metabolism and with cardiac complications in a cohort of 1,079 patients with thalassemia major (TM) enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project.MRI was used to quantify iron overload (T2* technique) and cardiac function (cine images) and to detect macroscopic myocardial fibrosis (late gadolinium enhancement technique). Glucose metabolism was assessed by the oral glucose tolerance test (OGTT).Patients with normal glucose metabolism showed significantly higher global pancreas T2* values than patients with impaired fasting glucose, impaired glucose tolerance, and diabetes. A pancreas T2* <13.07 ms predicted an abnormal OGTT. A normal pancreas T2* value showed a 100% negative predictive value for disturbances of glucose metabolism and for cardiac iron. Patients with myocardial fibrosis showed significantly lower pancreas T2* values. Patients with cardiac complications had significantly lower pancreas T2* values. No patient with arrhythmias/heart failure had a normal global pancreas T2*.Pancreatic iron is a powerful predictor not only for glucose metabolism but also for cardiac iron and complications, supporting the close link between pancreatic iron and heart disease and the need to intensify iron chelation therapy to prevent both alterations of glucose metabolism and cardiac iron accumulation.
Abstract 5230: Real-time monitoring of PROTAC and molecular glue targeted degradation in living cells
Authors: Neal C. Cosby, Kristin M. Riching, Sarah Mahan, Elizabeth A. Caine, Danette L. Daniels, Marjeta Urh
Journal: Cancer Research (2020)

Abstract The emergence of targeted protein degradation as a broad, new therapeutic modality has greatly expanded the opportunities for treatments of many diseases. Currently, small molecule degrader compounds fall under two major categories; molecular glues and heterobifunctional PROTACs. The two types of compounds both facilitate and induce a ternary complex consisting of an E3 ligase-degrader-target protein, bringing into proximity the machinery proteins required to ubiquitinate and ultimately degrade the target protein. Significant challenges exist in characterization and rank-ordering of degradation compounds in live cells given the differences in dynamics of protein loss and recovery among compounds. Currently, the availability of technologies to interrogate real-time protein degradation is severely lacking. Here, we present a live-cell, luminescence-based technology platform with these capabilities. We employ CRISPR/Cas9 endogenous tagging of target proteins with the small peptide, HiBiT, which has high affinity for and can complement with the LgBiT protein to produce NanoBiT luminescence. This allows for sensitive detection of endogenous protein levels in living cells, and can also serve as a BRET energy donor to study protein:protein or protein:small molecule interactions. We demonstrate the power of this technology in continuous 24-hour monitoring of endogenous target protein levels, and the ability to quantify key degradation parameters for compound ranking including rate, Dmax, and DMax50. We further show the ability to measure the mechanistic steps important for the degradation including kinetics of PROTAC- or molecular glue-induced ternary complex formation and target ubiquitination. These studies facilitate discernment of individual parameters required for successful degradation, ultimately enabling chemical design strategies for optimization and rank ordering of therapeutic degradation compounds. Citation Format: Neal C. Cosby, Kristin M. Riching, Sarah Mahan, Elizabeth A. Caine, Danette L. Daniels, Marjeta Urh. Real-time monitoring of PROTAC and molecular glue targeted degradation in living 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 5230.
Abstract 319: Impact of chemotherapy on lung cancer cells and their microenvironment, evaluated in tridimensional multicellular tumor spheroids
Authors: Pauline Hulo, Sophie Deshayes, Virginie Dehame, Marc Grégoire, Jaafar Bennouna, Christophe Blanquart
Journal: Cancer Research (2020)

Abstract Introduction: Pembrolizumab, an anti-PD1 antibody, is approved in non pretreated advanced Non Small Cell Lung Cancer (NSCLC) with high expression of PD-L1, more than 50 %, on tumor cells. Conversely, the combination of platinum-based chemotherapy + pembrolizumab in this indication is not restricted to the level of PD-L1 expression. This suggests that chemotherapy could sensitize tumor tissue to Immune Checkpoint Inhibitors (ICIs). Based on those clinical datas, we propose to evaluate the impact of chemotherapy on tumor cells and on their microenvironment by using tridimensional multicellular tumor spheroids (MCTS). Material and methods: MCTS integrated lung adenocarcinoma cells expressing GFP, fibroblasts with ruby fluorescent protein and monocytes/macrophages from healthy donors. MCTS were treated with repeated and combined chemotherapy drugs (carboplatin and gemcitabine, or carboplatin and paclitaxel), reproducing therapeutic schedules. Different biological factors were analysed : impact of chemotherapy on MCTS morphology, cell viability, invasion abilities, modifications in genes and protein expression profiles using differential gene expression sequencing (DGE-Seq) and flow cytometry, respectively. Results: Chemotherapy decreased MCTS size and cell viability. Whereas carboplatin/gemcitabine mainly affected lung cancer cells inside MCTS, carboplatin/paclitaxel seemed to be cytotoxic mainly on peripheral malignant cells. Fibroblasts were resistant to chemotherapy, unlike macrophages which were strongly affected. A large RNA analysis was performed using DGE-Seq and showed that expression of several genes, and notably of CD274 (PD-L1) and CD273 (PD-L2), were induced after treatment. We confirmed PD-L1 up-regulation byflow cytometry. Conclusion: Platinium-based chemotherapy up-regulate immune checkpoints expression in lung cancer cells. Our results are in line with the latest studies performed in mice. They underline that our MCTS model is closed to in vivo conditions. It could be developedas a drug screening tool. Citation Format: Pauline Hulo, Sophie Deshayes, Virginie Dehame, Marc Grégoire, Jaafar Bennouna, Christophe Blanquart. Impact of chemotherapy on lung cancer cells and their microenvironment, evaluated in tridimensional multicellular tumor spheroids [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 319.
Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention
Authors: Dhavalkumar D. Patel, James B. Bussel
Journal: Journal of Allergy and Clinical Immunology (2020)

The humoral immune response provides specific, long-lived protection against invading pathogens, via immunoglobulin production and other memory functions. IgG, the most abundant immunoglobulin isotype, has the longest half-life and protects against bacterial and viral infections. The neonatal Fc receptor (FcRn) transports IgG across barriers, for example, the placenta, enhancing fetal humoral immunity to levels similar to their mothers'. Importantly, FcRn, by protecting IgG from intracellular degradation, results in an approximately 21-day circulating IgG half-life and high plasma levels; similarly, FcRn recycles albumin and is the portal of entry for enteric cytopathic human orphan (echo) virus infection. Dysregulated immune responses may lead to antibodies against self-antigens (autoantibodies), resulting in organ-specific or systemic autoimmune diseases. Autoantibody-mediated diseases have been treated by nonspecific immunoglobulin-lowering/modulating therapies, including immunoadsorption, plasma exchange, and high-dose intravenous immunoglobulin. However, targeting FcRn with specific inhibitors results in reduction in only IgG levels. The effectiveness of FcRn inhibitors in autoimmune diseases, including myasthenia gravis and immune thrombocytopenia, provides further evidence that IgG is a primary driver in these autoantibody-mediated diseases. We describe the role of FcRn in human biology, including insights that clinical testing of FcRn inhibitors have provided into FcRn biology and autoimmune disease mechanisms, allowing fact-based speculation on their therapeutic potential.
Abstract 3731: Targeting the isocitrate dehydrogenase 1 (IDH1) metabolic enzyme in prostate cancer
Authors: Kevin Gonthier, Cindy Weidmann, Lilianne Frégeau-Proulx, Étienne Audet-Walsh
Journal: Cancer Research (2020)

Abstract Prostate cancer cells (PCa) are dependent on the androgen receptor (AR) for their aberrant proliferation and survival. We have recently discovered that AR induces a reprogramming of PCa cell metabolism by controlling the cytoplasmic wild-type enzyme isocitrate dehydrogenase 1 (IDH1), which results in an enhanced proliferation of tumour cells. However, the specific metabolic functions of IDH1 in PCa or how to use the reliance of tumour cells on this enzyme as a therapeutic avenue, is elusive. In in vitro human PCa models, we showed that IDH1 protein levels and activity are increased in an AR-dependent manner. Using pharmacological and genetic tools, we showed that IDH1 is a major contributor to the replenishment of NADPH levels in PCa. This cofactor plays a key role in the synthesis of biomaterials required for cellular division, and our results indicate that IDH1 contribute to 30-40% of total cellular NADPH levels. In that context, blockade of IDH1 was shown to alter the mTOR signaling, a central regulator of cellular anabolism, which is linked to decreased cellular proliferation rates. FDA-approved pharmacological inhibitors of mutant IDH1 significantly inhibited IDH activity and proliferation in PCa cells, suggesting that such inhibitors could be used to treat PCa patients even in absence of IDH1 mutation. Globally, our results demonstrate that IDH1 is a key player in proliferative anabolic pathways in PCa. Importantly, they also support the hypothesis that inhibition of IDH1 using already-approved molecules represents one viable therapeutic solution. Citation Format: Kevin Gonthier, Cindy Weidmann, Lilianne Frégeau-Proulx, Étienne Audet-Walsh. Targeting the isocitrate dehydrogenase 1 (IDH1) metabolic enzyme in prostate 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 3731.