bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C084: Crizotinib resistance mechanisms and potential therapeutic strategies to overcome the resistance in ROS1-rearranged non-small cell lung cancer
Authors: Katayama Ryohei , Gong Bo , Nishio Makoto , Fujita Naoya 
Published: March 2020

Abstract
ROS1 rearrangement was observed in about 1 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. To date, crizotinib, an ALK/ROS1 inhibitor was approved and widely used for the treatment of ROS1 rearranged NSCLC. However, the tumor relapses within a few years due to the emergence of crizotinib resistance by the secondary mutations in ROS1 kinase domain (e.g. G2032R) or other unidentified mechanisms. In this study, we explored crizotinib resistance mechanisms using ENU mutagenesis screening and the analysis of crizotinib resistant patient’s pleural effusion. We found several secondary mutations in ROS1 kinase domain including previously reported mutations. From a crizotinib resistant patient’s specimen, no secondary mutation in ROS1 was observed. By establishing a cell line from the specimen, we performed kinase inhibitor screening combined with crizotinib, and found that a combination of crizotinib with dasatinib or a few other tyrosine kinase inhibitors can suppress the growth. These results suggested that a bypass pathway mediated resistance through Src family kinase conferred resistance in this crizotinib resistant case. For overcoming the secondary ROS1 mutations mediated crizotinib resistance, we characterized several ROS1 inhibitors including a new selective ROS1/NTRK inhibitor DS-6051b in preclinical models of ROS1-rarranged cancers by newly establishing cell lines from TKI naïve ROS1 fusion positive NSCLC patients, or developing resistant mutation harboring HCC78 (SCL34A2-ROS1) or Ba/F3-CD74-ROS1 cell line models. Using these preclinical models, we demonstrated that DS-6051b induced dramatic growth inhibition of both wild type and G2032R mutant ROS1–rearranged cancers in vitro and in vivo, suggesting that DS-6051b might be effective in treating wildtype and crizotinib resistant mutant ROS1-rearranged lung cancer. This study revealed that potential resistance mechanisms in ROS1-rearranged NSCLC are similar to those identified in ALK rearranged NSCLC, and next-generation ROS1 inhibitor provides future promising therapeutic strategies to overcome the secondary mutation mediated resistance.
Citation Format: Ryohei Katayama, Bo Gong, Makoto Nishio, Naoya Fujita. Crizotinib resistance mechanisms and potential therapeutic strategies to overcome the resistance in ROS1-rearranged non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C084. doi:10.1158/1535-7163.TARG-19-C084
Abstract C126: A new therapeutic strategy for cancers with transcription elongation defects
Authors: Muhammad Belal 
Published: March 2020

Abstract
Increasing evidence suggest that the tumorigenic process is driven by various forms of transcriptional and epigenetic defects beyond somatic mutations. We recently described a novel non-genomic phenomenon associated with tumorigenesis that we call Transcription Elongation Defects (TEdeff), which is characterized by high levels of truncated transcripts, intron retention, and loss of gene body exon expression. The TEdeff phenotype exists in more than 20% of all human tumors and is linked to immunotherapy resistance (Modur et al, 2018). The aim of this study was to find a new therapeutic strategy for these types of tumors by targeting cellular pathways that are essential for TEdeff tumor survival. Computational analyses of RNA-sequencing data indicate that TEdeff tumors have extensive overexpression of the cytoplasmic protein homeostasis machinery, including several components of autophagy and proteasome degradation pathways. This strongly suggests that these cells may have increased dependency on cellular protein quality control due to elevated proteotoxic stress. Furthermore, we experimentally show that TEdeff cancer cell lines have a profound accumulation of protein aggregates (aggresomes) that appear to be associated with autophagy for clearance. Importantly, TEdeff cells, but not control cells with proficient transcription elongation (TEprof), are highly sensitive to autophagy inhibitors like chloroquine (CQ), but not proteasome inhibitors, which indicates their increased dependency on autophagy for survival. We also show evidence that the proteasomal degradation system may be defective in TEdeff cells, further supporting the hypothesis that these cells are dependent on alternative protein quality control mechanisms. Mechanistically, we propose that blocking the autophagy pathway maximizes proteotoxic stress, due to the accumulation of toxic aggresomes and proteins generated from defective transcripts, leading to a strong synthetic lethality in TEdeff cells. Therefore, autophagy inhibition may be a potent treatment strategy for TEdeff tumors, which are inherently resistant to current immunotherapies.
Citation Format: Belal Muhammad. A new therapeutic strategy for cancers with transcription elongation defects [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C126. doi:10.1158/1535-7163.TARG-19-C126
Abstract LB-A02: AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells
Authors: Hampsch Riley , Traphagen Nicole , Wells Jason , McCleery Charlotte , Fields Jennifer , Shee Kevin , Dillon Lloye , Pooler Darcy , Lewis Lionel , Demidenko Eugene , Huang Yina , Marotti Jonathan , Kinlaw William , Miller Todd Wayne 
Published: March 2020

Abstract
Despite adjuvant anti-estrogen therapy for patients with ER+ breast cancer, clinically dormant residual disease can persist for years and eventually cause tumor recurrence. Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed clinically relevant xenograft models of dormancy induced by estrogen withdrawal. Dormant breast cancer cells exhibited upregulated AMPK levels and activity. Metformin is an AMPK-activating drug approved to treat diabetes that is being tested in many ongoing clinical trials for treatment of cancer. We found that metformin promoted survival of dormant ER+ breast cancer cells through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. These findings indicate that AMPK has context-dependent effects in cancer, caution against the widespread use of an AMPK activator across disease settings, and warrant the development of cancer therapeutics targeting fat metabolism.
Citation Format: Riley Hampsch, Nicole Traphagen, Jason Wells, Charlotte McCleery, Jennifer Fields, Kevin Shee, Lloye Dillon, Darcy Pooler, Lionel Lewis, Eugene Demidenko, Yina Huang, Jonathan Marotti, William Kinlaw, Todd Wayne Miller. AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A02. doi:10.1158/1535-7163.TARG-19-LB-A02
Abstract LB-A17: Discovery and characterization of a novel small molecule antagonist of PD-L1
Authors: Ying Haiyan , Yang Fei , Zhang Mingming , Zhang Yongxian , Zhao Yuan , Chen Xin , Zhang Lei , Yu Hongping , Chen Zhui , Xu Yao-chang 
Published: March 2020

Abstract
Introduction: Immunotherapy has revolutionized cancer treatment in the last decade. Several monoclonal PD-1 and PD-L1 antibodies have been approved for various cancers. Unlike antibodies, small molecule inhibitors may offer potential advantages in oral dosing, adjustable control of drug exposure, improved accessibility to tumor and many other aspects. Therefore, small molecule antagonist which can efficiently block interaction of PD-1 and PD-L1 may render a novel alternative treatment approach with potentially improved clinical benefits. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel and orally available small molecule PD-L1 antagonist ABSK-041, demonstrating robust T-cell activating ability and strong anti-tumor activity in various preclinical models. Method: ABSK-041’s ability to block PD-1-PD-L1 interaction was evaluated by HTRF assay and cellular luciferase reporter assay. Its biological activity was evaluated in vitro in MLR and in vivo in syngeneic tumor models. Results: ABSK-041 strongly inhibits PD-1-PD-L1 interaction with IC50&lt;1 nM in vitro and very potently rescues PD-L1-induced suppression of T cell activation signaling in cells. It also efficiently rescues cytokine production of PD-L1 suppressed CD8+ T cell to a level comparable with PD-L1 antibody. In in vivo studies, oral administration of ABSK-041 strongly inhibits tumor growth to a extent similar to therapeutic anti-PD-L1 antibody. DMPK and safety profiling demonstrate excellent drug-like properties of ABSK-041. Conclusion: ABSK-041, presented here by Abbisko Therapeutics, is a highly potent and orally available small molecule PD-L1 antagonist. Its superior profile supports fast-track preclinical development.
Citation Format: Haiyan Ying, Fei Yang, Mingming Zhang, Yongxian Zhang, Yuan Zhao, Xin Chen, Lei Zhang, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of a novel small molecule antagonist of PD-L1 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A17. doi:10.1158/1535-7163.TARG-19-LB-A17
Abstract LB-B01: Investigation of immuno-oncology drugs with humanized mouse models: a panel of technologies to evaluate different pharmacological approaches
Authors: Mignard Caroline , Duchamp Olivier , Caradec Josselin , Bichat Francis , France Damien , Viviani Fabrice , Mirjolet Jean François 
Published: March 2020

Abstract
Immunotherapy is one of the most exciting recent breakthroughs in the field of cancer treatment. Different approaches are developed such as cancer vaccines, adoptive cellular immunotherapy or immune checkpoint blockade, and a number have been regulatory approved or are currently investigated in clinic. Effective immunity against cancer involves complex interaction between the tumor, the host and the environment. The assessment of cancer immunotherapy approaches in preclinical settings requires the use of appropriate animal models that sufficiently reflect the physiological situation in humans and that must be chosen carefully to address specific mechanisms of action. In light of evaluating the therapeutic potential of different immunomodulatory agents in mice xenografted with cancer cell lines or patient-derived xenografts, we developed multiple humanization strategies on different immuno-deficient mouse strains. Either human PBMCs, Hematopoietic Stem Cells (HSCs), or specific human immune cells such as Dendritic Cells (DCs), T cells, subset of T cells (e.g. gamma9 delta2 T cells) and NK cells were used, but also the combinations of immune subpopulations such as the co-transfer of autologous T cells and DCs. We will highlight some results of our therapeutic efficacy investigation and evaluation of novel immuno-oncology therapies eg. adoptive cell therapy, bispecific T-cell engager antibody, and vaccine immunomodulatory agents in such humanized mouse models, assessing survival, tumor growth and effects on tumors and immune cells by flow cytometry and immunohistochemistry analyses. All these different humanized models can permit to evidence significant in vivo antitumor efficacy of immunomodulatory agents and might help to increase the success rate in clinical trials.
Citation Format: Caroline Mignard, Olivier Duchamp, Josselin Caradec, Francis Bichat, Damien France, Fabrice Viviani, Jean François Mirjolet. Investigation of immuno-oncology drugs with humanized mouse models: a panel of technologies to evaluate different pharmacological approaches [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B01. doi:10.1158/1535-7163.TARG-19-LB-B01
Abstract LB-B15: New causal drivers of estrogen signaling revealed by dense time series of nascent RNA transcription
Authors: Langendorf Ryan , Basken Joel , Lai Maria , Azofeifa Joseph 
Published: March 2020

Abstract
Mechanistic understanding of Estrogen Receptor (ER) signaling will lead to new therapeutic targets for ER positive breast cancer. To this end, Arpeggio performed nascent RNA sequencing following estradiol (E2) treatment in MCF7 breast cancer cells every 15 minutes for 6 hours. To date, our study represents the densest time series of estrogen signaling ever reported. Arpeggio noted three transcriptional waves following E2 treatment: peaks at 30 minutes, 2.5 hours and 5 hours respectively. We noted that the early response was enriched for canonical ER signaling, however mid and late response were enriched for metabolic processes. Because our study was statistically powered with 24 time points, we could use delay-coordinate embedding to look for causal gene interactions. We implicated NME2 as the causal driver of the 5-hour transcriptional wave. Indeed, NME2 and Estrogen Receptor (ER) have been shown to co-localize where NME2 blocks ER effect. Our study represents a new methodology for target discovery in hormone driven cancers.
Citation Format: Ryan Langendorf, Joel Basken, Maria Lai, Joseph Azofeifa. New causal drivers of estrogen signaling revealed by dense time series of nascent RNA transcription [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B15. doi:10.1158/1535-7163.TARG-19-LB-B15
Abstract PL02-03: The zinc-finger degrome
Authors: Sievers Quinlan L. , Petzold Georg , Bunker Richard D. , Renneville Aline , Liddicoat Brian , Abdulrahman Wassim , Mikkelsen Tarjei , Ebert Benjamin L. , Thoma Nicolas H. 
Published: March 2020

Abstract
The small molecule drugs thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3) by mediating their interaction with Cereblon (CRBN), the substrate receptor of the CRL4CRBN ubiquitin ligase. Here we screened the human Cys2-His2 (C2H2) zinc finger (ZF) proteome for degradation by CRL4CRBN in the presence of thalidomide analogues, identifying 11 ZF targets. Structural and functional characterization of the C2H2 zinc finger degron demonstrates how diverse ZF domains bind the drug-CRBN interface. Computational ZF docking, in conjunction with biochemical analysis, predicts that at least 50 zinc-fingers bind the drug-CRBN complex in vitro, a larger number than previously anticipated. These results provide strategies to degrade other zinc finger transcription factors.
Citation Format: Quinlan L. Sievers, Georg Petzold, Richard D. Bunker, Aline Renneville, Brian Liddicoat, Wassim Abdulrahman, Tarjei Mikkelsen, Benjamin L. Ebert, Nicolas H. Thoma. The zinc-finger degrome [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PL02-03. doi:10.1158/1535-7163.TARG-19-PL02-03
Abstract A03: All the roads bring to Rome: How acetyl-CoA metabolism supports multistep pancreatic carcinogenesis
Authors: Carrer Alessandro , Trefely Sophie , Zhao Steven , Campbell Sydney , Sela Yogev , Sidoli Simone , Garcia Benjamin A. , Snyder Nathaniel W. , Stanger Ben Z. , Wellen Kathryn E. 
Published: March 2020

Abstract
Mutant KRAS is thought to initiate pancreatic tumorigenesis, orchestrating a program that leads to cell de-differentiation, proliferation, and symbiotic cooperation with neighboring cells, enabling the cancer cells to thrive in a particularly harsh microenvironment. Recent studies have highlighted the role of metabolites in regulating the epigenome. Although oncogenic KRAS is known to reprogram cellular metabolism, the role of metabolic control of the epigenome in pancreatic tumorigenesis is poorly understood. We showed that expression of KRASG12D in mouse pancreas promotes elevated histone acetylation levels in pancreatic acinar cells, and that this precedes tumor development. We hypothesized that augmented acetyl-CoA metabolism may play a role in facilitating pancreatic tumorigenesis. To test this, we generated mice deficient for Acly (acetyl-CoA producing enzyme) in pancreas (Pdx1-Cre; Aclyf/f mice). In the context of KRASG12D expression, ACLY deficiency reduces histone acetylation levels in pancreatic acinar cells and impairs formation of neoplastic lesions. ACLY deficiency also impairs pancreatitis-induced tumor development. In testing roles for acetyl-CoA-dependent processes in ADM, we found that targeting either histone acetylation by BET inhibition or cholesterol synthesis with statins suppressed tumor onset. In vivo, response to BET and cholesterol synthesis blockade is associated with recruitment of CD8+ T-cells. The findings indicate that ACLY-dependent metabolic and epigenetic remodeling promote tumor development and point to the potential to target acetyl-CoA metabolism for pancreatic cancer. Potential role of tumor-infiltrating leukocytic cells in modulating acetyl-CoA metabolism in vivo, cancer cell-autonomous mechanisms for acetyl-CoA levels regulation, as well as consequences for therapeutic targeting and dietary interventions, will be discussed.
Citation Format: Alessandro Carrer, Sophie Trefely, Steven Zhao, Sydney Campbell, Yogev Sela, Simone Sidoli, Benjamin A. Garcia, Nathaniel W. Snyder, Ben Z. Stanger, Kathryn E. Wellen. All the roads bring to Rome: How acetyl-CoA metabolism supports multistep pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A03.
Abstract A06: Elucidation of the extracellular adenosine pathway in metastatic pancreatic cancer
Authors: Chiarella Anna M. , Rustgi Rustgi K. 
Published: March 2020

Abstract
Pancreatic cancer is a deadly disease that is expected to kill over 45,000 people in the United States this year alone. More than 80% of pancreatic cancer patients begin treatment after the disease has already metastasized. We recently published on an autochthonous mouse model of pancreatic cancer (Pdx1-cre; LSL-KRASG12D/+; LSL-Trp53R172H; Rosa26LSL-YFP herein KPCY), whereby we studied the molecular consequences of losing the tumor suppressor P120-CATENIN (encoded by the gene Ctnnd1). We demonstrated that pancreas-specific Ctnnd1 heterozygous deletion (herein P120-het) in KPCY mice dramatically increased metastatic potential relative to KPCY control animals. Upon further investigation with co-immunofluorescence, we found that the metastatic lesions were largely devoid of any P120 protein. The metastatic cells with complete P120 loss appear more mesenchymal, a phenotype associated with tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and with increased metastatic potential. To determine the underlying processes downstream of P120 loss that may be driving EMT and metastasis, we performed RNA-sequencing on P120-WT (nonmetastatic) and P120-null (highly metastatic) tumor cells. Compared to the P120-WT tumor cells, the P120-null tumor cells revealed significant upregulation of several genes involved in extracellular adenosine signaling, Enpp3, Nt5e, and Adora2B. More recently, we confirmed upregulation of ENPP3, NT5E, and ADORA2B at the protein level, compared to healthy pancreas tissue, using immunohistochemistry (IHC). In the highly metastatic cells, Enpp3 (Ectonucleotide pyrophosphatase/phosphodiesterase-3) expression was increased 57-fold. ENPP3 is a type II glycoprotein involved in binding to and converting extracellular ATP into AMP. Nt5e/CD73 was increased 9-fold and also has ecto-nucleotidase activity to convert AMP to adenosine. Increases in extracellular adenosine can activate ADORA2B (a cell membrane receptor that binds adenosine and initiates downstream intracellular signaling), which was activated 4-fold. While this pathway has been shown to be important and therapeutically relevant in other cancers, it has yet to be fully characterized in the context of pancreatic cancer. In summary, using a model with increased metastatic capability, we have unraveled a novel panel of upregulated and functionally related genes that are related to increasing and sensing extracellular adenosine levels. Our recent data suggest that extracellular adenosine signaling may be a previously undiscovered mechanism for cells to acquire metastatic ability.
Citation Format: Anna M. Chiarella, Rustgi K. Rustgi. Elucidation of the extracellular adenosine pathway in metastatic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A06.