bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-293: IL-2 diphtheria toxin fusion protein with anti-PD1: in mouse B16-F10 melanoma model
Authors: Fu Juan , Pardoll Drew , Cheung Laurene 
Published: August 2018

Abstract
In tumor immunotherapy, regulatory T lymphocytes (Tregs) play an important role in the suppression of beneficial anti-tumor responses. In the non-immunogenic B16-F10 mouse melanoma model, tumors are found to be highly infiltrated by Tregs. DAB389IL-2 (Ontak, denileukin diftitox) is an IL-2 diphtheria toxin-related fusion protein that has been showed to deplete Tregs in both humans and mice. We treated mice with established B16F10 tumors with s-DAB389IL-2 (produced as a secreted protein from C. diphtheria) and observed a significant decrease in tumor growth rate in C57BL/6 mice. Also, s-DAB389IL-2 treatment increased the frequency of CD8+IFNγ+ T cells (TILs) in tumors and spleens. S-DAB389IL-2 treatment followed by PD-1 blockade resulted in greater tumor growth inhibition than either monotherapy alone. These data suggest that s-DAB389IL-2 plus anti-PD1 treatment can improve anti-tumor responses in non-immunogenic B16F10 melanoma and inhibit tumor growth. Additionally, we mutated a vascular leak inducing motif to construct s-DAB389IL-2 (V6A), which cause less vascular leak in vitro. S-DAB389IL-2 (V6A) inhibited tumor growth with similar efficacy to the original fusion toxin. As vascular leak is the major adverse effect caused by Ontak, DAB389IL-2 (V6A) shows promise as a better tolerated drug for further studies as a cancer immunotherapy.
Citation Format: Juan Fu, Drew Pardoll, Laurene Cheung. IL-2 diphtheria toxin fusion protein with anti-PD1: in mouse B16-F10 melanoma model [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 LB-293.
Abstract LB-302: Oncolytic poliovirus-mediated inflammation and immunity in breast cancer
Authors: Landa Karenia , Holl Eda , Brown Michael , Herndon James , Grimm Lars , Force Jeremy , Bigner Darell , Hwang Shelley , Gromeier Matthias , Nair Smita 
Published: August 2018

Abstract
Breast cancer is the most common malignancy among women in the United States and the second leading cause of cancer deaths in women. Disease prognosis, local recurrence rates and response to therapy are all related to receptor status of the individual cancer. Triple negative breast cancer (TNBC; ER-, PR-, and HER2-negative) is a subset of breast cancer with poor prognosis and high rate of local recurrence and metastasis with limited therapeutic options.
The oncolytic poliovirus, PVSRIPO, is a recombinant polio:rhinovirus chimera that has been engineered to eliminate neuropathogenicity and has demonstrated promising responses in patients with recurrent glioblastoma. PVSRIPO is oncolytic in tumor cells and enters cells via its receptor CD155, which is overexpressed in solid malignancies, including TNBC. Treatment of primary TNBC tissue with PVSRIPO induces IFN-I and pro-inflammatory cytokines. In a murine immunotherapy model, intratumoral injection of PVSRIPO induces IFN-I, IL12 and IFN-γ and rapid recruitment of neutrophils into the tumor followed by infiltration of DCs, T cells and B cells. Treatment of orthotopic breast tumors with PVSRIPO results in delayed tumor growth and increased survival in an immunocompetent murine immunotherapy model.
We have designed a pilot study to examine the effects of intratumoral injection of PVSRIPO into six women with TNBC with at least 1 cm of residual tumor after chemotherapy. The primary exploratory objective is to describe the changes in the amount of tumor infiltrating immune cells in tumor tissue pre- and post-injection of PVSRIPO. We will also collect blood at different time points during PVSRIPO treatment to evaluate inflammatory and immune signatures. We hypothesize that intratumoral administration of PVSRIPO will cause inflammation thus stimulating innate and adaptive immune activation.
This study is funded by the Department of Defense Breast Cancer Research Program award W81XWH-16-1-0354 (PI, Smita Nair).
Citation Format: Karenia Landa, Eda Holl, Michael Brown, James Herndon, Lars Grimm, Jeremy Force, Darell Bigner, Shelley Hwang, Matthias Gromeier, Smita Nair. Oncolytic poliovirus-mediated inflammation and immunity in breast 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 LB-302.
Abstract LB-362: A TGF-beta linked ECM-dysregulation programme in CAFs drives immune evasion and immunotherapy resistance
Authors: Chakravarthy Ankur Ravinarayana , Khan Lubaba , Bensler Nathan P. , Bose Pinaki , Carvalho Daniel Diniz De 
Published: August 2018

Abstract
Background
One of the key hallmarks of cancer is metastasis, which involves extensive extracellular matrix remodelling to permit extravasation from the primary tumour site before colonisation of distant sites. In this study, we defined the landscape of ECM-associated transcriptional dysregulation and performed in-silico associative analyses in terms of multiple -omics platforms, cellular composition and immunological parameters.
Methods
We defined the landscape of ECM gene dysregulation by integrating curated Gene Ontology ECM genes with genes differentially expressed between cancer and normal tissues from TCGA. ssGSEA scores for this set were then correlated with purity (ABSOLUTE), tested for stromal association using microdissected tumours and MethylCIBERSORT, and neoepitope counts derived using Topiary. Single-cell RNAseq data was used to validate CAF-origin. Linear models were used to identify transcriptomic, proteomic and genomic correlates, and finally, RNAseq data from three cohorts of PD1-blockade treated patients and 0.632 bootstrap evaluation of logistic regression or Random Forest models based on ECM genes, Cytolytic Activity, Mutational burden or their combinations was performed.
Results
A core set of 58 ECM genes is dysregulated and significantly enriched amongst genes differentially expressed between cancer and normal tissues pan-cancer. Those upregulated in cancers were found to be a negative prognostic factor pan-cancer and through integrative analysis of microdissected samples, deconvolution and single-cell RNAseq, were found to originate in Cancer Associated Fibroblasts. Transcriptome, proteome and genomics analyses implicated TGF-beta as a driver of this ECM-dysregulation signature and most notably, this programme was associated with heavily-mutated, neoantigen-high, CD8 high cancers, M1-macrophage-skewed tumours suggesting a role as a putative adaptation permitting immune evasion. Indeed, ECM dysregulation scores were significantly better predictors of response to PD1-blockade in pretreatment biopsies compared to cytolytic activity, an interferon gene signature, and mutational-burden, while TGF-beta expression alone was not, implicating a key role for CAF-specific ECM gene dysregulation in immune evasion.
Conclusion
A TGF-beta associated, CAF-derived signature of ECM-gene dysregulation broadly in operation across cancer types constitutes an immune evasion mechanism that indicates refractoriness to PD1-blockade.
Citation Format: Ankur Ravinarayana Chakravarthy, Lubaba Khan, Nathan P. Bensler, Pinaki Bose, Daniel Diniz De Carvalho. A TGF-beta linked ECM-dysregulation programme in CAFs drives immune evasion and immunotherapy resistance [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 LB-362.
Abstract LB-367: [18F]FAZA PET imaging reveals precise pharmacodynamics in vivo of the novel chemotherapeutic IACS-010759
Authors: Gammon Seth T. , Pisaneschi Federica , Bandi Madhavi , Smith Melinda , Rao Yi , Nanda Vashisht G. Yennu , Sun Yuting , Davies Michael , Francesco Emilia Di , Marszalek Joseph , Piwnica-Worms David 
Published: August 2018

Abstract
Genetic deletions and mutations resulting in defects in glycolysis, force these tumors to depend on oxidative phosphorylation (OxPhos) for growth. IACS-010759 is a nanomolar inhibitor of Complex I, and in phase I clinical trials at MD Anderson for both AML and solid tumors. While ex vivo monitoring of inhibition of oxygen consumption in leukocytes was sufficient for AML, non-invasive methods of monitoring target engagement in solid tumors was desired. Tumors, particularly those that rely on oxidative phosphorylation, yield hypoxic and reducing environments. These conditions are ideal for trapping 2-nitroimidazole based imaging agents, such as F18-labeled fluoroazomycin arabinoside ([18F]FAZA). IACS-010759 inhibited oxygen consumption in vitro with IC50 values ranging from 1.3 nM to 6 nM across a variety of cell lines with a diversity of glycolysis defects. In H460 NSLC, SKMEL5 melanoma, A375R melanoma, and D423-Fluc orthotopic GBM in vivo, at the MTD 10 mg/kg, a robust, up to 6 fold, (2 way ANOVA, p&lt;0.0001) decrease in FAZA T/B ratio was observed. A slight, 1.5-fold, but detectable increase in [18F]FDG was also observed at 10mg/kg in A375 and A375R cells (p=0.002), but smaller than the decrease [18F]FAZA retention. Thus neither cell death nor loss of perfusion could explain the reduction in [18F]FAZA retention. To further test the robustness of the mechanism of inhibition, the converse experiment was conducted. Both 2,4-dinitrophenol and pyruvate were utilized to stimulate oxygen consumption in vivo, and as predicted [18F]FAZA retention increases (p&lt;0.05 in both cases). Finally, [18F]FAZA retention by PET yielded the same IC50 for IACS-010759 as by IHC in a dose-dependent manner, with an apparent IC50 of 1.4 mg/kg (95%CI 0.48 to 4.1 mg/kg, n=12 mice) for A375R melanoma tumors. The PET measurement was more precise than an independently scored IHC metric based upon staining for pimonidazole from the same mice. [18F]FAZA can be a powerful PD marker for the complex-I inhibitor IACS-010759 in preclinical models, and is translatable to upcoming clinical trials in patients.
Citation Format: Seth T. Gammon, Federica Pisaneschi, Madhavi Bandi, Melinda Smith, Yi Rao, Vashisht G. Yennu Nanda, Yuting Sun, Michael Davies, Emilia Di Francesco, Joseph Marszalek, David Piwnica-Worms. [18F]FAZA PET imaging reveals precise pharmacodynamics in vivo of the novel chemotherapeutic IACS-010759 [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 LB-367.
Abstract LB-383: Towards automation of germline variant curation in cancer genetics
Authors: Ravichandran Vignesh , Shameer Zarina , Offit Kenneth , Joseph Vijai 
Published: August 2018

Abstract
Cancer care professionals are now increasingly asked to interpret multiplexed gene sequencing of patients at hereditary risk for cancer. Assessments for variant classification now require orthogonal data searches, requiring aggregation of multiple lines of evidence from diverse resources. The burden of evidence required for each variant to meet thresholds for pathogenicity or actionability now poses a growing challenge for those seeking to counsel patients and families following germline genetic testing. A computational tool that automates, provides uniformity and significantly accelerates this interpretive process is required. The automated tool described here, Pathogenicity of Mutation Analyzer (PathoMAN) automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein and disease specific information from public sources. When compared against expert curation aggregated from three groups - (i) Prostate Cancer Study; (ii) Breast Cancer Study and (iii) ClinVar. PathoMAN achieves high concordance (83.1% pathogenic, 75.5% benign) and negligible discordance (0.04% pathogenic, 0.9% benign) when contrasted against expert curation. Loss of resolution (8.6% pathogenic, 23.64% benign) and gain of resolution (6.6% pathogenic, 1.6% benign) are observed. We highlight the advantages and weaknesses related to the use of programmable automation of variant classification. PathoMAN provides a substantial advance in rapid classification of genetic variants by generation of robust models using a knowledge-base of diverse genetic data. It is an easily accessible, web-based resource that allows rapid pathogenicity assessment of a large number of variants. We also propose a new nosology for the five ACMG classes to facilitate more accurate reporting to ClinVar. The proposed refinements will better structure ClinVar to allow automation in cancer susceptibility reporting. Such bioinformatics tools are an essential prerequisite to reduce the manual workload of domain level experts.
Citation Format: Vignesh Ravichandran, Zarina Shameer, Kenneth Offit, Vijai Joseph. Towards automation of germline variant curation in cancer genetics [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 LB-383.
Abstract LB-394: Profiling of endogenous circular RNA molecules in formalin-fixed paraffin-embedded tissues from patients with B-cell malignancies using an enzyme-free digital counting method
Authors: Kristensen Lasse Sommer , Dahl Mette , Andersen Maria S. , Daugaard Iben , Hansen Thomas B. , Grønbæk Kirsten , Kjems Jørgen 
Published: August 2018

Abstract
Circular RNAs (circRNAs) are covalently closed endogenous RNA molecules with tissue- and disease specific expression patterns, which have potential as diagnostic and prognostic biomarkers in cancer. The landscape of circRNA expression has not been characterized in B-cell malignancies, and current methods for circRNA quantification have several limitations that prevent development of clinically applicable assays. Based on high-throughput RNA sequencing (RNA-seq) data, we designed assays for analyzing 52 unique circRNAs simultaneously, using a digital, enzyme-free technology termed NanoString, in cell lines and paired fresh frozen and formalin-fixed, paraffin-embedded (FFPE) patient samples (including mantle cell lymphoma, multiple myeloma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma and chronic lymphocytic leukemia). The data obtained using NanoString were compared to RNA-seq and reverse transcription-qPCR (RT-qPCR) data obtained on the same samples. RNA-seq profiling revealed a high expression of circRNAs in B-cell malignancies and the NanoString circRNA expression profiles were able to distinguish different B-cell malignancies. We detected circRNAs known to be deregulated in other cancers, including ciRS-7, circHIPK3 circCCDC66, circCDYL, circZKSCAN1 and circFBXW7, and identified a novel circRNA from the IKZF3 oncogene. NanoString data were more reproducible and quantitatively accurate than RNA-seq data and the technology works in particular well for low quality RNA samples. Together, we demonstrate that the NanoString technology enables specific, sensitive and accurate quantification of circRNAs in FFPE samples and provide a map of circRNA expression in B-cell malignancies.
Citation Format: Lasse Sommer Kristensen, Mette Dahl, Maria S. Andersen, Iben Daugaard, Thomas B. Hansen, Kirsten Grønbæk, Jørgen Kjems. Profiling of endogenous circular RNA molecules in formalin-fixed paraffin-embedded tissues from patients with B-cell malignancies using an enzyme-free digital counting method [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 LB-394.
Abstract LB-398: DNA-PKcs protects irradiated cells from persistent DNA damage signaling and accelerated senescence
Authors: Liu Yue , Efimova Elena V. , Ramamurthy Aishwarya , Kron Stephen J. 
Published: August 2018

Abstract
The DNA-dependent protein kinase catalytic subunit DNA-PKcs has long been considered as a promising target in cancer, based on its roles in DNA damage response and the potential for inhibitors to enhance sensitivity to genotoxic therapy. Multiple investigational DNA-PK inhibitors remain under evaluation, though several have failed in development and none have reached the clinic. DNA-PKcs has been assigned diverse roles in DNA damage response that overlap with ATM including direct phosphorylation of H2AX to form γH2AX and promoting double-strand break (DSB) repair by conventional non-homologous end-joining (NHEJ). Nonetheless, a recent report implicated DNA-PKcs as a negative regulator of ATM. This may resolve the paradox that while ATM inhibitors block H2AX phosphorylation, prevent ionizing radiation induced foci (IRIF) formation and suppress terminal arrest and onset of cellular senescence, DNA-PK inhibitors induce persistent γH2AX, delay IRIF resolution and promote senescence. Toward better defining DNA-PKcs roles in radiation response, we examined MCF7 mammary carcinoma cells for effects of DNA-PKcs shRNA knockdown or treatment with specific inhibitors on DNA damage response and senescence after irradiation. We confirmed a requirement for DNA-PK in resolution of γH2AX and IRIF by 24 h after irradiation. Rather than return to proliferation, surviving cells with DNA-PK defects developed characteristic features of senescence within five days in culture. To examine if this effect of DNA-PKcs inhibition was mediated by blocking DSB repair, we irradiated MCF7 cell lines expressing shRNAs targeting NHEJ factors Ku70, Ku80, XLF, XRCC4, PAXX, and LIG4 as well as scrambled control in the presence or absence of DNA-PKcs inhibitor NU7441. Strikingly, IRIF resolution at 24 h was similar to control in cell lines lacking NHEJ factors while NU7441 increased IRIF persistence and enhanced senescence in all cell lines. These results suggest that a critical role for DNA-PKcs in radiation response is to attenuate DNA damage signaling and prevent cellular senescence. Treating irradiated DNA-PKcs knockdown cells with the ATM inhibitor KU55933 at 24 h resolved persistent γH2AX and IRIF and blocked senescence. Taken together, our data demonstrate that DNA-PKcs regulates IRIF resolution and cell senescence by targeting ATM functions rather than directly affecting DSB repair.
Citation Format: Yue Liu, Elena V. Efimova, Aishwarya Ramamurthy, Stephen J. Kron. DNA-PKcs protects irradiated cells from persistent DNA damage signaling and accelerated senescence [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 LB-398.
Abstract LB-401: Induction of DISE by tumor suppressive microRNAs
Authors: Gao Quan Q. , Putzbach William T. , Murmann Andrea E. , Chen Siquan , Sarshad Aishe A. , Ambrosini Giovanna , Bartom Elizabeth T. , Hafner Markus , Peter Marcus E. 
Published: August 2018

Abstract
Many siRNAs and shRNAs induce a form of cell death in all cancer cells that involves silencing a set of critical survival genes, a process called death induced by survival gene elimination (DISE). Mechanistically a 6mer seed sequence (position 2-7 of the guide strand) is sufficient to confer DISE-inducing activity. We have now performed a strand specific screen testing the toxicity of all 4096 possible 6mer seed sequences in a neutral double stranded siRNA backbone. We found an asymmetric preference for guanine in positions 1-3 of the 6mer seed in the most toxic siRNAs which target survival genes that are GC rich in their 3'UTR. During over 800 million years of evolution miRNAs have evolved to avoid guanine in their seed sequences. However, two tumor suppressive miRNAs were found to be killing cancer cells through DISE using G rich toxic seeds in cells exposed to genotoxic stress: 1) the p53 inducible miR-34 family and most of its cell death inducing activity comes from its 6mer seed; and 2) miR-320a, a noncanonical miRNA that is still expressed in cancer cells when miRNA processing genes are mutated. Ago bound upregulated miR-320a is converted from a poorly to a highly toxic miRNA by removal of two adenine nucleotides from its 5' end. Our data suggest that most miRNAs have evolved to avoid induction of DISE but certain tumor suppressive miRNAs utilize this mechanism to kill cancer cells.
Citation Format: Quan Q. Gao, William T. Putzbach, Andrea E. Murmann, Siquan Chen, Aishe A. Sarshad, Giovanna Ambrosini, Elizabeth T. Bartom, Markus Hafner, Marcus E. Peter. Induction of DISE by tumor suppressive microRNAs [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 LB-401.
Abstract NG02: NFS1 undergoes positive selection in lung tumors and protects cells from ferroptosis
Authors: Alvarez Samantha W. , Sviderskiy Vladislav O. , Terzi Erdem M. , Papagiannakopoulos Thales , Moreira Andre L. , Adams Sylvia , Sabatini David M. , Birsoy Kıvanç , Possemato Richard L. 
Published: August 2018

Abstract
Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using RNAi-based loss of function screening, we identify environmental oxygen level as a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron-sulfur cluster (ISC) biosynthetic enzyme NFS1. Accordingly, mammary or subcutaneous tumours grow despite NFS1 suppression, while metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the ISC cofactors present in multiple cell-essential proteins upon exposure to O2 compared to other forms of oxidative damage. Additionally, insufficient ISC maintenance robustly activates the iron-starvation response and, in combination with glutathione biosynthesis inhibition, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage. These observations lead to the tantalizing hypothesis that one can trick cancer cells into taking up large quantities of iron and releasing intracellular iron stores via modulation of NFS1 or downstream effectors, such as IRPs, leaving them at increased risk for ROS-mediated cell death mechanisms such as ferroptosis.
Citation Format: Samantha W. Alvarez, Vladislav O. Sviderskiy, Erdem M. Terzi, Thales Papagiannakopoulos, Andre L. Moreira, Sylvia Adams, David M. Sabatini, Kıvanç Birsoy, Richard L. Possemato. NFS1 undergoes positive selection in lung tumors and protects cells from ferroptosis [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 NG02.