bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1666: A comprehensive DLBCL lymphoma PDX collection to evaluate the efficacy and resistant mechanism of rituximab
Authors: Qi Hui , Tang Xuzhen , Zou Zhiyuan , Fang Ying , Wang Li , Zhao Weili , Gu Qingyang , Ji Qunsheng 
Published: September 2020

Abstract
Rituximab has shown great efficacy in B-cell non-Hodgkin's lymphoma (NHL), by binding CD20 to induce cell destruction through activating apoptosis, complement and cell-mediated cytotoxity. However, the response rate of patients with relapsed or refractory CD20-positive NHL to standard rituximab treatment is less than 50%, and the non-responders, especially DLBCL patients, still could express high levels of CD20. Therefore, a translational in vivo platform to understand the mechanisms behind Rituximab resistance is in urgent need. We established and characterized a series of DLBCL lymphoma PDX. Eleven non-GCB DLBCL PDX models were selected for the Rituximab efficacy study, of which 3 are relapse DLBCL. IHC and RNAseq were conducted to evaluate CD20 status and expression of other genes. The anti-tumor efficacy of Rituximab in 11 PDX models revealed that 5 of them were sensitive to rituximab and 6 had a poor response. All these models are CD20 positive judged by IHC. By analyzing the correlation of tumor growth inhibition (TGI) and the genomic background of these PDX models, we identified several candidate genes such as BCL2L1, PDK1, TGF-β, Lgalsl and p56/p53Lyn that may contribute to drug resistance mediated by elevated apoptotic threshold, modulation of complement activity or diminished cellular cytotoxicity. Further validation studies are in progress. We established a series of DLBCL lymphoma PDX; with advanced genomic profiling method and validation, these models can be precisely used for subtype-specific therapy evaluation and the investigation of the mechanism of drug resistance.
Citation Format: Hui Qi, Xuzhen Tang, Zhiyuan Zou, Ying Fang, Li Wang, Weili Zhao, Qingyang Gu, Qunsheng Ji. A comprehensive DLBCL lymphoma PDX collection to evaluate the efficacy and resistant mechanism of rituximab [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 1666.
Abstract 1752: Inhibition of histone demethylase KDM6B as a promising target for non-small cell lung cancer
Authors: Lesbon Jessika C. , Xavier Pedro L. , Garnica Taismara K. , Rochetti Arina L. , Reis Rui M. , Müller Susanne , Fukumasu Heidge 
Published: September 2020

Abstract
Despite advances in diagnostic and therapeutic approaches, the majority of lung cancer patients still progress to advanced stages with metastatic lesions. Abnormalities in epigenetic mechanisms are related to the most malignant cancer phenotypes. Thus, there is an increasing interest in the development and validation of drugs that targets epigenetic proteins. Trimethylation of H3K27 is an important post-translational modification and some studies have shown that KDM6B (lysine (K)-specific demethylase 6B), an H3K27 demethylase, is a crucial regulator involved in tumorigenesis and play important roles in various types of cancers. In this study, our goal was to determine potential epigenetic targets to control invasion and migration of NSCLC cancer cells. Initially, KDM6B was found a promise target through in silico analysis for the inverse correlation between gene expression and overall survival on 2438 NSCLC cases from GEO, EGA and TCGA using KMplotter tool and selecting the genes according to HR and p-values (HR &gt; 1 and p &lt; 0.05). Next, NSCLC cell lines (A549, H23, H2126 and H1568) were evaluated for the expression of the KDM6B using CellExpress tool and next by real-time PCR and one cell was chosen for cytotoxicity of the KDM6B inhibitor (GSK-J4) for 72h by MTT assay. The IC50 value and the regression curve were calculated with 6.0 Prism (GraphPad Software, USA). KDM6B gene expression was inversely correlated with patient survival rate for pulmonary adenocarcinoma (HR= 2.81; p= 6,3E-09). All pulmonary adenocarcinoma cell lines expressed KDM6B gene and low expression in healthy lung tissue (Z-score= 2.8). The KDM6B IC50 for A549 cells was 2.78±0.09μM. These early findings report that KDM6B as a promising target for epigenetic therapy for pulmonary adenocarcinoma. Therefore, our next step will be to evaluate the potential of KDM6B inhibition on the phenotype of cancer cell migration and invasion and global analysis of gene expression to understand genes and mechanisms associated with possible inhibitory effects of KDM6B.
Citation Format: Jessika C. Lesbon, Pedro L. Xavier, Taismara K. Garnica, Arina L. Rochetti, Rui M. Reis, Susanne Müller, Heidge Fukumasu. Inhibition of histone demethylase KDM6B as a promising target for 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 1752.
Abstract 1758: Discovery of novel potent and selective inhibitors of PRMT5 with anti-tumor activity in hepatocellular carcinoma and lung pre-clinical models
Authors: Gonzalvez Francois , Vandyck Koen , Debing Yannick , Gupta Kusum , Misner Dinah , Zhang Qingling , Liu Jyanwei , Stoycheva Antitsa , Stevens Sarah , Symons Julian , Beigelman Leonid , Raboisson Pierre , Deval Jerome 
Published: September 2020

Abstract
Protein arginine methyltransferase-5 (PRMT5) regulates many essential biological processes by catalyzing the symmetric di-methylation of arginine (sDMA) on a variety of histones and non-histone proteins. PRMT5 activity is dysregulated across many hematological and solid tumor and its overexpression is associated with poor patient prognosis. PRMT5 is also often overexpressed in cancer cells. Genetic and pharmacological inactivation have confirmed the importance of PRMT5 activity to the survival of many cancer cells, including hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). Thus, inhibiting PRTMT5 activity has emerged as an attractive therapeutic strategy in oncology.
We used structure-based drug design to identify novel small molecule inhibitors of PRMT5. ALG-070005, ALG-070043 and ALG-070017 inhibited PRMT5 enzymatic activity in biochemical assays with half-maximal inhibitory concentrations (IC50s) values between 50-150 pM and showed high selectivity against a panel of six other PRMTs. In HepG2 cells (HCC), ALG-070005, ALG-070043 and ALG-070017 potently decreased sDMA levels and inhibited cell proliferation with IC50 values of 1, 3, and 0.2 nM, respectively. These compounds also exhibited similar antiproliferative activity in A549 NSCLC cells. The three novel PRMT5 inhibitors demonstrated favorable ADME/PK profiles with exposure levels in target organs well above IC50 values, even 24 hours after dosing. When dosed orally in mice, these Aligos compounds inhibited tumor growth in HCC and NSCLC xenograft models, with concomitant inhibition of sDMA in the tumor.
In conclusion, we identified and characterized novel potent and selective inhibitors of PRMT5 with antiproliferative effects in various preclinical models of HCC and lung cancers. These drug candidates also have a broad therapeutic potential in oncology beyond HCC and lung cancer.
Citation Format: Francois Gonzalvez, Koen Vandyck, Yannick Debing, Kusum Gupta, Dinah Misner, Qingling Zhang, Jyanwei Liu, Antitsa Stoycheva, Sarah Stevens, Julian Symons, Leonid Beigelman, Pierre Raboisson, Jerome Deval. Discovery of novel potent and selective inhibitors of PRMT5 with anti-tumor activity in hepatocellular carcinoma and lung pre-clinical models [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 1758.
Abstract 180: Systematic genomic analysis of matched PDX, PDX-derived organoids (PDXO), and PDX-derived cell lines (PDXC)
Authors: Xu Xiaoxi , Qian Wubin , Guo Sheng , Li Henry Q. 
Published: September 2020

Abstract
INTRODUCTION
Patient-derived xenografts (PDX) are considered predictive in vivo models for assessing cancer therapeutics due to their close genomic and histopathological resemblance to primary patient tumors. PDX can also be used to derive in vitro organoids (PDXO) and cell lines (PDXC), as we recently proposed and demonstrated, essentially creating matched pairs of in vitro and in vivo models. Cell lines serve as a conventional solution for fast and affordable evaluation of chemo- and targeted therapies, but they suffer from reduced clinical translatability. Organoids maintain organ structures and relevant functions in 3D culture, and are considered to be more physiologically relevant cancer models1. It is possible that the three experimental models have different genomic profiles, caused by different growing conditions, and that this will affect therapeutic evaluation, yet a systematic analysis is so far lacking.
METHODS
We developed a set of PDX-PDXO-PDXC model trios. Models were characterized for morphology, histopathology, genomics, and response to anticancer drugs, followed by a comparative analysis with an emphasis on genomic profiles.
RESULTS
We found that PDXO and PDXC have varied model establishment rates from PDX depending on cancer type. PDXO and PDXC show characteristic morphology. Like PDX, they exhibit model-specific growth kinetics and drug response. A high concordance of drug response was observed between PDX and matched PDXO. Genome-level mutation analysis showed good conservation of both somatic and driver mutations among the trios, indicating largely identical tumorigenesis mechanisms. However, significant transcriptomic differences were observed in pairwise comparisons between PDX-PDXO, PDX-PDXC, and PDXO-PDXC. We performed an in-depth analysis of differentially expressed genes, pathways, and gene networks to understand the underlying molecular mechanisms and their potential impact on drug evaluation.
CONCLUSIONS
Our study is the first large-scale comparative study to help understand the relatedness and uniqueness of PDX, PDXO, and PDXC on genomics.
REFERENCES
[1] Tuveson, D. & Clevers, H. Cancer modeling meets human organoid technology. Science 364, 952-955 (2019).
Citation Format: Xiaoxi Xu, Wubin Qian, Sheng Guo, Henry Q. Li. Systematic genomic analysis of matched PDX, PDX-derived organoids (PDXO), and PDX-derived cell lines (PDXC) [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 180.
Abstract 1811: Sorafenib-mediated apoptotic and autophagic cell death is increased by carnosic acid and a vitamin D2 analog in hepatocellular carcinoma (HCC)
Authors: Wang Xuening , Wu Qunfeng , Pham Kien , Luna Aesis , Danilenko Michael , Liu Chen , Studzinski George P. 
Published: September 2020

Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Its incidence is increasing, and currently there is no curative therapy for it in advanced cases. Sorafenib (Sf), a multikinase inhibitor, is an FDA approved drug for the treatment of unresectable hepatomas, but the improvement in patient survival is very short, so new approaches are needed to supplement the existing regimens. In this study we show that the addition of a plant antioxidant Carnosic acid (CA) and a vitamin D2 derivative Doxercalciferol (D2) to Sf can markedly enhance its cytotoxic effect on HCC cell lines Huh7 (Sf-sensitive) and HCO2 (partially Sf-resistant). In contrast, similar combinatorial treatment of Hu1545 cells (immortalized human hepatocytes) results in only a minimal increase in cell death (CD). The combination Sf-CA/D2 increases HCC cell death by enhancing both apoptosis and cytotoxic autophagy (AuPh). Apoptosis was shown by Annexin V binding analysis and by the increased levels of apoptosis-related proteins BIM, cleaved caspases 9 and 3. AuPh was demonstrated by increased cytoplasmic vacuolation and elevated protein levels of Beclin1, Atg3, and LC3-II. Individually, both CA and D2 enhance Sf-induced CD, but CA produces the predominant effect. These effects were significantly reduced by the addition of the Caspase 3 inhibitor Z-DEVD-fmk or the AuPh inhibitor Chloroquine, and by Beclin1 depletion. A pilot experiment with mice bearing a Huh7 HCC cell xenograft showed markedly increased survival of the animals when CA was added to Sf. These results suggest that CA alone or with D2 may increase the survival of Sf-treated HCC patients. Supported by NIH grants 1R01DK110024 (to CL) and 5R01 44722-27 (to GPS).
Citation Format: Xuening Wang, Qunfeng Wu, Kien Pham, Aesis Luna, Michael Danilenko, Chen Liu, George P. Studzinski. Sorafenib-mediated apoptotic and autophagic cell death is increased by carnosic acid and a vitamin D2 analog in hepatocellular carcinoma (HCC) [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 1811.
Abstract 1831: Mistletoe lectin induces apoptosis in MYC-driven cancers through post-translational downregulation of c-MYC protein
Authors: Kennelley Gabrielle , Yuan Eric , Shatat Mohammad , Gauthier Betsy , Yang Peiying , Difeo Analisa , Lee Richard 
Published: September 2020

Abstract
c-Myc is part of the Myc family proteins associated with cellular proliferation, differentiation, and apoptosis. Dysregulated c-Myc expression is associated with tumorigenesis, and cancers with c-Myc overexpression are often associated with poor prognosis, partly due to difficulty in targeting c-Myc. Mistletoe lectin (ML), derived from the European mistletoe plant, has shown variable efficacy in cancer patients. One case series following 12 patients with advanced hepatocellular carcinoma (HCC) showed 2 patients with &gt30% reduction in the tumor marker alpha-fetoprotein and 1 patient who had stable disease for 9 months. These cases indicate promising results. ML consists of a heteroprotein complex of an A- and B-chain connected by a disulfide bond. The A-chain was previously described to inhibit translation by 28s rRNA cleavage, while the B-chain binds cell surface glycoproteins to trigger internalization of the lectin. We found that purified mistletoe extract, consisting primarily of ML, downregulates c-Myc protein and induces apoptosis in in vitro and in vivo models of human-derived cancer, and that the efficacy of ML treatment is strongly correlated with MYC gene expression and c-Myc protein abundance in in vitro human models of HCC, ovarian cancer, small cell lung cancer, and lymphoma. MTS assay data demonstrated that exogenous MYC expression can sensitize low-MYC cell lines to ML treatment, suggesting that anti-cancer effects of ML are dependent on its ability to downregulate c-Myc. While ML may be able to downregulate many proteins via general translational inhibition, we found that of 296 proteins profiled by RPPA, c-Myc was one of 11 proteins decreased by ML with at least a 2-fold change (p&lt0.01). We also found that ML promotes c-Myc ubiquitylation, suggesting that ML regulates c-Myc protein stability, rather than synthesis. In summary, here we describe a novel mechanism of action for ML in downregulating c-Myc and promoting apoptotic cell death in various models of MYC-driven cancer, and provide evidence for MYC gene expression as a predictive marker for response. This research supports the development of ML-based therapies that may provide a c-Myc-targeting treatment in multiple cancer types.
Citation Format: Gabrielle Kennelley, Eric Yuan, Mohammad Shatat, Betsy Gauthier, Peiying Yang, Analisa Difeo, Richard Lee. Mistletoe lectin induces apoptosis in MYC-driven cancers through post-translational downregulation of c-MYC protein [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 1831.
Abstract 1881: Immune mediated interaction between radiation and cetuximab in a syngeneic murine model of head and neck squamous cell carcinoma
Authors: Jin Wonjong , Erbe Amy K. , Schwarz Ciara , Jaquish Abigail , Anderson Bryce R. , Sriramaneni Raghava N. , Jagodinsky Justin C. , Clark Paul A. , Morris Zachary S. 
Published: September 2020

Abstract
Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) treated with anti-EGFR (cetuximab) mAb-based immunotherapy often acquire therapy-resistance, reducing clinical benefit. We evaluated the efficacy of a combined modality in situ vaccination regimen aimed at overcoming resistance to cetuximab using a syngeneic tumor model.
Experimental Design: The murine HNSCC cell line MOC2 was transduced to express human EGFR (MOC2-huEGFR) and used as a syngeneic model of therapeutic resistance to cetuximab. The cells were tested for viability, radiosensitivity, and huEGFR-specific mAb binding efficacy in the presence of cetuximab. Antibody-dependent cellular cytotoxicity (ADCC) was tested by coculture of 51chromium-labeld MOC2-huEGFR with PBMC. Mice bearing these syngeneic tumors were treated with therapeutic regimens that included local radiation (RT), intratumoral (IT) cetuximab, and/or systemic immune checkpoint inhibitors, and tumor growth/survival rate were monitored.
Result: Cetuximab induced antibody-dependent cellular cytotoxicity (ADCC) in MOC2-huEGFR and PBMC co-cultures, but showed no effect on cell proliferation or radiosensitivity. Combined RT and IT-cetuximab treatment induced tumor growth delay, which required huEGFR expression, NK cells, and FcγR expression. In addition, combined RT+IT-cetuximab therapy greatly induced tumor infiltration by both CD8 T cells and NK cells. RT promoted NK cell-mediated ADCC effects against 51chromium-labeld MOC2-huEGFR with increased IFNγ expression. Proliferating tumor cells gradually increased Pd-l1 mRNA expression, and RT enhanced cell surface PD-L1 in MOC2-huEGFR cells. Systemic anti-PD-L1 antibody or IT-cetuximab alone did not show antitumor response against MOC2-huEGFR bearing mice; however, significant tumor growth inhibition was observed with combined anti-PD-L1, RT, and IT-cetuximab.
Conclusion: The MOC2-huEGFR HNSCC tumor model is immunologically “cold” and does not respond to either cetuximab or anti-PD-L1 therapies alone. In this model, we show that a combination of RT+cetuximab+anti-PD-L1 elicits a cooperative in situ vaccine effect. Combining RT, cetuximab and immune checkpoint blockade may enable anti-tumor immune response in HNSCC patients with immunologically cold, huEGFR-expressing tumors.
Citation Format: Wonjong Jin, Amy K. Erbe, Ciara Schwarz, Abigail Jaquish, Bryce R. Anderson, Raghava N. Sriramaneni, Justin C. Jagodinsky, Paul A. Clark, Zachary S. Morris. Immune mediated interaction between radiation and cetuximab in a syngeneic murine model of head and neck squamous cell carcinoma [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 1881.
Abstract 1936: Immunoproteasome inhibitors for the treatment of ALL
Authors: Jenkins Tyler W. , Downey-Kopyscinski Sondra , Colley William C. , Fields Jennifer L. , Fiering Steven N. , Kisselev Alexei F. 
Published: September 2020

Abstract
The t(4;11)(q21;q23) chromosomal translocation that creates MLL-AF4 fusion protein confers a poor prognosis protein in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib may be unacceptable to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914. Furthermore, ONX-0914 dramatically delayed growth of orthotopic xenograft tumors in mice. Thus, immunoproteasomes are therapeutic targets in ALL; replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues.
Citation Format: Tyler W. Jenkins, Sondra Downey-Kopyscinski, William C. Colley, Jennifer L. Fields, Steven N. Fiering, Alexei F. Kisselev. Immunoproteasome inhibitors for the treatment of 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 1936.
Abstract 1955: Inhibition of eIF4A by eFT226 blocks KRAS mutant tumor growth
Authors: Stumpf Craig R. , Goel Vikas K. , Chen Joan , Staunton Jocelyn , Santori Emily M. , Barrera Maria , Howard Haleigh , Webster Kevin R. , Chiang Gary G. , Thompson Peggy A. 
Published: September 2020

Abstract
Mutations in KRAS are among the most common oncogenic lesions across a variety of human cancers. Activation of KRAS directs signaling via the MAPK and PI3K pathways to promote tumor growth. One outcome of enhanced KRAS signaling is the induction of mRNA translation by eIF4A, eIF4E, and eIF4G, which together comprise the eIF4F complex. eIF4A is an RNA helicase that functions to unwind elements in the 5'-untranslated region (UTR) of mRNAs to facilitate scanning of the 40S ribosomal subunit. eFT226 is a highly potent and selective inhibitor of eIF4A that functions by forming a ternary complex between eIF4A, eFT226 and specific polypurine motifs in the 5'-UTR of select mRNAs, thus blocking ribosome scanning and inhibiting mRNA translation. This polypurine sequence motif is highly enriched in the 5'-UTR of eFT226 target genes, many of which are known proto-oncogenes. Translational profiling revealed KRAS to be a target of eFT226 and 5'-UTR sequence analysis of KRAS mRNA identified the polypurine regulatory motif, which imparts sensitivity to eFT226 mediated inhibition of translation. In cell-based reporter assays used to monitor translation, mutation of the KRAS 5'-UTR polypurine motifs resulted in a 10-fold decrease in sensitivity to eFT226 relative to the wild-type sequence. In a cell panel screen for in vitro apoptosis induction by eFT226, the most sensitive models were enriched for cell lines driven by KRAS mutations. Consistent with these results, treatment with eFT226 decreased KRAS protein levels, repressed downstream MAPK signaling, inhibited cell proliferation, and induced apoptosis in a collection of non-small cell lung, colorectal and pancreatic KRAS mutant cancer cell lines. The ability of eFT226 to block tumor cell growth and induce apoptosis is independent of the specific KRAS mutation present (e.g. G12C/V, G13D, Q61H/L) suggesting that eFT226 could be broadly efficacious in treating tumors with activating KRAS mutations. Treatment of KRAS mutant solid tumor xenografts with eFT226 as a monotherapy significantly inhibited tumor growth. Together, these results highlight the ability of eFT226 to inhibit growth and promote apoptosis in KRAS mutant tumors and support the clinical development of eFT226 in KRAS driven tumors. A clinical trial evaluating eFT226 in patients with solid tumor malignancies has initiated.
Citation Format: Craig R. Stumpf, Vikas K. Goel, Joan Chen, Jocelyn Staunton, Emily M. Santori, Maria Barrera, Haleigh Howard, Kevin R. Webster, Gary G. Chiang, Peggy A. Thompson. Inhibition of eIF4A by eFT226 blocks KRAS mutant tumor growth [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 1955.