bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4059: CRISPR-EXO - genetic deletion tool for treating chronic myelogenous leukemia
Authors: Lainšček Duško , Forstnerič Vida , Malenšek Špela , Skrbinek Mojca , Sever Matjaž , Jerala Roman 
Published: September 2020

Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplastic disease, occurring in 1 to 2 cases per 100.000 adults, which accounts for ~ 15 % of newly diagnosed leukemias in adult patients. The diagnosis is based upon the genetic translocation between the t(9;22)(q34;q11.2), resulting in the formation of Philadelphia fusion chromosome, coding for BCR-ABL1 oncoprotein. The life-long treatment relies on tyrosine kinase inhibitors (TKIs). In nearly in 2 % patients develop point mutations, leading to resistance to TKIs treatment. New solutions for treating cancer with genetic etiology are considered. CRISPR/Cas system, composed of guide RNA, targeting endonuclease Cas9 to specific target genomic region has been used before to mediate breakage of Philadelphia chromosome at the site of oncogenic translocation. We present a strategy to couple Cas9 to the exonuclease to promote large deletions at the cancer-specific target genomic site. Cotransfection with EXOIII exhibited the best increase in deletion formation of all tested exonucleases. To further improve the rate of genetic lesion formation, Cas9 and EXOIII were connected via coiled-coil heterodimer forming peptides, bringing the two enzymes into close proximity (CRISPR-EXO). This resulted in a potent increase of deletion formation compared to the standard CRISPR/Cas, cotransfection and genetic fusion. We performed an animal study for the use of the CRISPR-EXO system as a potential anti-cancer therapeutic tool. In case of the CRISPR-EXO system, we showed a significant increase in cell death due to higher genome editing in the BCR-ABL1 region. These findings were confirmed also in an animal cancer model, where animals with tumors, electroporated with CRISPR-EXO system showed improved survival and drastic reduction in tumor size.CRISPR-EXO upgraded CRISPR system based on tethering Cas9 protein to exonuclease EXOIII by heterodimeric coiled-coil forming peptides, resulted in highly efficient editing of BCR-ABL1 fusion gene, leading to enhanced death of CML cancer cells.
Citation Format: Duško Lainšček, Vida Forstnerič, Špela Malenšek, Mojca Skrbinek, Matjaž Sever, Roman Jerala. CRISPR-EXO - genetic deletion tool for treating chronic myelogenous leukemia [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 4059.
Abstract 4070: Development of MAEGI as a new class of immune gene therapy for cancer treatment
Authors: Chen Sidi 
Published: September 2020

Abstract
Current major types of immunotherapy include checkpoint blockade, adoptive cell transfer, human recombinant cytokines, and cancer vaccines. However, immunotherapy has met challenges in immunologically cold tumors. These challenges urge for new types of immunotherapies that are more potent and potentially less toxic. Recently, we have developed CRISPRa-mediated Multiplexed Activation of Endogenous Genes as an Immunotherapy (MAEGI) (Wang et al. 2019 Nature Immunology, in press). The CRISPR activation (CRISPRa) system uses a catalytically inactive Cas9 (dCas9), enabling simple and flexible gene expression regulation through dCas9-transcriptional activators paired with single guide RNAs (sgRNAs). This enables precise targeting of large gene pools of endogenous genes in a flexible manner. We demonstrate that MAEGI has therapeutic efficacy across three tumor types. Mechanistically, our preliminary work showed that MAEGI treatment elicits anti-tumor immune responses by recruiting effector T cells and remodeling the tumor microenvironment. We will perform advanced development, characterization and optimization of MAEGI, as a novel immune-gene therapy approach to elicit a potent and specific immune response to tumors based on their unique genetic composition.
Citation Format: Sidi Chen. Development of MAEGI as a new class of immune gene therapy for cancer treatment [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 4070.
Abstract 4140: Dissecting the structural basis for rational inhibitor design: Crystal and solution structures of human oncoprotein Musashi-2 N-terminal RNA recognition motif 1
Authors: Lan Lan , Xing Minli , Kashipathy Maithri , Douglas Justin , Gao Philip , Battaile Kevin , Hanzlik Robert , Lovell Scott , Xu Liang 
Published: September 2020

Abstract
RNA-binding proteins (RBPs) are key regulators of cellular functions, especially in post-transcriptional regulations. Dysregulation of RBPs is implicated in many diseases including cancer. One of the RBPs that is overexpressed in a variety of human cancer is Musashi-2 (MSI2). Elevated MSI2 expression is associated with ectopic oncogenic pathways including but not limited to NUMB/Notch, PTEN/mTOR, TGF-β/SMAD3, making MSI2 a promising therapeutic target for cancer. Protein structure is critical for drug discovery and structure-based rational design. Both MSI1 and MSI2 proteins contain two N-terminal RNA recognition motifs and play roles in post-transcriptional regulation of target mRNAs. We have identified several inhibitors of MSI1, all of which bind to MSI2 as well. In order to design MSI2 specific inhibitors and compare the differences of binding mode of the inhibitors, we set out to solve the structure of MSI2-RRM1, the key motif that is responsible for the binding. Here we report the crystal structure and the first NMR solution structure of MSI2-RRM1, and compare these to the structures of MSI1-RBD1 and other RNA binding proteins. A high degree of structural similarity was observed between the crystal and solution NMR structures. MSI2-RRM1 shows a highly similar overall folding topology to MSI1-RBD1 and other RNA binding proteins. The structural information of MSI2-RRM1 will be helpful for understanding MSI2-RNA interaction and for guiding rational design of MSI2 specific inhibitors.
Citation Format: Lan Lan, Minli Xing, Maithri Kashipathy, Justin Douglas, Philip Gao, Kevin Battaile, Robert Hanzlik, Scott Lovell, Liang Xu. Dissecting the structural basis for rational inhibitor design: Crystal and solution structures of human oncoprotein Musashi-2 N-terminal RNA recognition motif 1 [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 4140.
Abstract 4145: Performance of IntelliPlexTM companion diagnostics application in cancer management
Authors: Felicioni Lara , Buttitta Fiamma , Marchetti Antonio , Hu ShianPin , Chao ChenHung , Liang WenKai , Hu JuiYu , Palmer Stuart , Huang ChinShiou 
Published: September 2020

Abstract
Background: Cancer is a group of various diseases with diverse causes which lead to the uncontrolled growth of abnormal cells. Understanding the genetic alteration in genes associated with cancer optimizes therapy outcomes by tailoring treatment based on each patient genetic basis. Molecular profiling is therefore a crucial tool for precision medicine to improve cancer management.
Method: The IntelliPlexTM system, based on πCodeTM technology, provides a multiplexing solution for molecular profiling in just one reaction. PlexBio developed several single target gene assays utilizing DNA samples derived from formalin-fixed paraffin-embedded (FFPE) tumor tissues. The IntelliPlex EGFR Mutation kit is intended for detection of 40 mutations in the EGFR gene. The IntelliPlex BRAF V600 Mutation Kit is designed for identification of 7 nucleotide changes. The IntelliPlex KRAS Mutation Plus kit targets 25 single nucleotide changes in the KRAS gene and the IntelliPlex NRAS Mutation qualitative detects 33 single nucleotide changes in the NRAS gene. All IntelliPlex assays analyze the mutational status of each target in less than 5 hours (nucleic acid extraction not included) and allow high-throughput screening of up to 94 samples in parallel with minimal hands-on time. The performance of IntelliPlex system was evaluated on archived FFPE DNA specimens by comparing the results of the respective IntelliPlex assay with results previously obtained using the indicated commercially available molecular assays. All tests were conducted in a hospital lab located in Italy.
Results: Among 76 FFPE DNA specimens tested, the overall agreement between IntelliPlex system and the comparison method was found to be 93.4%. The individual concordance for each assay kit is 90.0%, 95.8%, 93.8%, and 93.8% for EGFR, KRAS Plus, NRAS and BRAF, respectively.
Conclusion: PlexBio's IntelliPlexTM system, a multiplex detection platform, is suitable to support precision medicine in cancer management. The system offers a rapid and cost-effective way to analyze patient specimens with high sensitivity and specificity in a clinical environment.
Citation Format: Lara Felicioni, Fiamma Buttitta, Antonio Marchetti, ShianPin Hu, ChenHung Chao, WenKai Liang, JuiYu Hu, Stuart Palmer, ChinShiou Huang. Performance of IntelliPlexTM companion diagnostics application in cancer management [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 4145.
Abstract 4195: Steviol induces pancreatic cancer cell death via targeting glucose metabolism and protein translation pathways
Authors: Kumari Sonam , Khan Sheema , Sikander Mohammed , Malik Shabnam , Chauhan Subhash C. , Jaggi Meena 
Published: September 2020

Abstract
Background Pancreatic cancer is one of the deadliest malignancies, and fourth leading cause of cancer-related deaths in the United States. Aberrant glucose metabolism in cancer cells leads to enhanced tumor growth and aggressiveness. Herein, we have identified an important constituent, steviol from the plant Stevia rebaudiana, which inhibits pancreatic cancer cells via modulation of glucose metabolism and protein translation.
Methods Glucose and Lactate assays were performed in pancreatic cancer cells (HPAF-II and AsPC1) using kits purchased from Cayman Chemical. The effect of steviol on the growth, colonization and invasion of pancreatic cancer cells was determined by using in vitro functional assays for cell viability (MTT and xCELLigence), migration (Boyden chambers), invasion (Matrigel) and colonogenicity. The cell cycle study was performed using propidium iodide and analysis done through ModFit software. Immunoblotting was performed to analyze the expression of key proteins associated with translation machinery and apoptotic signaling pathways.
Results Our results demonstrate that steviol inhibits proliferation and invasion of pancreatic cancer cells and modulates their glucose uptake and lactate secretion. Steviol treatment regulates the expression of proteins that control the translation machinery in a cell, which include mTOR, 4EBP1, eIF4E, eIF4B and eIF4G. Treatment of cells with steviol was observed to modulate cell cycle regulatory proteins, including p18, p21 and Cyclin D1 and block the cell cycle progression at G1 phase This followed the activation of apoptosis as indicated by upregulation of apoptotic protein, Bax and PARP cleavage.
Conclusion: These results suggest that steviol suppresses pancreatic cancer growth and progression by regulating the glucose metabolism and protein translation. This prospects steviol as a promising therapeutic modality for pancreatic cancer prevention and treatment alone or in combination with other existing chemotherapeutic drugs.
Citation Format: Sonam Kumari, Sheema Khan, Mohammed Sikander, Shabnam Malik, Subhash C. Chauhan, Meena Jaggi. Steviol induces pancreatic cancer cell death via targeting glucose metabolism and protein translation pathways [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 4195.
Abstract 4217: Synergy of tyrosine kinase inhibitor HQP1351 and MDM2-P53 antagonist, APG-115, in preclinical models of FLT3 mutant and TP53 wild-type acute myeloid leukemia
Authors: Fang Douglas D. , Tang Qiuqiong , Wang Qixin , Li Na , Fang Xu , Gu Jiaxing , Kong Yanhui , Rong Tao , Wang Guangfeng , Yang Dajun , Zhai Yifan 
Published: September 2020

Abstract
HQP1351 is a novel, orally bioavailable multi-kinase inhibitor targeting BCR-ABL, KIT, and FLT3. Currently, HQP1351 is in phase II clinical trials in relapsed and refractory chronic myeloid leukemia (CML) patients by targeting BCR-ABL. Besides, HQP1351 inhibits both wild-type and mutant FLT3 in kinase binding assay. APG-115 is another clinical stage, small molecule MDM2 antagonist. In the present study, we explored the antitumor effect of the combination of HQP1351 and APG-115, and the molecular mechanism in FLT3-ITD and TP53 wild-type acute myeloid leukemia (AML) in the preclinical setting. First, the effect of HQP1351 as single agent on cell viability in FLT3-ITD mutant and TP53 wild-type human AML cell lines, including MV-4-11 and MOLM-13. Second, antitumor activity of the combination was investigated in systemic and subcutaneous xenograft models in NOD/SCID mice derived from these cells. The results showed that HQP1351 alone exhibited potent antiproliferative activity in both cell lines in vitro, with nanomolar IC50 values. The activity was enhanced in the combination treatment with APG-115. In vivo, HQP1351 single agent demonstrated significant antitumor activity evidenced by a markedly reduction of tumor burden (i.e., CD45+ human tumor cells) in systemic MOLM-13 xenograft model. Treatment with HQP1351 at 3, 10 and 30 mg/kg significantly prolonged mice survival with median survival of 20.5 days, 26.0 days and 35 days, respectively, compared with 18 days in the control group. In subcutaneous MV-4-11 xenograft model, treatment with HQP1351 or APG-115 single agents achieved T/C values of 28.6% and 59.6%, respectively. The combination achieved synergistic antitumor activity with a T/C value of 13.4%. The benefit of the combination was also demonstrated in systemic MOLM-13 xenograft model. Mechanistically, the combined treatment synergistically downregulated p-FLT3, p-ERK, p-STAT5 and anti-apoptotic protein MCL-1, and thus enhanced antitumor effect. Taken together, our data provide scientific rationale for clinical development of the combination of HQP1351 and APG-115 in FLT3-ITD mutant and TP53 wild-type AML patients.
Citation Format: Douglas D. Fang, Qiuqiong Tang, Qixin Wang, Na Li, Xu Fang, Jiaxing Gu, Yanhui Kong, Tao Rong, Guangfeng Wang, Dajun Yang, Yifan Zhai. Synergy of tyrosine kinase inhibitor HQP1351 and MDM2-P53 antagonist, APG-115, in preclinical models of FLT3 mutant and TP53 wild-type acute myeloid leukemia [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 4217.
Abstract 4257: Detection of bone marrow metastases: Comparison of functional magnetic resonance imaging with bone marrow biopsy and aspiration
Authors: Zhao Hui , Wang Zhiyu , Li Yue Hua 
Published: September 2020

Abstract
Bone marrow metastases are frequently detected by unilateral bone marrow biopsy and aspiration (BMBA), which is invasive. In this study, the value of functional magnetic resonance imaging (MRI) of pelvis was compared with BMBA and its clinical implication was evaluated. Cancer patients with bone metastasis and CT scan of pelvis showed no bone metastasis at the site of BMBA were included. BMBA was performed after MRI scan. Apparent Diffusion Coefficient (ADC), volume transfer constant (Ktrans), Pure diffusion coefficient (D), Pseudo diffusion coefficient (D*) and Perfusion fraction (f) were detected. The sensitivity, specificity and accuracy of MRI was calculate. An internal cross-validation via bootstrap was conducted for MRI performance in terms of the area under the curve (AUC). 28 oncological patients (11 breast cancer, 8 lung cancer, 5 prostatic cancer; 4 other cancers ) were enrolled. 16 patients were confirmed bone marrow metastases by BMBA. The sensitivity, specificity and accuracy of MRI was 93%, 50% and 75%. The ROC of Ktrans was 78%, which was the best. MRI can be used as a supplement to BMBA to diagnose bone marrow metastasis.
Citation Format: Hui Zhao, Zhiyu Wang, Yue Hua Li. Detection of bone marrow metastases: Comparison of functional magnetic resonance imaging with bone marrow biopsy and aspiration [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 4257.
Abstract 4327: Progranulin (GP88) is an independent prognostic factor for prostate cancer patients
Authors: Taubert Helge W. , Abdulrahman Amer , Eckstein Markus , Jung Rudolf , Guzman Juan , Weigelt Katrin , Serrero Ginette , Yue Binbin , Geppert Carol , Stöhr Robert , Hartmann Arndt , Wullich Bernd , Wach Sven 
Published: September 2020

Abstract
Prostate cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study was to characterize GP88 protein expression in PCa by immunohistochemistry and to correlate the findings to the clinico-pathological data and prognosis. Immunohistochemical staining for GP88 was performed by TMA with samples from 442 PCa patients using an immunoreactive score (IRS). Altogether, 233 cases (52.7%) with negative GP88 staining (IRS&lt;2) and 209 cases (47.3%) with positive GP88 staining (IRS≥2) were analyzed. A significant positive correlation was found for the GP88 IRS with the PSA value at prostatectomy and the cytoplasmic cytokeratin 20 IRS, whereas it was negatively associated with follow-up times. The association of GP88 staining with prognosis was further studied by survival analysis (Kaplan-Meier, univariate and multivariate Cox's regression analysis). Increased GP88 protein expression appeared as independent prognostic factor for overall, disease-specific and relapse-free survival in all PCa patients. Interestingly, in the subgroup of younger PCa patients (≤65 years), GP88 positivity was associated with a 3.8-fold (P=0.004), a 6.0-fold (P=0.008) and a 3.7-fold (P=0.003) increased risk for death, disease-specific death and occurrence of a relapse, respectively. This finding gains impact against the background of increasing numbers of PCa cases among younger men below 65 years of age. Summarizing, GP88 protein positivity appears to be an independent prognostic factor for PCa patients.
Citation Format: Helge W. Taubert, Amer Abdulrahman, Markus Eckstein, Rudolf Jung, Juan Guzman, Katrin Weigelt, Ginette Serrero, Binbin Yue, Carol Geppert, Robert Stöhr, Arndt Hartmann, Bernd Wullich, Sven Wach. Progranulin (GP88) is an independent prognostic factor for prostate cancer patients [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 4327.
Abstract 4443: Inhibition of PGE2/EP4 pathway by ONO-4578/BMS-986310, a novel EP4 antagonist, promotes T cell activation and myeloid cell differentiation to dendritic cells
Authors: Kotani Tohru , Takano Hirotsugu , Yoshida Tomoko , Hamasaki Ryota , Kohanbash Gary , Takeda Kazuhiko , Okada Hideho 
Published: September 2020

Abstract
Prostaglandin E2 (PGE2) contributes to immunosuppression in the tumor microenvironment through one or more of its receptors (EP1-EP4), especially EP4 which is expressed at high levels on myeloid cells. ONO-4578/BMS-986310 is a novel EP4-selective antagonist that potently inhibits the PGE2-induced cAMP production in CHO cells expressing mouse and human EP4 receptors with single-digit nM IC50. Furthermore, ONO-4578/BMS-986310 shows excellent pharmacokinetic properties after oral dosing in mouse. ONO-4578/ BMS-986310 reverses PGE2-mediated suppression of T cell activation and promotes DC differentiation in vitro. Moreover, treatment with ONO-4578/BMS-986310 inhibits growth of CT26 and MC38 tumors in syngeneic mouse. The anti-tumor effect of ONO-4578/BMS-986310 is abrogated in immuno-deficient mice bearing CT26 tumors indicating that such effect is immune-mediated. ONO-4578/BMS-986310 treatment significantly prolongs survival of mice with highly aggressive SB28 gliomas in the brain. Flow cytometric analysis reveals that ONO-4578/BMS-986310 reduces infiltration of M2 macrophages in MC38 tumors compared with control mice. Microarray analysis of MC38 tumor tissues demonstrates up-regulation of cytotoxic T lymphocytes, natural killer cells and innate immunity-related genes after treatment with ONO-4578/BMS-986310. Finally, a combination of ONO-4578/BMS-986310 and anti-PD-1 antibody results in enhanced anti-tumor effects in GL261 and MC38 tumor-bearing mice compared with anti-PD-1 monotherapy.Our data demonstrate that ONO-4578/BMS-986310 promotes anti-tumor immunity and may be useful in the treatment of cancer patients. ONO-4578/BMS-986310 is being evaluated as monotherapy and in combination with nivolumab in an ongoing Ph1/1b clinical trials in patients with advanced solid tumors (NCT03155061, NCT03661632).
Citation Format: Tohru Kotani, Hirotsugu Takano, Tomoko Yoshida, Ryota Hamasaki, Gary Kohanbash, Kazuhiko Takeda, Hideho Okada. Inhibition of PGE2/EP4 pathway by ONO-4578/BMS-986310, a novel EP4 antagonist, promotes T cell activation and myeloid cell differentiation to dendritic 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 4443.