bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5148: ADGRG1 promotes tumorigenesis, invasion/migration, and cell-cell adhesion in triple-negative breast cancer cells
Authors: Bhat Raksha , Abdulkareem Noor M. , Yasser Hala , Thangavel Hariprasad , Trivedi Meghana V. 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with the highest risk of metastatic recurrence and shortest survival in patients. Chemotherapy, the current standard of treatment for systemic therapy in TNBC, has suboptimal efficacy but high toxicity. Therefore, drugs directed against new targets exhibiting superior efficacy and excellent safety profiles are urgently needed in the treatment of metastasis in TNBC. Recently, adhesion G protein-coupled receptors (GPCRs) have shown an important role in various cancer processes. Traditionally, GPCRs are considered excellent drug targets. In this study, we aimed to evaluate the role of ADGRG1, an adhesion GPCR, in TNBC. ADGRG1 was highly expressed in basal/TNBC compared to luminal subtypes in the Tumor Cancer Genome Atlas (TCGA) Provisional datasets. Higher expression of ADGRG1 predicted poor recurrence-free survival in TNBC patients as determined using the Kaplan-Meier plotter. ADGRG1 gene and protein expression was higher in LM2 derivative with higher lung metastatic potential compared to parental MDA-MB-231 cells. ADGRG1 knockdown using 2 independent target-specific validated siRNAs reduced cell growth by MTT assay in both MDA-MB-231 parental and LM2 cells. ADGRG1 knockdown decreased mammosphere formation in MDA-MB-231 Parental cells but not in LM2 cells. ADGRG1 knockdown significantly inhibited invasion and migration of both Parental MDA-MB-231 cells and their LM2 derivatives in Trans-well assay. In addition, ADGRG1 knockdown significantly decreased cell-cell interaction in the VybrantTM Cell Adhesion assay in both cell types. ADGRG1 was significantly overexpressed in circulating tumor cell (CTC) clusters compared to single CTCs from the LM2 xenograft models. Overall, our results indicate pro-tumorigenic and pro-metastatic role of ADGRG1 which needs further validation in animal studies. Understanding the role of ADGRG1 in cell-cell adhesion as well as its signaling in TNBC are crucial in discovering its potential as a novel and druggable target in TNBC.
Citation Format: Raksha Bhat, Noor M. Abdulkareem, Hala Yasser, Hariprasad Thangavel, Meghana V. Trivedi. ADGRG1 promotes tumorigenesis, invasion/migration, and cell-cell adhesion in triple-negative breast cancer 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 5148.
Abstract 5160: A GPCR candidate in pancreatic ductal adenocarcinoma: A potential repurposing opportunity
Authors: Salmerón Cristina , Sriram Krishna , Baird Alyssa , Insel Paul A. 
Published: September 2020

Abstract
The 5-year survival of patients with pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer (90%), is very low (~9% all stages). PDAC thus requires new, effective and safe therapies. By comparing transcriptomic data for PDAC (in The Cancer Genome Atlas) with that of normal pancreas (in the GTEx database), we discovered that many G protein-coupled receptors (GPCRs) are increased in expression in PDAC. One such GPCR is the histamine receptor H1 (HRH1). GPCRs regulate metabolism, growth/death and functional activities of normal and cancer cells, including features of the malignant phenotype. GPCRs are the largest family of targets of approved drugs but have been largely ignored in cancer therapy. We found that HRH1 is prominently (~32-fold) overexpressed in PDAC tumors compared to normal pancreatic tissue and that high HRH1 expression is an unfavorable prognostic marker for PDAC patients. HRH1 mRNA is also highly expressed in multiple human PDAC cell lines. Studies with such cell lines revealed that histamine, acting via HRH1, increases intracellular Ca2+, cell proliferation and migration, effects blocked by multiple FDA-approved HRH1 antihistamines. PDAC tumors and cancer cells isolated from KPC mice also have high HRH1 expression compared to normal mouse pancreas. Similar to human PDAC cells, the KPC cells showed histamine/HRH1-promoted increase in intracellular Ca2+. Altogether, our findings identify HRH1 as a prominently overexpressed, functional GPCR in human and mouse PDAC tumors and cells. HRH1 may thus be a novel therapeutic target; its blockade by FDA-approved antihistamines represents a novel potential repurposing approach for the treatment of PDAC.
Citation Format: Cristina Salmerón, Krishna Sriram, Alyssa Baird, Paul A. Insel. A GPCR candidate in pancreatic ductal adenocarcinoma: A potential repurposing opportunity [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 5160.
Abstract 5169: Tissue analysis of NAD(P)H: quinone oxidoreductase (NQO1) and catalase expression in patients with germ cell tumors (GCT)
Authors: Sadraei Neda Hashemi , Adra Nabil , Temm Constance , Kesler Kenneth A. , Idrees Muhammad T. , Boothman David A. , Einhorn Lawrence 
Published: September 2020

Abstract
Background: Testicular germ cell tumor (GCT) is the most common cancer in young men between 15 and 35 years of age. Cisplatin-based combination chemotherapy will cure 70% of patients with metastatic GCT. Patients who relapse can still be cured with salvage standard-dose or high-dose chemotherapy. However, about 15% of patients with relapsed/refractory GCT are incurable. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase elevated in several tumor types compared to normal tissue. NQO1 detoxifies quinones and reduces oxidative stress. NQO1 bioactivatable drugs induce DNA damage in cells overexpressing NQO1, but not in cells lacking it, hence delivering tumor-selective damage and cell death. Alterations in catalase expression can cause cytoprotection. The ratio of NQO1:catalase activities is presumed to be a predictive marker for therapeutic activity of NQO1 bioactivatable drugs. There is no existing data on NQO1 or catalase expression in GCTs.
Methods: Patients with testicular or extra-gonadal GCT who had surgery between January 2016 and December 2018 were identified from the Indiana University Melvin and Bren Simon Cancer Center Tissue Bank database. Patients with non-seminomatous GCT (NSGCT) of testis or primary mediastinal NSGCT were selected and specimens obtained. Immunohistochemistry staining was performed on tumor tissue to determine the quantity and intensity of NQO1 and catalase expression.
Results: NQO1 and catalase expression were determined in 16 patients. Thirteen specimens stained moderately to strongly positive for NQO1. Only 1 specimen stained negative. Conversely, no specimen stained strongly positive for catalase, and only 2 stained moderately positive. Fourteen specimens were catalase deficient or only mildly positive for catalase. The details of the immunostaining is summarized in the table below.
Immunohistochemistry staining for NQO1 and catalase in GCTImmunostainNegative(0)Mildly positive (&lt;10%)Moderately positive (10-50%)Strongly positive (&gt;50%)NQO1Quantity01114Intensity0547Combined score1267CatalaseQuantity3472Intensity31120Combined score7720
Conclusions: NSGCTs appear to have high levels of NQO1 and deficiency of catalase. NQO1 bioactivatable agents could serve as a potential therapeutic approach in patients with refractory testicular GCTs.
Citation Format: Neda Hashemi Sadraei, Nabil Adra, Constance Temm, Kenneth A. Kesler, Muhammad T. Idrees, David A. Boothman, Lawrence Einhorn. Tissue analysis of NAD(P)H: quinone oxidoreductase (NQO1) and catalase expression in patients with germ cell tumors (GCT) [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 5169.
Abstract 5237: High-throughput slide preparation for spatially-resolved, multiplexed quantification of protein or mRNA in tumor tissues with automation of GeoMx™ DSP Assays on Leica Biosystems BOND RX
Authors: Zollinger Daniel R. , Ketting Sarah , Sorg Kristina , Appelbe Oliver , Aaker Danielle , Cockfield Damian , Merritt Chris , Beechem Joseph M. 
Published: September 2020

Abstract
Characterization of the spatial distribution and abundance of proteins and mRNAs with morphological context within tissues enables a better understanding of biological systems in many research areas, including immunology and oncology. The GeoMxTM Digital Spatial Profiler (DSP) enables the highly-multiplexed detection of mRNA or protein targets within distinct regions of tissues, including FFPE. This assay utilizes in situ hybridization (ISH) probes or antibodies linked to indexing oligo barcodes via a photo-cleavable linker. The GeoMx DSP enables profiling of RNA or protein targets by releasing and collecting these barcodes from user-defined regions-of-interest.
Manual preparation of FFPE tissue uses conventional immuno-fluorescence (IF) and ISH reagents, however it requires greater than two hours of hands-on-time over 2 days. Protocols have been developed to enable the automation of these tissue preparation protocols using the Leica Biosystems BOND RX and BOND RXm Fully Automated Research Stainers. Here we describe protocols for the semi-automated preparation of GeoMx RNA and protein assays as well as the fully-automated preparation of GeoMx RNA assays. These protocols reduce the hands-on time of performing the assay to 72 minutes and 35 minutes for the semi- and fully-automated protocols, respectively. Signal-to-noise ratios (SNR) are highly concordant between serial sections processed manually and processed on the Leica BOND RXm using the GeoMx Immune Cell Profiling Panel for protein (58-plex) and GeoMx Immune Pathways Panel for RNA (84-plex). Furthermore, automated assays show high concordance between the BOND RX and BOND RXm instruments. Lastly, we demonstrate the use of the fully automated slide preparation protocol with the GeoMx Cancer Transcriptome Atlas, a panel that targets &gt;1,600 key cancer mRNAs that are read out by next-generation sequencing.
GeoMx Assays are for RESEARCH USE ONLY. Not for use in diagnostic procedures.
Citation Format: Daniel R. Zollinger, Sarah Ketting, Kristina Sorg, Oliver Appelbe, Danielle Aaker, Damian Cockfield, Chris Merritt, Joseph M. Beechem. High-throughput slide preparation for spatially-resolved, multiplexed quantification of protein or mRNA in tumor tissues with automation of GeoMx™ DSP Assays on Leica Biosystems BOND RX [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 5237.
Abstract 5247: Interleukin-11 could be a novel therapeutic target for lung adenocarcinoma patients
Authors: Ojeda Laura , Cirauqui Cristina , Molina-Pinelo Sonia , Garrido-Martín Eva M , Ramos-Paradas Javier , Yagüe Patricia , Santos Alba , Carrizo Nuria , Enguita Ana B. , Muñoz Maria Teresa , Solorzano Jose Luis , Paz-Ares Luis , Ferrer Irene 
Published: September 2020

Abstract
Interleukin-11 (IL11) has been associated with tumorigenesis in a wide variety of tumors, including lung cancer, and it has been proposed as a diagnostic biomarker for lung adenocarcinoma. However, it is still not clear how IL11 affects the tumorigenesis. It is possible that, as other cytokines, it has a dual role in the tumor cell and tumoral microenvironment. Thus, the inhibition of IL11 could be an interesting therapeutic option to test in these patients. First, we confirmed the pro-tumorigenic effect of IL11 in patients and mouse models of lung adenocarcinoma (cancer cell lines xenografts, patient derived xenografts; PDXs and genetically engineered mouse models; GEMMs). Later, we knocked-down the expression of IL11 or its specific receptor IL11RA in adenocarcinoma cell lines in order to analyze their tumorigenic properties in vitro and in vivo. We confirmed that fibroblasts are a relevant source of IL11, so we knocked-down IL11 expression in order to analyze how it affects the fibroblasts´ properties, including the secretion of other pro-tumorigenic cytokines and growth factors. We reported that an increased expression of IL11 correlates with a poorer survival in lung adenocarcinoma patients and that IL11 stimulation increases the proliferation rates in xenografts, PDXs and GEMMs. On the contrary, IL11 or IL11RA knockdown in adenocarcinoma cell lines reduces their pro-tumorigenic properties in vitro and in vivo. Finally, the silencing of IL11 in fibroblasts reduces their proliferation, migration and secretion of pro-tumorigenic cytokines and growth factors. In conclusion, we propose that IL11 plays a direct pro-oncogenic role in lung adenocarcinoma tumoral cell and an indirect role in tumoral microenvironment. The genetic ablation of IL11 has an anti-tumoral effect, so it could be interesting to develop a pharmacological tool which neutralizes the IL11-IL11RA signaling to test as a therapeutic strategy in preclinical models. Thus, IL11 could represent a potential therapeutic target that deserves to be more exhaustively studied in the clinical settings.
Citation Format: Laura Ojeda, Cristina Cirauqui, Sonia Molina-Pinelo, Eva M Garrido-Martín, Javier Ramos-Paradas, Patricia Yagüe, Alba Santos, Nuria Carrizo, Ana B. Enguita, Maria Teresa Muñoz, Jose Luis Solorzano, Luis Paz-Ares, Irene Ferrer. Interleukin-11 could be a novel therapeutic target for lung adenocarcinoma 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 5247.
Abstract 5276: Secretory pathway calcium ATPase 2 (SPCA2) promotes cell survival and chemoresistance in receptor positive breast cancer cells
Authors: Makena Monish Ram , Dang Donna , Mekile Allatah , Buckhaults Phillip , Rao Rajini 
Published: September 2020

Abstract
Introduction: Dysregulation of the Ca2+ toolkit has profound consequences for tumor growth and metastasis, raising hopes for novel avenues of therapeutic intervention. The Secretory Pathway Ca2+-ATPase Isoform 2 (SPCA2) has a dual function in sequestering Ca2+ and Mn2+ into secretory stores as well as eliciting their entry into cells by activating plasma membrane ion channels. We have previously showed that SPCA2 is implicated in breast cancer progression, microcalcifications, epithelial-mesenchymal transition, and metastasis.
Methods and Results: High SPCA2 expression was associated with poor overall survival in receptor positive breast cancer patients (n=548, P =8.7e-0.6; KM Plotter). Depletion of SPCA2 (SPCA2 KD) in MCF-7 cells significantly reduced cell proliferation (P &lt; 0.05). Analysis of the cell cycle (PI staining, Flow cytometry) revealed a significant increase (P &lt; 0.05) in the number of cells in the G0/G1 phase, and significant increase in apoptosis (via TUNEL assay) (P &lt; 0.05) in SPCA2 KD cells compared to control. Microarray analysis showed the p53 pathway is the most significantly upregulated pathway (P &lt; 0.05) in SPCA2 KD cells compared to control. P53 knockout abrogated SPCA2 mediated cell cycle arrest and apoptosis. Depletion of SPCA2 increased reactive oxygen species (ROS, measured by DCFDA dye and MitoSox Red using flow cytometry) leading to DNA damage (confocal microscopy), and activation of ATM/ATR pathway (Immunoblotting, P &lt; 0.05). As a consequence, SPCA2 KD cells showed specific hypersensitivity to DNA damaging agents used in breast cancer therapy (carboplatin, radiation, and doxorubicin) (determined by MTT assay) (P &lt; 0.05). Thus SPCA2 is a novel molecular target in breast cancer therapy. Curcumin is currently being evaluated in clinical trials of breast cancer. We show that curcumin causes dose-dependence inhibition of SPCA2 expression (P &lt; 0.05) in multiple receptor-positive cell lines, and that forced overexpression of SPCA2 decreased curcumin cytotoxicity. Interestingly, we did not observe these results with SPCA1, the housekeeping SPCA isoform, revealing isoform-specific function of Golgi calcium pumps in breast cancer subtypes.
Conclusion: These novel findings point to a causal link between SPCA2, breast cancer progression, and chemoresistance to DNA damaging agents. Decrease of SPCA2 expression by curcumin may have therapeutic potential in treating receptor positive breast cancer.
Citation Format: Monish Ram Makena, Donna Dang, Allatah Mekile, Phillip Buckhaults, Rajini Rao. Secretory pathway calcium ATPase 2 (SPCA2) promotes cell survival and chemoresistance in receptor positive breast cancer 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 5276.
Abstract 5328: mTOR inhibitor enhances anti-tumor effect of BET bromodomain inhibitor in small cell lung cancer
Authors: KUMARI ANJU , Gesumaria Lisa , Fetsch Patricia , Miettinen Markku , Hughitt Keith , Mock Beverly , Thomas Craig , Schrump David S. , Chen Haobin 
Published: September 2020

Abstract
Introduction: Small cell lung cancer (SCLC) is one of the two recalcitrant cancers designated by NCI, and its 2-year survival rate has not improved over the past two decades. Novel therapy is urgently needed. BET bromodomain inhibitor (BETi), which targets transcriptional coactivator BET bromodomain proteins, has been reported to be effective in SCLC. However, given that SCLC is notorious for rapid development of drug resistance, it is necessary to identify drugs that can synergize with BETi to form a combinatorial drug regimen.
Methods: A high-throughput drug combination matrix screen was performed to identify potential agents that can synergize with BETi. Synergy between the identified candidate drugs and BETi was further validated in various SCLC cell lines by using the CellTiter-Glo assay as well as in several SCLC PDX models by examining tumor growth suppression and survival of tumor-bearing mice. Cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP) was analyzed by IHC and western blot in SCLC PDX tumors and in vitro cell lines to assess apoptosis after drug treatment, respectively.
Results: The high-throughput screen identified multiple inhibitors of the PI-3K/AKT/mTOR pathway to synergize with BETi by causing a significantly higher rate of apoptosis and cell growth inhibition. A comparison among the inhibitors that specifically target PI-3K, AKT or mTOR revealed that the combination of BETi and mTOR inhibitor (mTORi) have the highest level of synergy. The BETi/mTORi combo also showed synergy in several SCLC cell lines that are initially resistant to single agent BETi. The antitumor effect of the BETi/mTORi combinatorial treatment was further confirmed in several SCLC PDX mouse models. When compared to either single agent or vehicle, the BETi/mTORi combo treatment led to a greater degree of tumor growth suppression and a more prolonged survival of the tumor-bearing mice. This enhanced antitumor effect is connected with a significantly more apoptosis (cleaved caspase 3 or PARP) found in SCLC tumor tissues and cell lines treated with the BETi/mTORi combo.
Conclusion: mTORi can enhance the antitumor effect of BETi in SCLC by causing more apoptosis.
Citation Format: ANJU KUMARI, Lisa Gesumaria, Patricia Fetsch, Markku Miettinen, Keith Hughitt, Beverly Mock, Craig Thomas, David S. Schrump, Haobin Chen. mTOR inhibitor enhances anti-tumor effect of BET bromodomain inhibitor in 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 5328.
Abstract 5547: Synergistic action of sitagliptin and checkpoint inhibition for ovarian cancer therapy
Authors: Moffitt Laura R. , Wilson Amy L. , Basri Bashirah , Wilson Kirsty L. , Plebanski Magdalena , Stephens Andrew N. 
Published: September 2020

Abstract
Ovarian cancer is the most lethal gynecological malignancy and treatment options have not improved in decades. Whilst ovarian tumors have an immune-mediated component, emerging immunotherapies (e.g. anti-PD-1, anti-PD-L1) have failed to achieve robust clinical response for ovarian cancer patients. There is an urgent need to develop new therapeutic strategies to improve survival rates in women, particularly those with recurrent, chemoresistant disease. In an ongoing study we are investigating the repurposing of sitagliptin, an anti-diabetes drug, as a novel immunomodulatory therapy in ovarian cancer. Ovarian tumors were generated in C57BL/6 wild-type mice by intrabursal implantation of ID8 murine ovarian cancer cells. Following the formation of primary tumors (~2 weeks), mice received a daily oral dose of sitagliptin (50mg/kg) until ethical endpoint. Anti-tumor immune responses were examined by flow cytometry and immunohistochemical staining according to tumor stage. Mice were assessed for overall survival compared to paclitaxel chemotherapy as standard-of-care. Daily sitagliptin treatment increased circulating Teff:Treg cell ratios in the blood, peritoneal fluid and tumor tissue at an early stage, and this was sustained throughout disease. Sitagliptin also enhanced T effector cell activation and proliferation, indicating that increased Teff:Treg ratios were a positive indicator of the anti-tumor immune response. Treatment with sitagliptin alone increased median survival time by 27% compared to both untreated controls and paclitaxel as standard-of-care, suggesting a beneficial effect mediated by anti-tumor immune responses. Of particular interest, sitagliptin treatment specifically increased the percentage of CXCR3+ T effector cells in the peritoneal cavity. Recent data has suggested that CXCR3+ T cells are functionally required for immune checkpoint inhibitors to exert efficacy. Thus, we hypothesize that sitagliptin may enhance the efficacy of immune checkpoint inhibitor therapies in ovarian cancers. Our ongoing studies are investigating the combination of sitagliptin with anti-PD-1 and anti-PD-L1 antibodies, as a rational approach to improving their efficacy in ovarian cancers. These studies will identify a clinically relevant and directly translatable approach to improve prognosis for ovarian cancer patients.
Citation Format: Laura R. Moffitt, Amy L. Wilson, Bashirah Basri, Kirsty L. Wilson, Magdalena Plebanski, Andrew N. Stephens. Synergistic action of sitagliptin and checkpoint inhibition for ovarian cancer therapy [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 5547.