bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2961: Ganoderma lucidum extracts inhibit mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
Authors: Huang Shile , Sohretoglu Didem , Zhang Chao , Luo Jun 
Published: August 2019

Abstract
Ganoderma lucidum (G. lucidum) extracts, as dietary supplements, have been found to possess potent anticancer activity, which is attributed to the presence of polysaccharides and triterpenes. However, the molecular mechanism underlying the anticancer action of G. lucidum extracts remains to be elucidated. Here we show that ReishiMax GLp, containing both polysaccharides and triterpenes of G. lucidum (GLPT), inhibited cell proliferation and induced cell death in human lung cancer cells (A549 and A427), and concurrently suppressed the signaling pathways mediated by the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation and survival. Interestingly, GLPT not only inhibited mTORC1-mediated phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), but also repressed mTORC2-mediated phosphorylation of Akt. Mechanistically, GLPT downregulated the phosphorylation and protein levels of insulin-like growth factor 1 receptor (IGFR) and phosphoinositide 3-kinase (PI3K), as well as the protein level of RAS homolog enriched in brain (Rheb). Besides, GLPT also activated AMP-activated protein kinase (AMPK) network. This is supported by the findings that GLPT increased the phosphorylation of AMPKα (T172), as well as its substrates tuberous sclerosis complex 2 (TSC2, S1387) and regulatory-associated protein of mTOR (raptor, S792). Ectopic expression of dominant negative AMPKα partially attenuated the inhibitory effect of GLPT on mTORC1, indicating that GLPT inhibits mTORC1 partly via activating AMPK. The results suggest that G. lucidum extracts execute the anticancer action at least partly by inhibiting the mTORC1/2 signaling through activation of AMPK and inhibition of IGFR/PI3K/Rheb in tumor cells. Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA.
Citation Format: Shile Huang, Didem Sohretoglu, Chao Zhang, Jun Luo. Ganoderma lucidum extracts inhibit mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2961.
Abstract 2962: Targeting BCL2 as a therapeutic strategy in neuroendocrine prostate cancer
Authors: Corella Alexandra N. , Lucas Jared M. , Kaipainen Arja , Coleman Ilsa M. , Morrissey Colm , Corey Eva , Nghiem Paul , MacPherson David , Nelson Peter S. 
Published: August 2019

Abstract
Small-cell neuroendocrine prostate carcinoma (SC/NEPC) is an aggressive subtype of prostate cancer (PC) with poor response to conventional therapies and no approved targeted therapies. The molecular mechanisms that drive the growth and survival of these tumors are poorly understood due to disease rarity and a lack of model systems for the subtype. SC/NEPC shares defining characteristics with other aggressive small-cell neuroendocrine tumors, such as “small-blue round cell” morphology and expression of chromogranin A. In this study, we compare whole transcriptome RNA-sequencing data from metastatic PCs and two additional SC/NE tumor types, small cell lung cancer (SCLC) and Merkel Cell carcinoma (MCC). By differential expression analysis of each neuroendocrine tumor type to Androgen Receptor-responsive Prostate Cancer (AR-PC), we identify 4,300 genes exhibiting shared expression patterns in multiple neuroendocrine tumor types. Among these “pan-neuroendocrine” genes are known and proposed drivers of the neuroendocrine transcriptional program including MYCN (p=8.7E-07, upregulated in SC/NEPC over AR-PC) and potential novel drivers of the neuroendocrine phenotype in PC such as MYCL (p=3.5E-05, upregulated in SC/NEPC over AR-PC). We also identify conserved expression patterns of druggable targets including BCL2 which has previously been reported as highly expressed in subsets of SCLC and MCC, but not SC/NEPC (p=1.24E-05, upregulated in SC/NEPC over AR-PC). We then analyzed a panel of cell lines and novel PDX models, which further confirm that the BCL2 protein is highly expressed specifically in the SC/NEPC phenotype. We determined that SC/NEPC cell lines and PDX models are sensitive to BCL2 family member inhibitors targeting BCL2, BCLXL, BCLW, including, ABT263, ABT199 and ABT737, at sub-micromolar concentrations, whereas models of ARPC were resistant. These inhibitors lead to apoptotic cell death in SC/NEPC. Collectively, our data suggests that BCL2 inhibition may present a novel targeted approach for SC/NEPC that warrants further evaluation.
Citation Format: Alexandra N. Corella, Jared M. Lucas, Arja Kaipainen, Ilsa M. Coleman, Colm Morrissey, Eva Corey, Paul Nghiem, David MacPherson, Peter S. Nelson. Targeting BCL2 as a therapeutic strategy in neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2962.
Abstract 2969: The antiviral agent Cidofovir induces DNA damage and mitotic catastrophe in HPV-positive and -negative head and neck squamous cell carcinomas in vitro
Authors: Speel Ernst-Jan M. , Verhees Femke , Legemaate Dion , Jacobs Robin , Haakma Wisse E. , Rousch Mat , Kremer Bernd 
Published: August 2019

Abstract
Objectives: Cidofovir (CDV) is an antiviral agent with anti-proliferative properties and is suggested as treatment option in head and neck squamous cell carcinoma (HNSCC) patients to improve outcome and quality of life. The mechanisms underlying the effectivity of CDV are not completely understood. The aim of our study was to investigate the efficacy of CDV in HPV-positive and -negative HNSCC cell lines in vitro and whether it is caused by a difference in response to DNA damage.
Materials and methods: Upon CDV treatment of HPV-positive and -negative HNSCC-, uterine cervical carcinoma (UCC)- and immortalized NOK- cell lines, cell viability was assessed with a MTT assay. Accumulation of DNA double strand breaks (DSBs) and activation of the DNA repair pathway were analyzed using immunofluorescence (IF) and Western blotting (WB), respectively. Apoptosis was detected by cleaved-PARP (WB) and mitotic catastrophe by phospho-Aurora Kinase and Cyclin B1 (IF).
Results: All cell lines responded to CDV. Treatment resulted in γ-H2AX accumulation and upregulation of DNA repair proteins, especially in the HPV-positive cells. CDV did not induce PARP cleavage but induced Cyclin B1 expression. Phospho-Aurora Kinase immunostaining showed a decrease in number of mitoses but an increase in aberrant mitoses suggesting mitotic catastrophe upon CDV treatment.
Conclusion: CDV inhibits cell growth in HPV-positive and -negative HNSCC and UCC cell lines which was more profound in HPV-positive cell lines. CDV treated cells showed accumulation of DNA DSBs. Although the DNA repair was activated, apoptosis did not occur. Rather our data indicate the occurrence of mitotic catastrophe.
Citation Format: Ernst-Jan M. Speel, Femke Verhees, Dion Legemaate, Robin Jacobs, Wisse E. Haakma, Mat Rousch, Bernd Kremer. The antiviral agent Cidofovir induces DNA damage and mitotic catastrophe in HPV-positive and -negative head and neck squamous cell carcinomas in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2969.
Abstract 2999: Hybrid complex between bispecific peptide and antibody for targeted cancer therapy
Authors: Yu Byeongjun , Hwang Dobeen , Jon Sangyong , Chung Junho 
Published: August 2019

Abstract
Antibodies have been used for cancer therapy for two decades, but they suffer from poor localization and penetration into solid tumors because of their large size. Peptides can be an alternative for treatment of solid tumors due to their small size. However, therapeutic use of peptides is limited because of their short plasma half-life. We present a new molecular platform based on a hybrid complex between bispecific peptide and antibody, designated as HyPEP-body, composed of bispecific peptides labeled with a hapten as a pharmacophore and an anti-hapten antibody. Two different peptides are joined together with linker and then, labeled with the hapten. The bispecific pharmacophore are bound to the anti-hapten antibody through antigen-antibody interaction. The pharmacophores which can be chemically optimized or replaced with other peptides are in charge of therapeutic function, while the antibody imparts long plasma half-life. As a model study, we constructed HyPEP-body that simultaneously binds extra domain B (EDB) and vascular endothelial growth factor (VEGF) with EDB binding peptide, VEGF binding peptide, cotinine and anti-cotinine antibody. Complexation with the antibody extended the plasma half-life of the bispecific pharmacophores. Furthermore, bispecific pharmacophores released from the antibodies distributed more widely in the tumor tissue than the antibodies. Finally, treatment of the HyPEP-body inhibited tumor growth in U87MG, human glioblastoma, xenograft mouse model. This versatile hybrid platform will enhance the value of peptide therapeutics and suggest an innovative solution to the development of bispecific antibodies that has suffered from productivity issues.
Citation Format: Byeongjun Yu, Dobeen Hwang, Sangyong Jon, Junho Chung. Hybrid complex between bispecific peptide and antibody for targeted cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2999.
Abstract 30: The development of a 3D cell-culture model of drug-induced oral mucositis
Authors: Lambros Maria P. , Fei QinQin , Moreno Jonathan 
Published: August 2019

Abstract
Purpose: Mucositis is a debilitating disease affecting cancer patients. Mucositis is an adverse effect of radiation or chemotherapy. In the past, our lab has developed a model of radiation-caused mucositis using a validated human tissue substitute of oral mucosa and studied the post radiation cellular and molecular stresses and their prevention. In this project, we wished to develop an in-vitro model of chemical-, or drug-induced oral mucositis. For this purpose, we used a three dimensional (3-D) cell culture model of oral mucosa and as the drug to induce mucositis we used everolimus. Everolimus belongs to rapalogs which represent important therapies against cancer but one of its adverse-effects is mucositis. Mucositis caused by everolimus develops early in therapy and progresses quickly to grade 3 making patients to postpone life-saving therapies. Thus, it is very important to understand and prevent the development of everolimus-caused mucositis.
Methods: The 3-D cell cultures of primary human oral keratinocytes grown on top of primary human oral fibroblasts were purchased from MatTek Corporation. These 3-D cell cultures (tissues) are similar to human oral mucosal tissue and have been validated as its substitutes. Different 3-D tissues were treated for 24, 40 and 60 hours with 8, 16, 32, and 64 ng/ml of everolimus. Tissues which received no treatment were used as controls. We then evaluated the tissue histology using H and E staining, and gene expression using RNA-sequencing.
Results: Tissues which were treated with everolimus show signs of distress based on the concentration of everolimus and the duration of the treatment. Low and medium concentration of everolimus (8ng/ml) and (16 or 32 ng/ml), respectively, show no, or minimal tissue distress after 24 hours of treatment duration. Tissues which received a high concentration of everolimus (64 ng/ml) even at a short duration of treatment, show signs of distress, as evidenced by atypical proliferation at the keratinous epithelium, vacuoles, or shredded keratin layers, as well as, higher apoptosis, and expression of pro-inflammatory cytokine genes. In general, the higher the concentration of everolimus and the longer the duration of the treatment, the more the signs of the stress in tissues.
Conclusion: The cell and molecular stress that the 3-D tissue cultures of human oral mucosa experience depends on the drug concentration and the duration of treatment.
Acknowledgment We thank Novartis for their support.
Citation Format: Maria P. Lambros, QinQin Fei, Jonathan Moreno. The development of a 3D cell-culture model of drug-induced oral mucositis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 30.
Abstract 3008: PSMA glycosylation and aggressive prostate cancer progression
Authors: Burch Tanya C. , Mackay Stephen S. , Oduor Ian O. , Otto Joseph J. , Lance Raymond S. , Troyer Dean A. , Semmes Oliver John , Nyalwidhe Julius O. 
Published: August 2019

Abstract
Introduction: Prostate cancer has a heterogeneous spectrum of clinical outcomes with phenotypes ranging from indolent asymptomatic cases to very aggressive metastatic and lethal forms. Our long term objective is to identify molecules and characterize mechanisms for PCa progression to aggressive lethal disease. PSMA, a membrane bound glycoprotein is significantly over-expressed in more aggressive and metastatic prostate carcinomas with a negative correlation with patient prognosis. The role of its glycans in disease progression and in the development of biomarkers for the disease and potential therapeutics are currently unknown. Aberrant glycosylation of glycoproteins has been observed in many malignancies, and these changes influence disease progression. Our rationale is that differential glycosylation of PSMA correlates with PCa aggressive disease progression. In this study, we characterize N-linked glycosylation profiles in disease stratified PCa cells and prostate proximal fluids show differential expression of specific PSMA conjugated glycan structures that correlates with aggressive phenotypes.
Methods/Results: PSMA was isolation from PCa cell lysates and post-DRE urines by column based affinity chromatography followed by SDS-PAGE and Western Blot and Coomassie staining. The fractionated PSMA protein band was excised and processed for proteomic and glycomic analysis. Isolated PSMA was trypsin digested and treated with PNGaseF and other glycosidases to cleave of N-linked glycans from the peptides. Isolated glycans were subjected to permethylation before MALDI-TOF-MS and high resolution, high mass accuracy and high sensitivity LC/MS/MS on an Orbitrap Fusion Lumos Tribrid MS instrument with multiple fragmentation capabilities (CID, HCD, ETD and EThcD) for glycan identification and quantitation. Validation of differential glycan expression was further performed by targeted glycan based MS and lectin based biochemical technologies.
Conclusions: Our preliminary studies show that there is differential expression of PSMA N-linked glycans with disease severity in prostate cancer cells and post DRE urine samples. Further analyses are currently underway using an extensive cohort of post DRE urine samples and additional studies are focusing on uncovering the mechanisms that are modulated by PSMA glycosylation that are responsible for PCa disease progression. These could assist in the development of novel diagnostic and therapeutic strategies for the disease.
Citation Format: Tanya C. Burch, Stephen S. Mackay, Ian O. Oduor, Joseph J. Otto, Raymond S. Lance, Dean A. Troyer, Oliver John Semmes, Julius O. Nyalwidhe. PSMA glycosylation and aggressive prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3008.
Abstract 3021: The role of survivin splice variants in pancreatic ductal adenocarcinoma Gemcitabine resistance
Authors: Kabagwira Janviere , Gonda Amber , Kwong Mei Li 
Published: August 2019

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis and an increased chemoresistance. Dysfunction in alternative splicing has been associated with chemoresistance in many cancers. Alternative splicing of survivin mRNA generates six splicing isoforms some of which are associated with cancer progression and chemoresistance. Survivin is a member of the inhibitors of apoptosis (IAPs) family and a cell cycle-associated oncoprotein overexpressed in almost all cancers. Interestingly, some of these survivin splice variants are proapoptotic (2α and 2β) while others are antiapoptotic (survivin, Δex3, 3α and 3β). It has been reported that increased levels of survivin 2β and 3β play a role in chemoresistance in ovarian cancers and other tumors, but this has not been studied in pancreatic cancer. Our recent RT-qPCR data also show an overexpression of all survivin splice variants in chemoresistant PDAC cell lines compared to the chemo-sensitive cell line. We, therefore, hypothesize that increased expression of survivin splice variants 2β and 3β contribute to chemo-resistance in PDAC. To test this hypothesis, we repeatedly selected the resistant cells from the normally chemosensitive MiaPaca2 cell line after exposure to gemcitabine. We then assessed the levels of survivin splice variants in the new cell line (gemcitabine-resistant MiaPaca2). Using the Alamar blue assay, we confirmed that Panc1 and gemcitabine-resistant MiaPaca2 are more resistant to gemcitabine compared to MiaPaca2 cells. We also observed a statistically significant overexpression of survivin 2β and 3β in gemcitabine-resistant cell lines compared to the more sensitive MiaPaca2 cells. To further test our hypothesis, we will knockdown survivin 2β and 3β in Panc1 and gemcitabine-resistant MiaPaca2, and/or overexpress these splice variants in MiaPaca2 cells then assess response to gemcitabine. The outcomes of this study might create new biomarkers for predicting the clinical outcomes of gemcitabine treatment and generate new therapeutic targets for pancreatic cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Janviere Kabagwira, Amber Gonda, Mei Li Kwong. The role of survivin splice variants in pancreatic ductal adenocarcinoma Gemcitabine resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3021.
Abstract 3041: CD72 as a potential new therapeutic target in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)
Authors: Euw Erika Von , Taschereau Eileen , Ou Da Ming , Mead Monica , Larson Sarah , Slamon Dennis 
Published: August 2019

Abstract
Cluster of differentiation 72 (CD72) is a 45 kDa type II transmembrane glycoprotein expressed primarily on the surface of B cells. In a search for a novel lymphoma specific target, public datasets were leveraged to assess mRNA expression. We investigated CD72 mRNA expression in cell lines (data from CCLE), patients (data from TCGA) and normal tissues (data from GTEx). The absence of CD72 in normal tissue and the presence in B cells and non-Hodgkin lymphomas (B-NHL) made CD72 a potential target for the treatment of B-NHL, mainly DLBCL and MCL.
CD72 expression on the cell surface was tested by FACS in 15 DLBCL and 5 MCL cell lines. Of these, 12 DLBCL and 4 MCL were positive for CD72, while 3 DLBCL and 1 MCL showed no CD72 expression. In all cell lines tested, the cell surface expression of CD72 correlated with mRNA expression.
To evaluate the potential of CD72 as an ADC target, 4 cell lines were treated in vitro with three commercial monoclonal anti-CD72 primary antibodies (clones J4-117, 3F3 and BU40), and MMAF-conjugated secondary antibody. The cell lines used were RL (DLBCL, CD72+), SCC-3 (DLBCL, CD72-), Jeko-1 and Mino (both MCL, CD72+). The cell growth inhibition after 96 hrs of treatment for for all control conditions; anti-CD72 primary antibody, IgG isotype, MMAF secondary antibody alone or combined with IgG isotype; tested in all cell lines, CD72+ or CD72- ranged from -3 to +4%. Conversely, anti-CD72 primary antibodies plus MMAF secondary antibody had marked growth inhibition effect ranged from 24 to 80% on the three CD72+ cell lines and no effect on cell growth in CD72- cell line, suggesting internalization of CD72 and growth inhibition dependent on the presence of CD72 on the cell surface.
This is the first study demonstrating a potential role for CD72 as a novel target for DLBCL and MCL. These data suggest that CD72 may be a candidate for an ADC approach in DLBCL and MCL.
Cell line% growth inhibition anti-CD72 + MMAF 2°Anti-CD72 clone J4-117Anti-CD72 clone 3F3Anti-CD72 clone BU40SCC-3 (CD72-)-31-5RL (CD72+)503330Jeko-1 (CD72+)433024Mino (CD72+)778066
Citation Format: Erika Von Euw, Eileen Taschereau, Da Ming Ou, Monica Mead, Sarah Larson, Dennis Slamon. CD72 as a potential new therapeutic target in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3041.
Abstract 3048: Targeting protein deglycosylation as a newly identified vulnerable point in melanoma
Authors: Lin Victor J.T. , Zolekar Ashwini , Mishra Nigam M. , Ho Yin Ying , Hayatshahi Hamed S. , Parab Abhishek , Sampat Rohit , Liao Xiaoyan , Hoffmann Peter , Liu Jin , Emmitte Kyle A. , Wang Yu-Chieh 
Published: August 2019

Abstract
As an enzyme that removes N-glycans from glycopeptides, N-glycanase 1 (NGLY1) deglycosylates denatured glycoproteins and allows proteasome-mediated protein degradation to efficiently occur. Although NGLY1 is known for this pivotal function, information regarding the responses of human cancer and normal cells to NGLY1 suppression is limited. Here, we examined how NGLY1 expression affects viability, tumor growth, and responses to therapeutic agents in melanoma cells and an animal model. Molecular mechanisms contributing to NGLY1 suppression-induced anticancer responses were revealed by systems biology and chemical biology studies. Using computational and medicinal chemistry-assisted approaches, we established novel NGLY1-inhibitory small molecules. Compared with normal cells, NGLY1 was upregulated in melanoma cell lines and patient tumors. NGLY1 knockdown caused melanoma cell death and tumor growth retardation. Targeting NGLY1 induced pleiotropic responses, predominantly stress signaling-associated apoptosis and cytokine surges, which synergize with the anti-melanoma activity of chemotherapy and targeted therapy agents. Pharmacological and molecular biology tools that inactivate NGLY1 elicited highly similar responses in melanoma cells. Unlike normal cells, melanoma cells presented distinct responses and high vulnerability to NGLY1 suppression. Our work demonstrated the significance of NGLY1 in melanoma cells, provided mechanistic insights into how NGLY1 inactivation leads to eradication of melanoma with limited impact on normal cells, and suggested that targeting NGLY1 represents a novel anti-melanoma strategy with the opportunity for a broad therapeutic window.
Citation Format: Victor J.T. Lin, Ashwini Zolekar, Nigam M. Mishra, Yin Ying Ho, Hamed S. Hayatshahi, Abhishek Parab, Rohit Sampat, Xiaoyan Liao, Peter Hoffmann, Jin Liu, Kyle A. Emmitte, Yu-Chieh Wang. Targeting protein deglycosylation as a newly identified vulnerable point in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3048.