bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 23: Caloric restriction slows tumor growth and metastases in both hormone-sensitive and hormone-resistant prostate cancers
Authors: Gitman Robert S. , LaRose Meredith , Trabulsi Edouard J. , Palagani Ajay , DeAngelis Tiziana , Kelly William K. , Gomella Leonard G. , Simone Nicole L. 
Published: July 2016

Abstract
Introduction: The purpose of this study is to assess the effect of caloric restriction (CR) on prostate cancer (PCa) tumor burden, proliferation, and overall survival with and without radiation treatment (RT). Additionally, we determined if the beneficial effect of CR noted are due to a reduction in pro-inflammatory markers hypothesized to enhance PCa tumorgenesis.
Methods: To assess the effect of CR in vivo, 40 male 12 week-old NCRNu-M mice were injected with LNCaP or PC3 tumor cells. Once tumors were palpable, mice were randomly assigned to one of four treatment groups in cohorts of 10: ad libitum (AL) diet, 6.5Gy of radiation (RT), 30% reduction in caloric intake (CR), or CR+RT. Tumor growth and proliferation rate were measured 3 times per week via calipers and live bioluminescent imaging. Additionally, PCa tumor tissue were analyzed to determine if CR can exert its effect on tumor growth and metastases via IGF-1R signaling pathway.
Results: Adding CR to RT decreased tumor progression. In the PC3 murine model, when compared to AL, RT reduced tumor size by 22%, 77% with CR, and 80% with CR+RT. In the LNCaP murine model, compared with AL, CR reduced tumor size by 49% and a 55% reduction with CR+RT. Primary tumor formation began 9 weeks post tumor injection in the radiated cohort and was delayed to 15 weeks post tumor injection in the CR and CT+ RT cohorts. Additionally, time to metastasis was delayed with CR (86 days to metastasis in AL, 93 with RT, and 108 when combining CR+RT). Molecularly, CR decreased multiple members of the IGF-1R signaling pathway. The total IGF-1 and IGF-1R levels exhibited 50% reduction with CR and CR+RT but total INSR levels. CR also induced a significant decrease of pGSK3β and pAKT levels.
Conclusions: For the first time, we have shown that decreasing calories by 30% in both hormone-sensitive and hormone-refractory prostate cancer models, enhance the efficacy of radiation. Our experiments show that even CR alone and in combination with RT can improve PCa tumor proliferation rate, tumor burden, time to metastasis, and overall survival. We hypothesize that these changes are in part, due to the decrease of the IGF-1R signaling pathway. We propose that CR may be used as a novel therapeutic intervention to enhance outcomes of radiation treatment by altering the molecular profile of prostate tumors.
Citation Format: Robert S. Gitman, Meredith LaRose, Edouard J. Trabulsi, Ajay Palagani, Tiziana DeAngelis, William K. Kelly, Leonard G. Gomella, Nicole L. Simone. Caloric restriction slows tumor growth and metastases in both hormone-sensitive and hormone-resistant prostate cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 23.
Abstract 2307: Improved CAR safety by a non-lethal switch to control CAR activity at the T-cell surface membrane
Authors: Juillerat Alexandre , Marechal Alan , Filhol Jean-Marie , Duchateau Philippe , Poirot Laurent 
Published: July 2016

Abstract
Adoptive immunotherapy using engineered T-cells has emerged as a powerful approach to treat cancer. The potential of this approach relies on the ability to redirect the specificity of T cells through genetic engineering. Novel specificities in T cells have been typically implemented through the genetic transfer of the so-called chimeric antigen receptors (CARs). CARs are synthetic receptors that associated an extracellular targeting moiety with one or more intracytoplasmic signaling domain derived from lymphocyte activation receptors. Present CAR architectures are designed to combine all relevant domains within a single polypeptide, thereby; they combines advantages of MHC unrestricted target recognition to the potent native effector mechanisms of the T cell. Although adoptive transfer of CAR T cells is proven to be an effective strategy to cancer therapy, potential adverse effects such as Cytokines Release Syndrome (CRS) and/or the risk of on-target off-tumor targeting are still a major concern. To date only suicide mechanisms that can eradicate the engineered T-Cell “at will” or mRNA CAR transfection approaches have been proposed to addresses this safety issue.
Here, we describe the development of a small molecule based switch-on technology to control the surface presentation of a chimeric antigen receptor in T-cells. By grafting protein domains that can interact upon addition of a small molecule drug in the hinge domain of the CAR architecture, we are able to turn a T-cell endowed with an engineered CAR from an off-state to an on-state, in term surface presentation as well as for its specific cytolytic properties. This system offers the advantage of a “transient CAR T-cell” for safety while letting open the possibility of multiple cytotoxicity cycles using a small molecule drug. This non-lethal control system of CAR engineered T-cells represents an important advance for the safety of this technology.
Citation Format: Alexandre Juillerat, Alan Marechal, Jean-Marie Filhol, Philippe Duchateau, Laurent Poirot. Improved CAR safety by a non-lethal switch to control CAR activity at the T-cell surface membrane. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2307.
Abstract 2315: Dynamic SPECT imaging of PSMA-specific CAR T cells in mice bearing prostate cancer
Authors: Emami-Shahri Nia , Foster Julie , Sosabowski Jane , Maher John , Papa Sophie 
Published: July 2016

Abstract
Immunotherapy using CAR-T-cells is acquiring an expanding role in the treatment of malignant disease. However, efficacy of solid tumour CAR-T-immunotherapy has proven inconsistent. Limitations include poor T-cell trafficking to tumour deposits, insufficient T-cell longevity in-vivo and the occurrence of both predicted and unanticipated on-target and off-target toxicity. To refine this therapeutic approach, it is desirable to develop systems that allow the monitoring of T-cell location and persistence in-vivo.
A retroviral vector named PiN-4 was constructed, which co-expresses: (i) an interleukin (IL)-4-responsive chimeric cytokine receptor (4αβ); (ii) a prostate-specific membrane antigen (PSMA)-targeted CAR (P28z) and (iii) hNIS, which promotes the uptake of technetium-99m pertechnetate (99mTcO4−) in viable cells. IL-4 enriched human 4P28zN+ T-cells were administered intravenously to Nod Scid Gamma (NSG) mice bearing prostate tumour xenografts.
Measurement of the tumour xenografts by bioluminescent imaging (BLI) found that only PSMA-expressing tumours responded to 4P28zN+ T-cell treatment. Longitudinal SPECT-CT imaging further confirmed this with the preferential accumulation of 4P28zN+ T-cells in PSMA-expressing tumours compared to PSMA-negative tumours.
Use of NIS as a T-cell imaging reporter brings several potential advantages. It promotes receptor-mediated uptake of the inexpensive, low toxicity and clinically useful SPECT tracer, technetium-99m pertechnetate (99mTcO4−). In addition, the ectopic expression of NIS is well tolerated by host cells and hNIS functions only in viable cells. These data demonstrate proof of concept for the utility of hNIS as an imaging reporter in genetically engineered T-cells.
Citation Format: Nia Emami-Shahri, Julie Foster, Jane Sosabowski, John Maher, Sophie Papa. Dynamic SPECT imaging of PSMA-specific CAR T cells in mice bearing prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2315.
Abstract 2344: Discovery and characterization of new original blocking antibodies targeting the CD73 immune checkpoint for cancer immunotherapy
Authors: Giraudon Paoli Marc , Augier Severine , Royannez Blemont Marilyne , Rodriguez Céline , Rispaud Blanc Hélène , Chanteux Stéphanie , Gourdin Nicolas , Gauthier Laurent , Ménétrier Caux Christine , Morel Yannis , Caux Christophe , Paturel Carine , Perrot Ivan 
Published: July 2016

Abstract
CD73 (NT5E) is a cell membrane ectoenzyme of the NTPDase family that plays a major role in the conversion of AMP into Adenosine (Ado). Within the tumor microenvironment, accumulation of Ado causes immune suppression and dysregulation of immune cell infiltrates resulting in tumor spreading. CD73 expression in the tumor environment has been associated with poor disease outcome and/or with a pro-metastatic phenotype. Thus, targeting CD73 may promote anti-tumor immunity by reducing Ado accumulation and may block tumor cell metastasis by inhibiting CD73 on tumor cells. Here, we describe the generation and characterization of novel anti-human CD73 antibodies, intended for the treatment of a wide range of cancers. The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement n°602200. Antibodies were discovered that inhibited CD73 function by different mechanisms, including the direct blocking of CD73 enzymatic activity or the down-modulation of membrane CD73 expression. Epitope mapping revealed that antibodies acting by these different modes of action bound to distinct sites on CD73. All selected antibodies cross-react with cynomolgus CD73 protein and have strong avidity and affinity for membrane or recombinant CD73, by flow cytometry and Surface Plasmon Resonance, respectively. Antibodies that inhibit CD73 enzymatic activity strongly reduce AMP catabolism by both recombinant and cellular CD73 with IC50 in the nanomolar range. They also efficiently reverse ATP- and AMP-mediated T cell suppression in in vitro assays in presence of both CD39+ and CD73+ cells. The antibodies that induce down-modulation of cellular CD73 expression do not block recombinant CD73 enzyme activity and partially inhibit cellular CD73 activity; they reverse ATP- but not AMP-dependent T cell suppression. The antibodies displaying the most interesting features were humanized. Evaluation of their activity in animal models is ongoing.
Citation Format: Marc Giraudon Paoli, Severine Augier, Marilyne Royannez Blemont, Céline Rodriguez, Hélène Rispaud Blanc, Stéphanie Chanteux, Nicolas Gourdin, Laurent Gauthier, Christine Ménétrier Caux, Yannis Morel, Christophe Caux, Carine Paturel, Ivan Perrot. Discovery and characterization of new original blocking antibodies targeting the CD73 immune checkpoint for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2344.
Abstract 2354: Cancer vaccine development for hepatocellular carcinoma - HEPAVAC
Authors: Kutscher Sarah , Accolla Roberto , Ma Yuk T. , Heidenreich Regina , Izzo Francesco , Koenigsrainer Alfred , Loeffler Markus , Mueller Phillip , Mayer Andrea , Rammensee Hans-Georg , Sangro Bruno , Francque Sven , Valmori Danila , Weinschenk Toni , Singh-Jasuja Harpreet , Buonaguro Luigi 
Published: July 2016

Abstract
The HEPAVAC Consortium aims to develop a highly innovative, novel cancer vaccine approach for hepatocellular carcinoma (HCC). The international project consortium consists of 9 European Partners from academia and the biotech industry with complementary and substantial expertise in developing immunotherapeutic strategies to treat cancer. The project has started in September 2013 and is supported by the European Commission's 7th Framework Program (www.hepavac.eu).
HCC/normal adjacent tissue matched samples have been collected for HLA immunopeptidome analysis. 17 HCC samples from HLA-A*02+ patients and 15 samples from HLA-A*24+ patients have been analysed by mass spectrometry (LC-MS/MS). RNA-expression profiles have been established for 12 HCC samples. HLA-presentation/expression of peptides and mRNA on primary HCC samples are compared to &gt;140 normal tissue samples from relevant organs (including heart, brain, lung, kidney, liver, nerve, skin etc.) from Immatics’ database.
A total of 9051 HLA-A*02-restricted different tumor-associated peptides (TUMAPs) have been identified from HLA-A*02+ samples, while a total of 3286 different HLA-A*24-restricted TUMAPs have been identified from HLA-A*24+ samples. Of these, 33 HLA-A*02+ TUMAPS and 33 HLA-A*24+ TUMAPs have been validated, including peptide synthesis, immunogenicity testing and pharmaceutical evaluation. Most promising TUMAP candidates show selective expression only in HCC samples and no expression in normal tissues. In parallel, more than 6600 HLA-DR TUMAPs have been identified in Hep3B cells transfected with CIITA as well as an average of 1500 HLA-DR TUMAPs have been identified in HCC samples.
A total of 16 newly identified HCC-specific epitopes have been selected for the HEPAVAC vaccine cocktail and are currently synthesized according to GMP standard. Of these, 7 are restricted to HLA- class I A*02; 5 HLA-A*24 and 4 HLA class II. In parallel, preclinical studies assessing the formulation and combination of the immunological RNA-based adjuvant (RNAdjuvant®) with peptide cocktails are underway. A multi Center phase I/II clinical trial in early HCC patients is predicted to start in July 2016.
Citation Format: Sarah Kutscher, Roberto Accolla, Yuk T. Ma, Regina Heidenreich, Francesco Izzo, Alfred Koenigsrainer, Markus Loeffler, Phillip Mueller, Andrea Mayer, Hans-Georg Rammensee, Bruno Sangro, Sven Francque, Danila Valmori, Toni Weinschenk, Harpreet Singh-Jasuja, Luigi Buonaguro. Cancer vaccine development for hepatocellular carcinoma - HEPAVAC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2354.
Abstract 2401: RD3-loss orchestrates GC-signaling independent evolution of progressive neuroblastoma
Authors: Meghna Singh , Rachel Wolansky , Herman Terence S. , Aravindan Natarajan 
Published: July 2016

Abstract
Recently we recognized the transcriptional/translational loss of Retinal degeneration Protein 3 (RD3) in high-risk progressive neuroblastoma (HR-NB) and defined its novel tumor evolution stabilization function. Studies have shown that RD3 competitively binds to guanylate cyclases (GCs) and maintains GC expression, stability, as well as restores GC localization. Accordingly, we investigated the role of GCs, if any, in RD3-loss associated evolution of HR-NB. Utilizing an in vivo mouse model of spontaneous HR-NB coupled with ex vivo approaches using metastatic site derived aggressive cells (MSDACs), we examined the transcriptional and translational expression of GCs and validated with high-content confocal immunofluorescence. Further, utilizing a cGMP competitive enzyme immunoassay, we investigated both intracellular and soluble GC activity. Whole genome microarray analysis revealed a differential activation of GC signaling transcriptional machinery in three different clones of MSDACs (compared to parental SH-SY5Y cells) ex vivo. Immunoblotting identified a consistent translation of GCs (GC-1 and GC-2) in a manifold of metastatic tumors (compared to non-metastatic primary xenografts) in vivo and in MSDACs ex vivo. Confocal immunofluorescence analysis validated the near-identical expression of GC1 and GC2 both in SH-SY5Y cells and MSDACs. cGMP immunoassay recognized indistinguishable intracellular and soluble GC activity in clones of differentiated/undifferentiated MSDACs as opposed to the clones of SH-SY5Y. For the first time, the results of this study define the transcription and translation blueprint of GCs in HR-NB and, further imply that the RD3-loss may dictate GCs-signaling independent alternate molecular flow-through in the evolution of HR-NB.
Acknowledgements: Stephenson Cancer Center, NIH COBRE 1P20GM103639-01, Broken Arrow Lady Elks Auxiliary, and Oklahoma TSET.
Citation Format: Singh Meghna, Wolansky Rachel, Terence S. Herman, Natarajan Aravindan. RD3-loss orchestrates GC-signaling independent evolution of progressive neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2401.
Abstract 2436: Exploring genomic alterations in pediatric cancer using ProteinPaint
Authors: Zhou Xin , Edmonson Michael N. , Wilkinson Mark R. , Patel Aman , Wu Gang , Liu Yu , Li Yongjin , Zhang Zhaojie , Rusch Michael , Parker Matthew , Becksfort Jared , Downing James R. , Zhang Jinghui 
Published: July 2016

Abstract
Current cancer genome data portals have focused primarily on presenting data generated from adult cancer studies. These portals typically lack features for exploring pathogenic germline mutations, somatic gene fusions, and gene expression profiling, all of which are important biomarkers for risk stratification of pediatric cancer. We have developed ProteinPaint (https://pecan.stjude.org/proteinpaint/), a web service hosting 30,000+ validated somatic SNV/indels and fusion transcripts detected in 1,654 pediatric tumor samples from 17 subtypes, 252 pathogenic or loss-of-function germline lesions detected in &gt;1000 pediatric cancer patients of 21 subtypes, and gene expression profiles derived from RNA-Seq of 928 pediatric tumors. Cancer genomic alterations are shown on novel “disc-on-stem” skewer graphs which were designed to depict the diverse prevalence, complex allelic alteration, and temporal origin of sequence mutations and gene fusions. Adult somatic cancer mutation data from the COSMIC database can be displayed in parallel with pediatric cancer data sets for cross-study comparison. We will demonstrate examples of how ProteinPaint's integrative view of genomic alteration, gene expression and pediatric-adult data comparison has facilitated the evaluation of somatic and germline mutation pathogenicity in a clinical setting. Custom data including sequence mutations in the MAF format used by the Cancer Genome Atlas (TCGA) project, copy number alterations, and structural variations can all be imported and visualized alongside published pediatric and adult cancer data sets. Furthermore, ProteinPaint supports curation and annotation of fusion transcripts predicted from RNASeq data and analysis of tumor clonal evolution with a 2-D plot of mutation frequency of paired diagnosis and relapse samples. ProteinPaint delivers a premium user experience with animation and interactive features for visualizing large cancer mutation datasets, and can serve as a workbench to import, explore and interpret user data. Its framework continues to expand as its intuitive visualization has enabled non-bioinformatics scientists and clinicians to access and manipulate genomic data for discovery and clinical reporting.
Citation Format: Xin Zhou, Michael N. Edmonson, Mark R. Wilkinson, Aman Patel, Gang Wu, Yu Liu, Yongjin Li, Zhaojie Zhang, Michael Rusch, Matthew Parker, Jared Becksfort, James R. Downing, Jinghui Zhang. Exploring genomic alterations in pediatric cancer using ProteinPaint. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2436.
Abstract 2442: EWS/FLI1 activates GLI1 indirectly through GLI2 in Ewing Sarcoma
Authors: Christensen Laura , May William A. 
Published: July 2016

Abstract
GLI1 expression in Ewing tumors has been shown to be enhanced by EWS/FLI1 expression in both model transformation systems and in Ewing cell lines. In Ewing cells, GLI1 has been shown to produce significant phenotypic effects consistent with a role in Ewing tumor formation and propagation. Also consistent with an important role is the demonstrated correspondence between the transcriptional target sets of EWS/FLI1 and of GLI1 in Ewing tumor cells. The principal physiologic developmental regulator of GLI1 is the diffusible Sonic Hedgehog ligand which binds the cell surface tumor suppressor Patched with consequent activation of the transmembrane protein Smoothened. In Ewing tumors, the enhancement of GLI1 expression has been shown to be Hedgehog independent and to occur downstream of Smoothened. Indeed, evidence has been published that EWS/FLI1 directly activates the GLI1 promoter. While there is experimental evidence that GLI1 inhibition may be clinically useful in Ewing tumors, preclinical evidence for one inhibitory approach has been disappointing. Interestingly, direct transcriptional activation of GLI1 has not been demonstrated to be of significance in other most other physiologic or pathologic contexts. We speculated that direct transcriptional activation of GLI1 by EWS/FLI1 might be only part of the story in Ewing tumors.
Since GLI2 is the most potent physiologic transcriptional activator of GLI1, we undertook to investigate the role of GLI2 in Hedgehog/GLI (HH-GLI) signaling in Ewing Tumors. We found that GLI2 is broadly expressed in Ewing tumors. Based on GLI2 overexpression and on shRNA knockdown of GLI2, we found that GLI2 expression increases GLI1 expression in Ewing cell lines. Via GLI2 knockdown, we have found that GLI2 has biologic effects similar to or greater than GLI1 in Ewing cells. Finally, we demonstrate that EWS/FLI1 enhances nuclear localization of GLI2, suggesting an additional indirect mechanism by which EWS/FLI1 activates HH-GLI signaling and GLI1 expression in Ewing tumors.
These data indicate that GLI2 is an active player in HH-GLI pathway activation in Ewing tumors. They also suggest that measures which target GLI2 may have equal or greater efficacy to those aimed at GLI1.
Citation Format: Laura Christensen, William A. May. EWS/FLI1 activates GLI1 indirectly through GLI2 in Ewing Sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2442.