bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-063: Phospholipid drug conjugates show specificity for a broad range of tumor cells and provides a novel approach for targeted or precision therapy
Authors: Longcor Jarrod , Banach Maria , Hoover Randall 
Published: August 2018

Abstract
The majority of anticancer drugs in clinical use have their utility limited by their toxicity to all proliferating cells, including normal cells and the inability to exert their effect on all of the tumor cells. Novel cytotoxic agents continue to be developed with unique mechanisms of action meant to provide increased targeting, however, many of these compounds still lack absolute tumor selectivity and continue to be limited in their therapeutic utilization due to off-target effects. Antibody drug conjugates (ADCs) have been design to bind to specific epitopes on the surface of tumor cells and have offered an alternative method to target tumor cells in an effort to reduce associated toxicities. Although highly selective, very few antibody drug conjugates are therapeutically useful since they only achieve modest cellular uptake and limited cell killing activity. Here we describe the development of a novel targeting platform using phospholipid ether (PLE) molecules to provide tumor cell specific targeting. These molecules known as phospholipid drug conjugates (PDCs) show high specificity for tumor cells; 6 to 30-fold increase in targeting tumor cells over normal tissue, result in up to 20% of exposed compound entering in to the tumor cells (as compared to &lt; 1% of an ADC), and show a range of compounds can be conjugated to them. We have tested the uptake of our PDCs across over 80 different tumor cell lines and have shown consistent preferential uptake by tumor cells versus normal cells even when in co-culture. This could result in an improvement of the therapeutic index for many compounds.
Citation Format: Jarrod Longcor, Maria Banach, Randall Hoover. Phospholipid drug conjugates show specificity for a broad range of tumor cells and provides a novel approach for targeted or precision therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-063.
Abstract LB-074: Examining SENP Localization In HEK-293 Cells Using MG-132 And Cycloheximide
Authors: Robinson Michael , Umbaugh Charles S. , Figueiredo Marxa L. 
Published: August 2018

Abstract
Post translational modifications are changes to proteins that occur during or after synthesis by the ribosome. Often these modifications are necessary to form mature proteins. SUMOylation (Small Ubiquitin-like Modifier, SUMO) is a type of post translational modification that has a connection to a protein, Laminin Receptor, that contributes to the aggressiveness and proliferation of cancer.
SUMO proteases, called SENPs, remove SUMO groups from SUMOylated proteins. Because Laminin Receptor may be a SUMOylated protein and is in the nucleus, we wanted to first explore how SENP-2 and SENP-3 localize under various cellular conditions. To understand the behavior of SENPs under cellular stress, we transfected human embryonic kidney cells, called HEK-293 cells, with SENP-2 or SENP-3 tagged to the fluorescent protein EGFP. We treated the cells with MG-132, a proteasome inhibitor, or with cycloheximide, a protein synthesis inhibitor. We used live imaging to qualitatively understand how SENP-2 and SENP-3 localize in the cell in normal conditions and under cell stress. Then, we looked for differences in cytosolic and nuclear partitioning of SENP-2 and SENP-3 by western blot. The exposure of SENPs to the two inhibitors helped us to understand the behavior of the SUMO proteases between the nucleus and cytoplasm.
Citation Format: Michael Robinson, Charles S. Umbaugh, Marxa L. Figueiredo. Examining SENP Localization In HEK-293 Cells Using MG-132 And Cycloheximide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-074.
Abstract LB-079: The interaction of MSI1 and AGO2 promotes glioblastoma multiforme progression under environmental stress
Authors: Chen Hsiao-yun , Chiou Shih-Hwa 
Published: August 2018

Abstract
Glioblastoma multiforme (GBM) is the high-grade astrocytoma; it is the most common and aggressive malignant brain tumor. GBM is largely resistant to therapy and experiences a corresponding poor prognosis. Therefore, GBM progression and recurrence are the main therapeutic challenges frequently faced by patients with refractory tumors. Nevertheless, the underlined molecular mechanism remains unknown. The RNA-binding protein musashi1 (MSI1) is expressed in stem cell compartments and in the aggressive tumor, only little is known about its function and mechanism in fact decision of target mRNA and post-transcription control. In this study, we describe a mechanism by which stress induces tumor progression via elevated cytoplasmic translocation of MSI1 in malignant neoplasms. MSI1 forms ribonucleoprotein (RNP) complexes with its downstream mRNAs at the 3'-untranslated region (3'UTR) or coding domain sequence (CDS) in the nucleus. Upon stress conditions, the MSI1/mRNA complex translocates to the cytosol where Argonaute2 (AGO2) is recruited and directly interact with MSI1. The MSI1/AGO2 complex modulates mRNA stability depending on their binding locations on the mRNA targets. Blocking of MSI1 shuttling by either a nuclear export inhibitor (Leptomycin B, LMB) or NES/NLS mutant attenuates GBM tumor growth in the mouse model. Importantly, the MSI1-AGO2 complex enhances GBM cells proliferation and survival under stress stimulation. MSI1 directly binds to AGO2 in the cytosol through its C-terminus. Orthotopic delivery of MSI1-C-terminus decoy peptides, which disrupt the MSI1/AGO2 interaction, effectively reduces stress-induced tumor progression. These results provide new insights into the function of MSI1 and suggest a novel peptide-based therapeutic strategy against refractory malignancies.
Citation Format: Hsiao-yun Chen, Shih-Hwa Chiou. The interaction of MSI1 and AGO2 promotes glioblastoma multiforme progression under environmental stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-079.
Abstract LB-088: Cytokine-transgenic NOG mice engrafted with human peripheral blood cells support natural killer cell expansion
Authors: Volden Paul 
Published: August 2018

Abstract
Harnessing natural killer (NK) cells and their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) forms the basis for many ongoing immuno-oncology efforts. Currently, most preclinical in vivo studies of ADCC-dependent efficacy rely on syngeneic models, which mandate the generation and use of surrogate therapies to overcome differences between mouse and human immune systems. These steps add time and cost, and can be particularly challenging for advanced antibody therapeutics (e.g. bispecific antibodies and antibody-drug conjugates). A humanized immune system (HIS) model that supports human NK cells could improve evaluations of human NK cell-dependent cancer therapies. However, HIS models have largely failed to support human NK cell-engraftment, rendering them inadequate for ADCC studies. Prior work has shown that human cytokine-transgenic hIL2-NOG and hIL15-NOG mice support the development of human NK cells from engrafted human hematopoietic stem cells (HSCs). Furthermore, the hIL15-NOG model has been shown to support in vivo expansion and long-term engraftment of isolated human NK cells. These properties suggest hIL2-NOG and/or hIL15-NOG might also sufficiently support NK cells following engraftment of peripheral blood mononuclear cells (PBMCs). Such a model could enable cost-effective and efficient in vivo studies of human NK cells and therapeutic human antibodies. To test this hypothesis, NOG, hIL-2 NOG, and hIL-15 NOG mice were engrafted with PBMCs from a single donor and at one of three increasing cell doses. The onset of graft vs host disease and peripheral blood human immune cell subsets were monitored through the duration of this study. Results showed that hIL15-NOG mice had a slightly diminished survival compared to conventional NOG. Nevertheless, hIL15-NOG survived up to 7 weeks after PBMC engraftment without any signs of graft vs host disease. Although hIL2-NOG mice showed the best engraftment rate for NK cells and other immune cell subpopulations, the overall survival was severely decreased post engraftment. Comparing NK cell-engraftment in hIL15-NOG and conventional NOG mice, we observed a tenfold increase of NK cell numbers in hIL15-NOG mice, independent of engrafted PBMC numbers, making it a highly suitable HIS model for studying NK cells.
Citation Format: Paul Volden. Cytokine-transgenic NOG mice engrafted with human peripheral blood cells support natural killer cell expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-088.
Abstract LB-089: Targeting WNT signaling in vivovia Tankyrase inhibition
Authors: Schatoff Emma M. , Leach Benjamin I. , Foronda Miguel , Zafra Maria Paz , Goswami Sukanya , Dow Lukas E. 
Published: August 2018

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 95% of CRCs show hyperactive WNT signaling, yet there are no targeted therapies that effectively suppress the WNT pathway. The majority (~80%) of these tumors harbor a mutation in APC, a scaffold component of the ‘destruction complex', which is a critical negative regulator of WNT. Using genetically defined mouse models of CRC, we recently showed that restoring Apc function can induce WNT suppression, and rapid and sustained disease regression. While there is no way to restore normal APC protein in human CRCs, it may be possible to restore the function of the APC-associated destruction complex by inhibiting Tankyrase (TNKS) enzymes. Tankyrase inhibitors have been shown to stabilize AXIN, prevent degradation of the destruction complex, and decrease levels of WNT signaling. While in vitro studies have shown promise, it is unclear whether TNKS inhibition could provide a therapeutic benefit in vivo. Some published work reports significant anti-tumor activity, while others suggest overt dose-limiting toxicity. Thus, while TNKS inhibition holds significant potential, it is not clear whether TNKS enzymes are a viable target for CRC therapy. To circumvent the limitations of drug delivery, potency, and specificity, we generated mice with inducible, fluorescent reporter-linked shRNAs targeting Tnks and its redundant family member Tnks2. Here we show that potent, simultaneous shRNA-mediated knockdown of both genes is sufficient to stabilize Axin in vivo, similar to treatment with a pan-TNKS inhibitor, XAV939. We show that Tnks1/2 knockdown stabilizes Axin, suppresses WNT signaling, and blocks hyperproliferation driven by Apc loss. In contrast to current studies using small molecule TNKS inhibitors, our work suggests that there is a viable therapeutic window of TNKS1/2 inhibition in vivo, and that this strategy enables control of hyperactive WNT signaling in CRC and other WNT-associated cancers.
Citation Format: Emma M. Schatoff, Benjamin I. Leach, Miguel Foronda, Maria Paz Zafra, Sukanya Goswami, Lukas E. Dow. Targeting WNT signaling in vivovia Tankyrase inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-089.
Abstract LB-091: Hedgehog signaling induces drug resistance in gastric cancer cells via upregulation of ABCG2
Authors: YU BEIQIN , GU DONGSHENG , ZHANG XIAOLI , LIU BINGYA , XIE JINGWU 
Published: August 2018

Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. Currently, there are no specific therapeutic options to cure gastric cancer, and chemotherapy is frequently used. Some patients respond initially to chemotherapy but all patients eventually succumb to the disease. Thus, identifying molecular mechanisms responsible for chemotherapy resistance may help design novel strategies to sensitize cancer cells to chemotherapy. In this study, we revealed that treatment with chemotherapeutic reagents CDDP and 5Fu induced expression of GLI1, GLI2 and PTCH1 in gastric cancer cell lines, suggestive of hedgehog (Hh) signaling activation. GLI1 knockdown sensitized gastric cancer cells to CDDP and 5Fu treatment whereas ectopic GLI1 expression desensitized cancer cells to these treatments. Further analyses indicate elevated Hh signaling is associated with an increase in putative cancer stem cell marker expression, such as ABCG2. We found that GLI1 protein binds to the promoter of ABCG2 through a Gli-binding consensus site. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, resulted in an increase of drug sensitivity both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance.
Citation Format: BEIQIN YU, DONGSHENG GU, XIAOLI ZHANG, BINGYA LIU, JINGWU XIE. Hedgehog signaling induces drug resistance in gastric cancer cells via upregulation of ABCG2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-091.
Abstract LB-107: Repurposing endogenous immune pathways to improve chimeric antigen receptor T-cells potency
Authors: Sachdeva Mohit , Busser Brian , Temburni Sonal , Juillerat Alexandre , Poirot Laurent , Duchateau Philippe , Valton Julien 
Published: August 2018

Abstract
CAR T-cell therapies hold great promise for treating a range of liquid malignancies but are however challenged to access and eradicate solid tumors. To overcome this hurdle, CAR T-cell were engineered to secrete different cytokines known to improve T-cell antitumor activity, prevent T-cell anergy and reduce activation induced cell death. While cytokine-expressing CAR T-cell were shown to be be highly active against solid tumor in in vivo models, they have also led to toxicity associated with the systemic release of cytokine. Therefore, new engineering strategies enabling the fine tuning of cytokine secretion by CAR T-cell are warranted. We sought to explore one of these engineering strategies by integrating an IL-12 chimeric heterodimer expression cassette under the control of the endogenous promoters regulating PD1 or CD25. Because both genes are known to be activated upon tumor engagement by CAR T-cells, they could be repurposed to secrete cytokine only in the vicinity of a given tumor. This approach would reduce the potential side effects induced by their systemic secretion while maintaining their capacity to improve antitumor activity. By combining TALEN® technology with AAV6 repair vectors delivering the CAR to the TRAC locus and the IL-12 to the CD25 or PD1 loci, we have engineered CAR and IL-12 expressions under the respective control of TCR and CD25 or PD1 regulatory elements. This double targeted insertion led to the disruption of PD1 and TRAC genes, to the expression of a tool CAR and to the conditional secretion of IL-12 in the media. Such secretion was found to be transient, dependent on tumor engagement and to follow the regulation patterns of CD25 or PD1 genes, commonly observed upon T-cell activation. In addition, it was also found to enhance the antitumor activity and the proliferative capacities of CAR T-cells. Similar results were obtained when IL-15 was substituted for IL-12. This proof of concept paves the way for seamless multi-repurposing of immune pathways to generate smarter CAR T-cells able to sense and react to their environment in a highly regulated and specific manner.
Citation Format: Mohit Sachdeva, Brian Busser, Sonal Temburni, Alexandre Juillerat, Laurent Poirot, Philippe Duchateau, Julien Valton. Repurposing endogenous immune pathways to improve chimeric antigen receptor T-cells potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-107.
Abstract LB-113: Enhanced anti-tumor efficacy of CEACAM1-targeting antibody after affinity maturation
Authors: Eun So-Young , Lee Mijung , Park Hye-Young , Oh Miyoung , Yum Hye In , Yoon Aerin , Lee Eunhee , Nam Hyemi , Yun Sungtae , Cho Hyunjung , Hur Minkyu , Kim Jaehwan , Cho Byoung Chul , Won Jonghwa 
Published: August 2018

Abstract
Since the huge success of PD-1 blocking antibodies in clinical studies, anti-cancer therapy has changed its strategic gear to immunotherapy, which showed the strongest potential to eradicate cancer without detrimental side effects. Antibodies targeting similar immune checkpoint proteins with immunosuppressive functions have started to surge into clinical trials. CEACAM1 (CCM1) is also a potential target for anti-cancer immunotherapy because it is an ITIM-containing inhibitory molecule expressed on activated T cells and NK cells, on which it suppresses T/NK cell-mediated pro-inflammatory immune responses. CCM1-CCM1 homophilic interaction inhibits ZAP-70 phosphorylation in the TCR proximal signaling complex, thereby suppressing T cell activation. The anti-cancer therapeutic potential of CCM1-blockade has already been demonstrated in mouse models and one of the anti-human CCM1 antibodies entered into a phase I clinical trial once. As previously reported, our clone C25 (an anti-CCM1 monoclonal antibody) activated T cells and enhanced T/NK cell-mediated tumor cell-killing in a CCM1-dependent manner. The clone C25 was further engineered to have higher efficacies through mutagenesis within the variable regions of heavy and light chains. Here, we describe mutated variants of C25 with improved in vitro tumor-killing efficacies as well as higher binding affinities while maintaining fundamental characteristics of their parental clone C25. Most importantly, C25 and its variants exclusively bind to CCM1, but not to any other homologs of the CCM family. Such strong target-specificity will be a crucial point that distinguishes our clones from the other anti-CCM1 antibodies having off-target binding activities. We are currently investigating the CCM1-dependent anti-cancer therapeutic efficacy of our final clone on the patient-derived tumor xenografts implanted in a humanized mouse model. The target-ligand expression profiling on tumor tissues from lung cancer patients revealed strong clues for patient selection criteria and co-treatment options.
Citation Format: So-Young Eun, Mijung Lee, Hye-Young Park, Miyoung Oh, Hye In Yum, Aerin Yoon, Eunhee Lee, Hyemi Nam, Sungtae Yun, Hyunjung Cho, Minkyu Hur, Jaehwan Kim, Byoung Chul Cho, Jonghwa Won. Enhanced anti-tumor efficacy of CEACAM1-targeting antibody after affinity maturation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-113.
Abstract LB-115: Tumor intrinsic PD-1/PD-L1 signalling induces mesenchymal to epithelial transition in canine osteosarcoma cells
Authors: Parys Maciej , Nekulová Marta , Vojtěšek Bořivoj , Faktor Jakub , Lima Ana , Hupp Theodore 
Published: August 2018

Abstract
Osteosarcoma (OS) is the most common primary tumor of the bone in both humans and dogs. The dog, with its spontaneously occurring OS, shared pathogenic pathways and active immune system is one of the best models for studying novel immunotherapeutic approaches to human OS. Checkpoint blockade using antibodies against PD-1 has revolutionized the current approach to treatment of melanoma and other cancers. Recent reports have also shown that tumor intrinsic signalling plays a potential role in the success of PD-1 blockade in melanoma although studies in OS have not been published to date. PD-1/PD-L1 signalling has been reported to have role in epithelial to mesenchymal transition. In this study, we wanted to characterize intrinsic PD-1 signalling in canine osteosarcoma. We have created a canine specific PD-1 monoclonal antibody and we identified that PD-1 is intrinsically expressed in the cell line tested- OSA31. To further characterize the effects of PD-1 expression in this cell line we cloned canine PD-1 into a pcDNA 3.1 expression vector and transfected the cell line. Transfection of the cell line with PD-1 resulted in phenotypic changes characteristic for mesenchymal to epithelial transition. Interestingly overexpression of PD-1 as well as blockade of this receptor using the created antibody, resulted in decrease in cellular proliferation. To our knowledge this is the first report to identify role of PD-1 in mesenchymal to epithelial transition. These findings also suggest that PD-1 may be a promising therapeutic target in canine OS and warrant future clinical trials.
Citation Format: Maciej Parys, Marta Nekulová, Bořivoj Vojtěšek, Jakub Faktor, Ana Lima, Theodore Hupp. Tumor intrinsic PD-1/PD-L1 signalling induces mesenchymal to epithelial transition in canine osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-115.