bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-B26: Novel eIF4A inhibitors target both cellular and microenvironment components in pancreatic ductal adenocarcinoma
Authors: Safari Maryam , Kim Yu Ri , Deng Changchun , Bates Susan E. 
Published: August 2018

Abstract
We are investigating the potential utility of targeting protein translation via inhibiting the translation initiation factor 4A (eIF4A) with a new class of Pateamine A derivatives to treat pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most refractory human malignancies with poor response to therapy and low survival rates. PDAC resistance to therapy is thought to comprise both cellular and microenvironment components. A key cellular aberration is thought to be the activating KRAS mutations found in over 90% of pancreatic cancers, signaling proliferation and survival. One postulated effect of KRAS mutation is to activate C-Myc, a central oncogene in PDAC, with elevated expression and high protein levels in over 40% of cases. A key microenvironment component is elevated hyaluronic acid content in the stroma of pancreatic cancers (4 to 12 times that of normal pancreatic tissues), which increases interstitial fluid pressure and is thought to impair drug perfusion efficiency, as well as the infiltration of immune cells. Here we report a promising therapeutic intervention for PDAC via targeting the eIF4A component of the translation initiation complex using a new class of Pateamine A derivatives, DMDA PatA and MZ735. Using cytotoxicity assays, immunoblotting, immunocytochemistry and confocal imaging we show activity of the Pateamine A derivatives on PDAC cell lines. Our primary data shows treatment with nanomolar concentrations of these compounds inhibits cell proliferation with IC50s ranging from 20 to 40nM for DMDAPatA and 5 to 20 nM for MZ735 in various PDAC cells. Immunoblotting shows a reduction in c-MYC, hyaluronic acid synthase HAS3, and hyaluronic acid receptor CD44 in PDAC cell lines following treatment with eIF4A targeting compounds. Finally, confocal imaging confirmed the reduction of hyaluronic acid and CD44 in the eIF4A inhibitor-treated PDAC cells. We believe Pateamine A derivatives represent a new class of anticancer agents that have the potential to address both altered cellular and microenvironment components in PDAC.
Citation Format: Maryam Safari, Yu Ri Kim, Changchun Deng, Susan E. Bates. Novel eIF4A inhibitors target both cellular and microenvironment components in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B26.
Abstract LB-B28: Abietane natural products as novel therapeutics against solid tumors
Authors: Lang Walter , Ling Taotao , Lee Jangsoon , Ueno Naoto T. , Rivas Fatima 
Published: August 2018

Abstract
Dysregulation of protein synthesis can lead to aberrant cellular proliferation and survival, a hallmark of cancer. Protein synthesis is a multistep process tightly controlled by specific translation factors. In eukaryotes, at the initiation point, the 43S preinitiation complex is formed by the association of several factors [eukaryotic initiation factor 2 (eIF2), GTP and methionyl initiator tRNA] with the 40S ribosomal subunit and the eukaryotic initiation factor 3 (eIF3). Over expression of eIFs has been reported in breast cancer, particularly in the most aggressive subtype, triple negative breast cancer (TNBC). More than one million global cases of breast cancer are diagnosed yearly and approximately 15% are characterized as triple negative breast cancer (TNBC), a subtype that lacks effective targeted therapy modalities. Recently, we generated a library of cell permeable abietane natural product derivatives (i.e. SJ6038) and showed that these compounds are more potent against TNBC over the estrogen receptor positive cellular models. These compounds were tagged with biotin for affinity enrichment and with a fluorescent chromophore to facilitate protein target(s) identification. A SILAC proteomics approach was used to distinguish specific binding targets from the non-specific ones. Gene Ontology analysis showed the targets identified were affiliated with regulation of protein synthesis. Ingenuity Pathway Analysis suggested that abietanes may exert their anticancer effects on critical biological pathways such as the eIF2, eIF4/p70S6K, and mTOR signaling pathways. Live cell experiments utilizing fluorescent abietane derivatives demonstrate that these probes localize to subsections of the ER, supporting the SILAC findings. Time of Exposure and Dose Response experiments further demonstrate that Abietane derivatives affect the eIF2 signaling axis. Using chemical biology and medicinal chemistry approaches, we show that abietane natural products preferentially promote cell death in TNBC cellular models by targeting the eIF2 signaling axis. These compounds will serve as unique chemical tools targeting the eIF2/eIF4 signaling axis and advance from hit- to lead for further preclinical development as a targeted therapy against aggressive solid tumors.
Citation Format: Walter Lang, Taotao Ling, Jangsoon Lee, Naoto T. Ueno, Fatima Rivas. Abietane natural products as novel therapeutics against solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B28.
Abstract LB-B34: LIF as a novel cancer immunotherapy target: modulating the tumor microenvironment with MSC-1, a humanized anti-LIF monoclonal antibody
Authors: Magram Jeanne , Pandya Naimish , Hoffman Kimberly , Hallett Robin , Giblin Patricia , Sinclair Angus , Anido Judit , Ruano Isabel Huber , Sala Ada , Pascual Monica , Chiganças Vanessa , Wasserman Robert , Seoane Joan 
Published: August 2018

Abstract
Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine involved in many physiological and pathological processes. LIF is highly expressed in a subset of tumors across multiple tumor types and has been shown to correlate with poor prognosis. LIF is hypothesized to contribute to tumor growth and progression by acting on multiple aspects of cancer biology, including immunosuppression of the tumor microenvironment and is a key regulator of cancer initiating cells (CICs). MSC-1, a first-in-class, humanized monoclonal antibody (IgG1), is a potent and selective inhibitor of LIF. MSC-1 leads to STAT3 inhibition by disrupting LIF signaling through the LIF receptor (LIFR). Blocking LIF with MSC-1 decreased tumor growth in multiple mouse tumor models and drove reprogramming of the tumor microenvironment through modulation of immunosuppressive macrophages and of several immune cell types. These findings form the basis of a robust therapeutic hypothesis, whereby MSC-1 treatment may lead to clinical activity in multiple cancer indications. Clinical testing is planned to initiate in the end of 2017 and trials will incorporate target engagement and PD biomarkers as well as efficacy endpoints.
Citation Format: Jeanne Magram, Naimish Pandya, Kimberly Hoffman, Robin Hallett, Patricia Giblin, Angus Sinclair, Judit Anido, Isabel Huber Ruano, Ada Sala, Monica Pascual, Vanessa Chiganças, Robert Wasserman, Joan Seoane. LIF as a novel cancer immunotherapy target: modulating the tumor microenvironment with MSC-1, a humanized anti-LIF monoclonal antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B34.
Abstract 1001: Gut microbiota modulate T cell trafficking into human colorectal cancer
Authors: Cremonesi Eleonora , Governa Valeria , Garzon Jesus , Mele Valentina , Amicarella Francesca , Muraro Manuele G. , Droeser Raoul , Bolli Martin , Slotta-Huspenina Julia , Terracciano Luigi , Zajac Paul , Spagnoli Giulio C. , Eppenberger-Castori Serenella , Janssen Klaus-Peter , Borsig Lubor , Iezzi Giandomenica 
Published: August 2018

Abstract
Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related death. CRC infiltration by immune cells, including cytotoxic CD8+ T cells (CTLs), IFN-gamma-producing T-helper 1 cells (Th1), Foxp3+ regulatory T cells (Tregs) and CD16+ MPO+ neutrophils, is associated with favorable prognosis. However, chemokines driving these cell populations into the tumor site, their cellular sources and their microenvironmental triggers remain to be elucidated. Aim: We investigated the chemokine/chemokine receptor network promoting CRC infiltration by immune cells associated to favorable prognosis. Results: CRC infiltration by immune cells was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper 1 cells, and CCL17, CCL22 and CXCL12 for T-helper 1 and regulatory T cells. Most of these chemokine genes were expressed by tumor cells upon exposure to gut bacteria in vitro and in vivo. Indeed, chemokine expression levels were significantly higher in orthotopic xenografts than in intraperitoneal tumors, and were drastically reduced by antibiotic treatment of tumor-bearing mice. Importantly, in human CRC samples, extents of chemokine production and immune cell infiltration was significantly associated with bacterial loads. Conclusion: Gut microbiota stimulates chemokine production by CRC cells, thus favoring T cell recruitment into tumor tissues.
Citation Format: Eleonora Cremonesi, Valeria Governa, Jesus Garzon, Valentina Mele, Francesca Amicarella, Manuele G. Muraro, Raoul Droeser, Martin Bolli, Julia Slotta-Huspenina, Luigi Terracciano, Paul Zajac, Giulio C. Spagnoli, Serenella Eppenberger-Castori, Klaus-Peter Janssen, Lubor Borsig, Giandomenica Iezzi. Gut microbiota modulate T cell trafficking into human colorectal cancer [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 1001.
Abstract 1002: Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1
Authors: Partlova Simona , Hladikova Kamila , Koucky Vladimir , Fialova Anna , Spisek Radek , Boucek Jan , Zabrodsky Michal , Halaska Michael , Tachezy Ruth , Grega Marek , Fonteneau Jean-François 
Published: August 2018

Abstract
Human papillomavirus (HPV) type 16 infection is one of the most important etiological agents of oropharyngeal squamous cell carcinoma. Patients with HPV-positive squamous cell carcinomas of the head and neck were reported to have a better clinical outcome than patients with HPV-negative tumors. Because HPV16 E6 and E7 oncoproteins are highly immunogenic and constitutively expressed within the tumor cells, HPV-specific T cell immunity may contribute to the better prognosis of HPV-positive tumors. We analyzed the frequency, phenotype and function of HPV16 E6/E7-specific tumor-infiltrating T cells (TILs) in oropharyngeal tumors and tested the effect of anti-PD1 mAb (nivolumab), soluble Tim-3 (sTim-3) and homeostatic in vitro expansion on these characteristics. We show that 73.1% of HPV-associated oropharyngeal tumors are positive for HPV16-specific T cells capable of producing IFNγ upon stimulation with E6/E7 peptide pools. These IFNγ-producing HPV-specific TILs were mainly PD-1+Tim-3-CD8+ T cells, identifying Tim-3 rather than PD-1 as a marker of T cell dysfunction. Consequently, specific IFNγ production was further enhanced by combined nivolumab plus sTim-3 treatment, but not with nivolumab alone. Our data provide the rationale for exploring additional setups of anti-PD-1 mAb treatment, including combinations with other check-point blockers, such as Tim-3 and/or with HPV16-directed therapeutic vaccines.
Citation Format: Simona Partlova, Kamila Hladikova, Vladimir Koucky, Anna Fialova, Radek Spisek, Jan Boucek, Michal Zabrodsky, Michael Halaska, Ruth Tachezy, Marek Grega, Jean-François Fonteneau. Dysfunction of HPV16-specific CD8+ T cells derived from oropharyngeal tumors is related to the expression of Tim-3 but not PD-1 [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 1002.
Abstract 1020: Characterization of the immune landscape and analysis of tumor response after anti-PD-1 blockade in a 3D ex vivo system of non-small lung cancer
Authors: Mediavilla-Varela Melanie , Page Melba Marie , Kreahling Jenny , Altiok Soner 
Published: August 2018

Abstract
Background: Immuno-oncology drugs face the challenge that cell lines and animal models cannot recapitulate the full intimacies of the tumor microenvironment. Although these models have aided in the discovery of new medical modalities, only 8% of these models have had a successful translation. Furthermore, the phenotype of the microenvironment of various tumor types has not been assessed in depth. Nilogen Oncosystems' proprietary 3D-EX vivo drug screening platform analyzes fresh patient tumor tissue that remains embedded in its natural environment. With our model, the characteristics of the tumor microenvironment can be accurately revealed in response to checkpoint inhibitors in non-small cell lung cancer (NSCLC) and correlates can be found among different platforms.
Methods: For the 3D-EX vivo platform, microspheres were produced from procured fresh tumor tissue from NSCLC cancer patients. They were then treated with Keytruda ex vivo and treatment-mediated changes in TIL subpopulations were analyzed using flow cytometric analysis, cytokine release by Bio-Rad's 17-plex cytokine assay as well as gene expression by NanoString's 770 gene Immune Panel.
Results: Ex vivo treatment of the 3D microspheres with Keytruda, showed significant changes in T-cell activation and immune cell populations in 26% of NSCLC tumors. This was observed by the simultaneous increase in IFN-γ and TNF-α upon cytokine analysis. Furthermore, we found a differential expression of signature genes such as CD8, CXCL10, CXCL9, EOMES, Granzyme A/B, IFN-γ, related to T-cell subpopulations via Nanostring analysis, which was accompanied by an increase in Granzyme B via flow cytometry.
Conclusion: The positive and negative associations between expression of immune function genes, TIL activation, and cytokine production by ex vivo treatment shows that Nilogen Oncosystems' 3D-Ex vivo platform can accurately recapitulate the tumor microenvironment and exhibits the importance of a comprehensive analysis of the tumor immune microenvironment for a better understanding of the mechanism of action of immuno-oncology drugs that may aid in developing biomarkers that can be used for patient selection.
Citation Format: Melanie Mediavilla-Varela, Melba Marie Page, Jenny Kreahling, Soner Altiok. Characterization of the immune landscape and analysis of tumor response after anti-PD-1 blockade in a 3D ex vivo system of non-small lung cancer [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 1020.
Abstract 106: Shock and ROR! Targeting ROR1 and ROR2 in a preclinical patient-derived model of ovarian cancer
Authors: Henry Claire E. , Hacker Neville F. , Ford Caroline E. 
Published: August 2018

Abstract
BACKGROUND: New targets for ovarian cancer treatment are critically needed. The Wnt receptors ROR1 and ROR2 are overexpressed in all histotypes of ovarian cancer and appear to play a role in both the tumour and the surrounding microenvironment. We have previously conducted an extensive suite of in vitro experiments, exploring the functional role of ROR1 and ROR2 in ovarian cancer. Silencing either receptor using siRNA inhibited ovarian cancer cell migration and invasion, and silencing both receptors had an even stronger inhibitory effect on the metastatic potential of ovarian cancer cellS. We have also shown that silencing ROR1 and ROR2 sensitises chemoresistant ovarian cancer cells to chemotherapy. Combined, these studies have confirmed the importance of RORs in ovarian cancer, and provided a strong argument for these receptors potential as clinical targets.
However, these previous studies have utilised simple 2D in vitro models to investigate cancer cell growth and migration, which does not allow investigation of stromal involvement in ROR driven metastasis.
AIM: To investigate targeting ROR1 and ROR2 in a 3D primary co-culture model of epithelial ovarian cancer dissemination to the omentum.
METHODS: Primary fibroblasts (NOF) and mesothelial (HPMC) cells were isolated from fresh samples of omentum collected from women with benign or non-metastatic conditions and cultured with collagen to produce a organotypic 3D model. Stable shRNA knockdown of ROR1, ROR2 and double ROR1/ROR2 in OVCAR4 ovarian cancer cells were incorporated into the 3D model to measure adhesion, or using a transwell to measure invasion. Gene expression changes in primary cells upon OVCAR4 interaction was evaluated using indirect transwell co-culture.
RESULTS: Double knockdown of ROR1 and ROR2 strongly inhibited cell adhesion (p&lt;0.05) and invasion (P&lt;0.05) to the omentum model. ROR2, but not ROR1, was up- regulated in primary fibroblasts when cultured with OVCAR4 (P=0.05) and ectopic overexpression of ROR2 in NOFs increased cell migration.
CONCLUSION: The combination of ROR1 and ROR2 signalling influences ovarian cancer dissemination to the omentum, however ROR2 may also play a specific role in stromal activation during metastasis. Therefore, targeting both ROR1 and ROR2 may be a powerful approach to treating ovarian cancer. The development of a number of monoclonal antibodies targeting ROR1 currently in phase 1 trials for other tumour types makes this clinically feasible in the near future.
Citation Format: Claire E. Henry, Neville F. Hacker, Caroline E. Ford. Shock and ROR! Targeting ROR1 and ROR2 in a preclinical patient-derived model of ovarian cancer [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 106.
Abstract 1081: TCF12 regulates metastasis-promoting genes in pancreatic cancer
Authors: Maurin Michelle M. , Newberg Justin Y. , Black Mik A. , Jones Devin J. , Jenkins Nancy A. , Copeland Neal G. , Mann Karen M. 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with poor patient outcome. While acquired oncogenic activation of KRAS is an initiating event, disease progression requires functional perturbation of additional genes and cellular pathways. We have taken a comparative genomics approach to identify progression drivers using a mouse model of metastatic PDAC driven by Sleeping Beauty (SB) insertional mutagenesis in the context of oncogenic Kras (SB PDAC). Statistical enrichment analysis of high read depth insertions from SB PDAC tumors defined 48 drivers predicted to contribute to disease progression. Among these drivers, Tcf12 was associated with increased metastatic incidence in the SB PDAC mouse model. We demonstrated significant increases in primary tumor burden and metastatic spread by single gene knockdown of TCF12 in an orthotopic mouse model of pancreatic cancer. TCF12 encodes a basic helix-loop-helix (bHLH) transcription factor that partners with other bHLH transcription factors in different cellular contexts, including TWIST, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), PTF1A, a pancreas-specific transcription factor with essential roles in pancreas development and cancer, and SMAD3, a TGFß-related transcription factor involved in cellular migration. TCF12 resides in a chromosomal region (15q21) frequently lost in pancreatic cancer, and decreased TCF12 expression is associated with poor patient prognosis. RNASeq analysis identified genes with TCF12 consensus binding sites within 10 kb of their promoter regions that are differentially expressed upon TCF12 knockdown. A subset of these genes function in Wnt or TGF-beta signaling pathways and show consistent decreases in expression upon TCF12 knockdown in orthotopic tumors. ChipSeq analysis and functional validation studies are ongoing to confirm these genes are direct TCF12 transcriptional targets involved in pancreatic tumor metastasis.
Citation Format: Michelle M. Maurin, Justin Y. Newberg, Mik A. Black, Devin J. Jones, Nancy A. Jenkins, Neal G. Copeland, Karen M. Mann. TCF12 regulates metastasis-promoting genes in pancreatic cancer [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 1081.
Abstract 1083: GAP43, a novel potential metastases promoter in non-small cell lung cancer
Authors: Zhang Fanrong , Jin Jiaoyue , Wu Junzhou , Chen Kaiyan , Huang Minran , Yu Herbert , Ying Lisha , Su Dan 
Published: August 2018

Abstract
Metastasis is a serious sequela with dismal prognosis in non-small cell lung cancer (NSCLC). To identify novel biomarkers for predicting NSCLC metastasis, we performed high-throughput Luminex assays to profile the transcriptional level of 36 genes in 37 operable NSCLC patients who had distant metastases within 3 years after surgery and 33 paired patients without relapse after operation. Among the 36 genes, growth associated protein 43 (GAP43), an axonal membrane protein, was identified related to distant metastases. Multivariate cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.71-fold increase in risk for metastasis than those with low levels (95% confidence interval 1.69-8.14, P = 0.001). Analysis of a patient cohort of 1,926 NSCLC revealed that patients with high levels of GAP43 had worse progression-free and overall survival. In vitro experiments showed that GAP43 knockdown suppressed NSCLC cell migration and invasion, while GAP43 overexpression facilitated their migration and invasion. Immunofluorescence assay indicated that the linear polymer microfilament F-actin became cracked after GAP43 knockdown. Furthermore, animal studies using left ventrical injection demonstrated that GAP43 silenced NSCLC cells were less likely to metastasize to brain and bone than the controls. Together, our findings suggest that GAP43 may be an independent predictor for NSLCL metastasis, and it may facilitate distant metastasis through targeting F-actin.
Citation Format: Fanrong Zhang, Jiaoyue Jin, Junzhou Wu, Kaiyan Chen, Minran Huang, Herbert Yu, Lisha Ying, Dan Su. GAP43, a novel potential metastases promoter in non-small cell lung cancer [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 1083.