bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3992: Immune regulation of disseminated tumor cell clearance versus metastatic growth
Authors: Korkaya Hasan , Lee Eunmi , Piranioglu Raziye , Ouzounova Maria , El-Andaloussi Abdeljabar , Asm Iskander , Korkaya Ahmet K. , Zhou Gang , Arbab Ali , Rodriguez Paulo 
Published: July 2017

Abstract
Metastatic disease is the end stage of extremely inefficient processes that entail overcoming multiple barriers including anti-tumor immunity. Although evidences from preclinical and clinical settings suggest that dissemination of malignant cells is an early process, majority of disseminated cells either eliminated or remain dormant in distant organs, while very few cells eventually develop successful metastasis. Therefore, it is widely accepted that dynamic and reversible tumor cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated.
We provide evidence that monocytic and granulocytic subsets of myeloid derived suppressor cells (m-MDS, g-MDSC) infiltrated in primary 4T1 tumor and distant organs with different time kinetics regulate spatiotemporal tumor plasticity. Using co-culture experiments and syngeneic mouse models of murine 4T1 (metastatic) tumor, we demonstrated that tumor infiltrated m-MDSCs facilitate tumor cell dissemination from the primary site by inducing the EMT/CSC phenotype. In contrast, g-MDSCs infiltrated in the lungs support metastatic growth by reverting the EMT/CSC phenotype and thus promoting tumor cell proliferation. In contrast, less invasive EMT6 tumors fail to induce efficient pulmonary infiltration of g-MDSCs and results in clearance of disseminated tumor cells in the lungs. Gene expression analyses of tumors and MDCS subsets in primary tumor site and distant organs at different time points reveal mechanistic temporal regulation of in vivo tumor plasticity by m-MDSC and g-MDSC subsets in 4T1 tumor-bearing mice. However, the lung microenvironment of EMT6 tumor-bearing mice display a gene expression signature of anti-tumor immunity which predict better survival in breast cancer patients. In our functional studies, we demonstrate that EMT6 tumor-bearing animals efficiently eliminate disseminated tumor cells in the lungs. Furthermore, g-MDSCs isolated from 4T1-tumor bearing animals significantly enhance metastatic growth of already disseminated tumor cells.
Consistent with the “seed and soil” hypothesis, our studies provide a molecular mechanism by which the immune system regulate spatiotemporal tumor plasticity and generation of permissive or anti-tumorigenic microenvironment in distant organs determining the fate of disseminated tumor cells.
Citation Format: Hasan Korkaya, Eunmi Lee, Raziye Piranioglu, Maria Ouzounova, Abdeljabar El-Andaloussi, Iskander Asm, Ahmet K. Korkaya, Gang Zhou, Ali Arbab, Paulo Rodriguez. Immune regulation of disseminated tumor cell clearance versus metastatic growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3992. doi:10.1158/1538-7445.AM2017-3992
Abstract 3998: Alerting the immune system by removing epigenetic silencing of Th1 chemokines
Authors: Sonnemann Heather M. , Giles Amber J. , Reid Caitlin M. , Hutchinson Marsha-Kay N. , Park Deric M. , Gilbert Mark R. 
Published: July 2017

Abstract
BACKGROUND: Solid tumors employ multiple mechanisms to evade an immune response. However, the potential to enhance the immune response to cancer has been proven in several malignancie and is under investigation in many others, including primary CNS tumors. Brain tumors in particular lack robust T-cell infiltration. Recent studies have found that certain tumors can be induced to express T-cell attracting chemokines, CXCL9 and CXCL10, by interferon gamma (IFNg). This response is further amplified using methyltransferase inhibitors (Peng, et al. Nature 2015. Vol 527: 249-253.), resulting in increased Tcell trafficking to tumors both in vitro and in vivo. We hypothesized that T-cell trafficking to brain tumors could likewise be enhanced with DNA and histone methyltransferase inhibitors to induce CXCL9 and CXCL10 transcription.
METHODS: Assays were performed on 7 human glioma brain tumor cell lines. CXCL9 and CXCL10 expression were measured by real-time PCR. Two commercially available methyltransferase inhibitors, 5-AZA-dC and GSK126, were utilized to demethylate DNA and histone H3 (K9 and K27), respectively. Histone methylation status was examined using Western blot. T-cell migration was measured using transwell migration assays.
RESULTS: IFNg increased CXCL9 and CXCL10 transcription in brain tumor lines. GSK126 and 5-AZA-dC enhanced expression of CXCL9 and CXCL10 compared to IFNg alone. Migration assays confirmed T-cell trafficking towards chemokines produced by tumor cells in response to methyltransferase inhibitors.
CONCLUSIONS: These studies demonstrate that brain tumors express T-cell attracting chemokines CXCL9 and CXCL10 in response to IFNg. Further, GSK126 and the combination of GSK126 and 5-AZA-dC enhanced expression of CXCL9 and CXCL10 transcription by real-time PCR and T-cell trafficking by migration assay. Together, these data provide a potential means to increase T-cell trafficking into tumors and potentially enhances the efficacy of immune therapies for brain tumors.
Citation Format: Heather M. Sonnemann, Amber J. Giles, Caitlin M. Reid, Marsha-Kay N. Hutchinson, Deric M. Park, Mark R. Gilbert. Alerting the immune system by removing epigenetic silencing of Th1 chemokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3998. doi:10.1158/1538-7445.AM2017-3998
Abstract 400: NCI's CPTAC Phase III, proteogenomic analysis of additonal cancer types
Authors: Hannick Linda I. 
Published: July 2017

Abstract
The Clinical Proteomics Tumor Analysis Consortium (CPTAC) is a National Cancer Institute initiative that seeks to uncover the molecular basis of cancer using a proteogenomic approach to study prospective cancer specimens. Leidos Biomed provides an infrastructure for supporting the collection of high quality biospecimens and data, in addition to project and subcontract management for the program. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. Phase II of CPTAC, completed in 2016, collected over 500 cases from breast, colon and ovarian patients. In early 2016, CPTAC Phase III began to collect and analyze 200 cases of each of ten additional cancers. The goal is to collect 200 qualified cases of five to six tumor types over a five-year period, although the program is currently accruing from ten. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to a sequencing center and tissues to proteomics groups. Data are combined and analyzed by translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons. Proteomic data are made available through the Data Coordinating Center. We report here on progress in collection of tissues and clinical data, and use of biorepository, proteomics and genomics and analysis centers.
Citation Format: Linda I. Hannick. NCI's CPTAC Phase III, proteogenomic analysis of additonal cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 400. doi:10.1158/1538-7445.AM2017-400
Abstract 4005: HDAC inhibitors regulate M2 tumor-associated macrophage function through histone acetylation
Authors: Groot Amber E. de , Zarif Jelani C. , Pienta Kenneth J. 
Published: July 2017

Abstract
Macrophage tumor infiltration in metastatic prostate cancer is a predictor of patient prognosis. Macrophages influence tumors in contrasting ways depending on their polarization: M1 macrophages have anti-tumor functions while M2 macrophages are pro-tumor. The external stimuli influencing macrophage differentiation and M2 polarization have been largely elucidated but the resulting downstream changes remain unknown. There are a number of epigenetic differences between M1 and M2 macrophages that act as important functional determinants. Recent work studying these epigenetic changes has implicated histone deacetylases (HDACs), as critical regulators in macrophage differentiation and in maintaining M1 or M2 function. Pan-HDAC inhibitors (HDIs) such as the clinically utilized suberanilohydroxamic acid (SAHA) target a wide range of HDACs and provide a means for manipulating macrophage histone acetylation. Though HDIs have been found to attenuate inflammatory functions in M1 macrophages, the field has yet to explore effects of histone acetylation in M2 macrophages. Using M2 macrophages derived from human CD14+ monocytes, we found that SAHA regulates M2 macrophage polarization and function through alteration of histone acetylation. Work is ongoing to test expression levels of canonical M2 markers such as the mannose receptor CD206 and scavenger receptor CD163 in M2 macrophages exposed to SAHA either during or after M2 polarization. Additionally, investigation into the ability of these populations to secrete M2 cytokines such as IL-10 and VEG-FA and induce EMT in prostate cancer cells is also being pursued. These results contribute to scientific knowledge of epigenetic regulation in macrophage function and elucidate strategies to decrease the pro-tumor function of tumor-infiltrating M2 macrophages. This work lays the foundation for using epigenetic regulators to modulate the tumor microenvironment and advance cancer medicine.
Citation Format: Amber E. de Groot, Jelani C. Zarif, Kenneth J. Pienta. HDAC inhibitors regulate M2 tumor-associated macrophage function through histone acetylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4005. doi:10.1158/1538-7445.AM2017-4005
Abstract 4027: Developing biophysical platforms to study KRAS membrane interaction in artificial membranes
Authors: Jean-Francois Frantz L. , Stephen Andrew G. 
Published: July 2017

Abstract
In our studies, we leverage the techniques that we believe will allow us to better understand and tackle KRAS membrane interaction. RAS proteins are small GTPases that oscillate between an active GTP-bound and inactive GDP-bound state to function as plasma membrane localized molecular switches in growth factor regulated signaling pathways. Mutation in HRAS, KRAS and NRAS are present in nearly 30% of human tumors. In particular, KRAS is mutated in almost 90% of pancreatic adenocarcinomas. Considering the requirement of the plasma membrane for KRAS activity, we are setting up ‘screenable’ biophysical platforms to understand the importance of lipids and find small molecules that could prevent KRAS membrane association in reconstituted systems. The two main techniques that are being developed are Surface Plasmon Resonance and Confocal Imaging in model membranes. Using these two techniques, we have been able to better understand the main lipids that drive KRAS membrane association and set up platforms that can be screened by small/large molecules. Biophysical techniques are frequently used by pharmaceutical companies as primary or secondary screening platforms. Developing such platforms for KRAS membrane interaction could enable the discovery of anti-cancer tool compounds.
Citation Format: Frantz L. Jean-Francois, Andrew G. Stephen. Developing biophysical platforms to study KRAS membrane interaction in artificial membranes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4027. doi:10.1158/1538-7445.AM2017-4027
Abstract 4117: Mechanisms of acquired resistance to c-Src kinase inhibitor in triple negative breast cancer
Authors: Gilani Rabia A. , Lachacz Eric J. , Phadke Sameer , Bao Li Wei , Cheng Xu , Jiagge Evelyn M. , Soellner Matthew B. , Merajver Sofia D. 
Published: July 2017

Abstract
Triple negative breast cancers (TNBCs) are especially lethal due to their high metastatic potential and propensity to recur. TNBCs comprise the only subset of breast cancer for which there are no FDA-approved targeted therapies. We have developed a mechanistically novel dual c-Src/p38 inhibitor, UM-164, that has potent in vivo anti-TNBC activity. However, single-agent targeted therapies are prone to resistance and rational drug combinations can overcome or prevent resistance. We developed TNBC cells lines that are resistant to UM-164. Significant morphology and cell signaling changes occurred in the drug-resistant cell lines. Most crucial is the observation that in drug-resistant cell lines the activation of c-Src and/or p38 does not return in the presence of UM-164, suggesting that resistance is not occurring via constitutive activation enabling mutations of c-Src and/or p38 kinases. However, compared to their drug-sensitive counterparts, the UM-164-resistant cells have significantly hyperactivated MEK1/2 and ERK1/2 signaling when treated with UM-164. Thus, we tested combinations of UM-164 + MEK1/2 inhibitors in several TNBC cell lines and patient derived xenografts. We found that trametinib (Mekinist®, an FDA-approved inhibitor of MEK1/2) is synergistic (Chou-Talalay CI at ED90 = 0.4, CI &lt; 1 denotes synergy) with UM-164 to inhibit the growth of UM-164-resistant MDA-MB-231 and SUM-149 cell lines. These results support our hypothesis that activation of MEK/ERK signaling can act as an escape mechanism that leads to resistance to UM-164. Future research into rational combinations of targeted therapies delivered in data driven schedules may hold the key to improving survival in TNBC.
Citation Format: Rabia A. Gilani, Eric J. Lachacz, Sameer Phadke, Li Wei Bao, Xu Cheng, Evelyn M. Jiagge, Matthew B. Soellner, Sofia D. Merajver. Mechanisms of acquired resistance to c-Src kinase inhibitor in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4117. doi:10.1158/1538-7445.AM2017-4117
Abstract 4125: Comparison between knockdown of Pim-1, Pim-2 and Pim-3 identifies Pim-2 as the most relevant Pim oncogene in hepatocellular carcinoma
Authors: Weirauch Ulrike , Kürz Pia , Aigner Achim M. 
Published: July 2017

Abstract
Introduction Pim-Kinases (Pim - proviral integration site for moloney murine leukemia virus; Pim-1, -2, -3) are a family of serine/threonine kinases with oncogenic potential. They are overexpressed in various solid tumors including hepatocellular carcinoma (HCC) and have been found responsible for malignant transformation, induction of cell proliferation and inhibition of apoptosis. While the main focus has been on Pim-1 so far, the other Pim kinases, esp. Pim-2, have not been explored in detail.
Objectives The aim of this study was to compare the tumor-inhibitory effects of the single and combined of Pim family members in HCC, for evaluating their individual contributions and potential as therapeutic target. To this end, RNA interference (RNAi) for specific gene knockdown was employed.
Materials and methods Different HCC cell lines were transfected with small interfering RNAs (siRNAs) for inducing RNAi and transient target gene downregulation. Various cellular and molecular effects were analysed.
Results Transient siRNA transfection led to robust and specific knockdown of the selected Pim kinase(s) on mRNA and protein level. This resulted in anti-proliferative and pro-apoptotic effects. Most profound consequences on cell growth, cell cycle and apoptosis were observed upon Pim-2 knockdown, with little additive effects upon combined inhibition. These cellular changes were paralleled by alterations of various genes involved in cell cycle, cell survival, EMT and other important cellular processes.
Conclusion In hepatocellular carcinoma, Pim-2 represents a functionally relevant oncogene. We demonstrate its higher potential as compared to the other Pim family members, and analyze various consequences of its inhibition or knockdown on the cellular and molecular level. Taken together, this identifies Pim-2 as a potentially relevant target gene for therapeutic intervention.
Citation Format: Ulrike Weirauch, Pia Kürz, Achim M. Aigner. Comparison between knockdown of Pim-1, Pim-2 and Pim-3 identifies Pim-2 as the most relevant Pim oncogene in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4125. doi:10.1158/1538-7445.AM2017-4125
Abstract 4127: Targeting MDM4 in hepatocellular carcinoma to reactivate p53 signaling
Authors: Woodfield Sarah E. , Shi Yan , Patel Roma H. , Chen Zhenghu , Ibarra Aryana M. , Vasudevan Sanjeev A. 
Published: July 2017

Abstract
Objective: New therapeutic strategies are desperately needed for hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related deaths worldwide. Most patients with HCC lack mutations in the p53 tumor suppressor gene. Therefore, we hypothesized that targeting MDM4 or MDM2 to reactivate p53 signaling could be effective in this disease.
Methods: HCC cell lines (SK-Hep1, Huh-7, Hep3B) were profiled for gene and protein expression of MDM4 with qPCR and immunoblotting assays, respectively. The effects of MDM4 inhibitor NSC207895 on the same cell lines were analyzed with MTT assays for cytotoxicity and qPCR experiments to look at changes in expression of p53 downstream targets, in comparison to the effects of MDM2 inhibitor Nutlin-3a. Effects of MDM4 on targets other than p53, including family members p63 and p73, were examined in cells with mutant or null p53 for changes in expression with qPCR experiments.
Results: Three HCC cell lines showed expression of MDM4. Inhibition of MDM4 showed cytotoxic (high dose, 0.16-15.0 μM) and anti-proliferative (low dose, 0.05-0.3 μM) effects in all three cell lines, including p53 mutant Huh-7 and p53 null Hep3B cells. The same cell lines were strongly resistant to Nutlin-3a. Gene expression analyses were conducted with cells exposed to NSC207895 to examine effects of MDM4 inhibition on p53 targets Bax, Puma, and p21. In SK-Hep1 cells, NSC207895 treatment led to 2.5-fold overexpression of Bax, 27.4-fold of Puma, and 23.1-fold of p21. Huh-7 showed 11.8-fold upregulation of Puma and 12.4-fold of p21, and Hep3B exhibited a very strong 58.4-fold increase in p21 gene expression with the same treatment. Interestingly, Hep3B showed 5.9-fold overexpression of p63 and 1.99-fold of p73 gene expression with NSC207895 exposure, suggesting novel interactions between MDM4 and p63/p73 in the absence of p53.
Conclusions: Inhibition of MDM4 shows efficacy in in vitro models of HCC through upregulation of p53, p63, and p73 to activate p53 tumor suppressive signaling. Thus, targeting MDM4 may be a viable option for all HCC patients, no matter the p53 mutation status.
Citation Format: Sarah E. Woodfield, Yan Shi, Roma H. Patel, Zhenghu Chen, Aryana M. Ibarra, Sanjeev A. Vasudevan. Targeting MDM4 in hepatocellular carcinoma to reactivate p53 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2017-4127
Abstract 4135: Inactivation/loss of PTPRS promotes ERK activation that sensitizes colorectal cancer cells to ERK inhibitors
Authors: Davis Thomas B. , Yang Mingli , Schell Michael J. , Wang Heiman , Ma Le , Pledger W. Jack , Yeatman Timothy J. 
Published: July 2017

Abstract
The RAS pathway is a driver of many cancers, and has been targeted for the development of a variety of therapeutic inhibitors of BRAF, MEK, and more recently ERK. One of challenging issues is to predict response to targeted therapies. Here we report identification of PTPRS, a receptor-type protein tyrosine phosphatase, as a regulator/biomarker of ERK activation and inhibitor response in colorectal cancer. To identify the genes with high frequency mutations that might be predictive of RAS pathway dependence (“addiction”), we used a gene expression signature score to stratify 468 colorectal cancer tumors that also underwent targeted exome sequencing for 1321 cancer-associated genes. We found that, when the masking effects caused by mutant KRAS, BRAF and NRAS was iteratively removed, mutant PTPRS was strongly correlated with RAS pathway activation, with a mutation rate of 10.4% (22 out of 211 remaining tumors). This led us to inactivate PTPRS in vitro using a specific peptide inhibitor, siRNA or CRISPR approaches in various colorectal cancer cell lines. Inhibition/loss of PTPRS significantly elevated phosphorylation of ERK and AKT and substantially sensitized cancer cells to the treatment of ERK inhibitors, which was enhanced by an AKT inhibitor. Surprisingly, PTPRS did not modulate the activity of EGFR and the ERK kinase, MEK. Our data indicate that PTPRS negatively regulates ERK signaling downstream of the EGFR/RAS/RAF/MEK pathway in a mechanism independent of AKT and DUSP6. As a result, inactivation/loss of PTPRS promotes ERK activation and “addiction”, thereby contributing to increased sensitivity to ERK inhibitors.
Citation Format: Thomas B. Davis, Mingli Yang, Michael J. Schell, Heiman Wang, Le Ma, W. Jack Pledger, Timothy J. Yeatman. Inactivation/loss of PTPRS promotes ERK activation that sensitizes colorectal cancer cells to ERK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4135. doi:10.1158/1538-7445.AM2017-4135