tbuckley/cabot-search huggingface dataset:
Abstract 5944: Matrilysin/MMP-7 compromises a novel border interaction between perlecan/HSPG2 and semaphorin 3A to support prostate cancer invasion
Authors: Brian J. Grindel, Daniel A. Harrington, Leland Chung, Mary C. Farach-Carson
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) cells interact with the stroma and extracellular matrix (ECM) during tumor expansion and invasion during metastasis. Dissecting the complex matrix-cancer interplay is essential to halting tumor progression. A vital component of the ECM is perlecan/heparan sulfate proteoglycan 2 (HSPG2). As a large extracellular proteoglycan, perlecan helps orchestrate tumor angiogenesis, proliferation, differentiation and invasion. Actively metastasizing cancer cells must proteolytically degrade several tissue borders which perlecan patrols, including the basement membrane, vasculature, reactive stromal matrix and bone marrow. Investigating the effects of perlecan on metastatic PCa cells showed full length perlecan and specifically conserved domain IV of perlecan triggers clustering of PCa cells. Perlecan cleavage by the pro-tumor protease matrilysin/matrix metalloproteinase (MMP-7) reverses this, favoring cell dispersion and tumor dyscohesion. Network analysis of a reverse phase protein array and subsequent western blots revealed clustered cells on intact perlecan/Dm IV induced a strong focal adhesion kinase (FAK) dephosphorylation/deactivation. Alternatively, FAK was highly phosphorylated/activated on MMP-7 cleaved perlecan/Dm IV consistent with an adhesive and dispersive/metastatic phenotype. Several lines of evidence indicate Dm IV interacts with the classically known axon guidance protein semaphorin 3A (Sema3A), to shut off pro-metastatic FAK activation. Notably, a C-terminus directed Sema3A antibody mimics the clustering activity of Dm IV. We showed Dm IV binds to Sema3A in ELISA and quartz crystal microbalance experiments and the interaction is abrogated by the Sema3A antibody. Interestingly, Sema3A also is sensitive to MMP-7 proteolytic activity. Finally, transient knockdown of Sema3A in PCa cells inhibits the clustering effect by a Dm IV substrate. This work shows that perlecan is an effective border molecule because it coordinates with Sema3A to repulse and cluster cells by switching off FAK activity. However, PCa cells expressing active MMPs, such as MMP-7, can destroy this Sema3A/perlecan complex to develop an invasive, metastatic phenotype associated with lethal disease. Citation Format: Brian J. Grindel, Daniel A. Harrington, Leland Chung, Mary C. Farach-Carson. Matrilysin/MMP-7 compromises a novel border interaction between perlecan/HSPG2 and semaphorin 3A to support prostate cancer invasion [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 5944. doi:10.1158/1538-7445.AM2017-5944
Abstract 3122: Pharmacogenomic profiling to identify novel therapeutic strategies in colorectal cancer
Authors: Jarle Bruun, Peter W. Eide, Kushtrim Kryeziu, Anita Sveen, Astrid Murumägi, Matthias Kolberg, Mariliina Arjama, Olli Kallioniemi, Ragnhild A. Lothe
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is amongst the most frequent cancers worldwide and the fourth most common cause of cancer mortality. Surgery is the standard treatment of care, while chemotherapy and/or radiotherapy are offered to subgroups of patients according to disease stage. Current guidelines do not have sufficient accuracy to identify chemotherapy responders, resulting in under- or overtreatment of many patients.To discover novel therapeutic strategies for CRC we performed a high-throughput drug screen containing 461 approved and preclinical drugs on a representative panel of 42 CRC cell lines. Integrative pharmacogenomic profiles were explored by matching data from gene expression, exome sequencing, copy number and reverse-phase protein arrays. These analyses identified defined molecular subgroups sensitive to targeted drugs like Inhibitors of EGFR, IGF-1R and downstream signaling mediators like B-Raf, MEK, PI3K/AKT, as well as inhibitors of aurora mitotic kinases, heat shock protein 90 and p53. Additionally, a correlation between microsatellite instability and sensitivity against topoisomerase-I inhibitors was found. Comparison of the most sensitive and the most resistant cell models against HSP90 inhibitors indicated that drug sensitivity does not depend on target expression but is likely attributed to the cell line-specific expression of client proteins. Real-time cell analyses measured with the xCELLigence system demonstrated a strong impact on cell proliferation but not on the migration of HSP90-sensitive cells treated with HSP90 inhibitors as compared to resistant cells. These integrative analyses have unraveled pharmacogenomic relationships that if validated in in vivo model systems, might be used to stratify patients for therapeutic intervention in biomarker guided clinical trials. Citation Format: Jarle Bruun, Peter W. Eide, Kushtrim Kryeziu, Anita Sveen, Astrid Murumägi, Matthias Kolberg, Mariliina Arjama, Olli Kallioniemi, Ragnhild A. Lothe. Pharmacogenomic profiling to identify novel therapeutic strategies in colorectal 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 3122. doi:10.1158/1538-7445.AM2017-3122
Abstract 2038: Reactive oxygen species-mediated synergism of fenretinide and romidepsin in preclinical models of T-cell lymphoid malignancies
Authors: Monish Ram Makena, Balakrishna Koneru, Min H. Kang, C. Patrick Reynolds
Journal: Cancer Research (2017)

Abstract Introduction: T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. Romidepsin is a histone deacetylase (HDAC) inhibitor that achieved FDA registration as 2nd line therapy for peripheral and cutaneous T-cell lymphomas. The cytotoxic retinoid fenretinide achieved durable complete responses against T-cell lymphomas in early-phase clinical trials and T-cell lymphoma patients who failed prior romidepsin treatment responded to fenretinide. Fenretinide is currently being evaluated in a Phase IIa clinical trial for relapsed/refractory PTCL patients (NCT02495415). We investigated the potential for using these two agents in combination in TCLMs. Methods and Results: Using the DIMSCAN assay, we demonstrated cytotoxic synergy between romidepsin and fenretinide in fifteen TCLM cell lines at clinically-achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous (COG-LL-317m and TX-LY-183x PDX) and disseminated (COG-LL-317m Luc expressing the luciferase gene) TCLM xenograft models than single agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS, measured by DCFDA dye)-dependent increase in pro-apoptotic proteins (Bim, tBid, Bax and Bad), apoptosis (via TUNEL assay), and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin was abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and shRNA knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity and apoptosis. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in fibroblasts and blood mononuclear cells. Conclusion: Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in non-malignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs. Citation Format: Monish Ram Makena, Balakrishna Koneru, Min H. Kang, C. Patrick Reynolds. Reactive oxygen species-mediated synergism of fenretinide and romidepsin in preclinical models of T-cell lymphoid malignancies [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 2038. doi:10.1158/1538-7445.AM2017-2038
Abstract 2144: A novel method for high-throughput discovery of neo-antigens and corresponding T-cell receptors
Authors: Songming Peng, Jesse Zaretsky, Michael T. Bethune, Alice Hsu, David Baltimore, Antoni Ribas, James Heath
Journal: Cancer Research (2017)

Abstract Immunotherapies that boost the ability of endogenous T cells to destroy cancer cells have demonstrated therapeutic efficacy in several human malignancies. Cytotoxic T cells actively recognize peptide antigens, which are displayed on major histocompatibility complexes (MHCs) on the surface of the malignant cells, to play a central role in cancer immunotherapy. However, efficient methods for identifying the tumor antigens and the corresponding T cell receptors are still limited. We report here a DNA-barcode nanoparticle and microfluidics-based method to sort and enumerate neoantigen-specific T cells, at an unprecedented level of sensitivity. The method also permits the matching of a single neoantigen to a specific CD8+ T cell with the TCR a/b gene sequence. The resultant information informs an immunotherapy regimen that is specific for that patient, which can be used to custom-design effective ACT therapies. Citation Format: Songming Peng, Jesse Zaretsky, Michael T. Bethune, Alice Hsu, David Baltimore, Antoni Ribas, James Heath. A novel method for high-throughput discovery of neo-antigens and corresponding T-cell receptors [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 2144. doi:10.1158/1538-7445.AM2017-2144
Abstract 3986: Regulation mechanism and clinical significance of KPNA2 promotes MDSCs infiltrating in epithelial ovarian cancer
Authors: Shuting Huang, Min Zheng, Yuanzhong Wu
Journal: Cancer Research (2017)

Abstract Myeloid-Derived Suppressor Cells (MDSCs) are a population of immune cells that negatively regulate immune responses, which could promote tumor invasion and metastasis. Recently research has revealed that tumor could actively reshape the immune-microenvironment for its progression. We recently demonstrated that KPNA2 is a candidate oncogene in ovarian cancer that was closely related to MDSCs density, and found there was a positive position feedback between KPNA2 expressed and MDSCs density, which might contribute to the poor prognosis of patients. Based on these results, we combined clinical sample analysis, animal model and experimental studies to do further molecular and genomic research. The conduction of this project will help explain the molecular mechanisms of how KPNA2 regulates ovarian cancer through suppressing the immune system, and provide new strategies by molecular targeted therapy combining biological therapy for ovarian cancer. Note: This abstract was not presented at the meeting. Citation Format: Shuting Huang, Min Zheng, Yuanzhong Wu. Regulation mechanism and clinical significance of KPNA2 promotes MDSCs infiltrating in epithelial ovarian 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 3986. doi:10.1158/1538-7445.AM2017-3986
Abstract 2015: Mesenchymal stem cell correlates oral leukoplakia malignant transformation through regulate T cell response
Authors: Yichen Chen, Bailin He, Da Ma, Jingjing Song, Xi Wang, Bin Cheng, Zhi Wang
Journal: Cancer Research (2017)

Abstract Introduction Leukoplakia is one of the most common clinically presented oral potential malignant disorders (OPMD). Detailed understanding of leukoplakia-associated molecular or cellular changes would help us better undertand about the progress of leukoplakia malignant transformation. In this study, we examined the potential involvement of MSC in this very progress, and demonstrated lesion resident MSCs may favour leukoplakia malignant transformation through its strong immunoregulation on T cell. Methods Eighteen six-week-old female Sprague-Dawley rats (180-220g) were given 0.05g/L 4NQO in drinking water for 22 weeks for development of lesions. Lesions classfied by histological HE stainnig. MSCs were obtained from single cell suspesion of lesions, and cultured with splenocyte to study its immunoregulate ability. Results 1. MSC-like cells are enriched in carcinogen induced leukoplakia and cancers. Representative results showing the lesions on tongue of rats. And relative proportion of MSC phenotype marker (CD29+, CD31-, CD45-, CD90+) in oral lesions (OMSC) were counted by flow cytometry. 2. Leukoplakia-derived MSC (L-OMSC), cancer-derived MSC (C-OMSC), and the normal mucosa-derived MSC (N-OMSC) share the similar stemness properties. 3. Cancer lesion have less infiltrating T cells (quantified by IHC and FCM of CD3 ). Cancer-derived MSCs suppress T cell proliferation, but not promote T cell apoptosis and inhibit T cell migration to the lesions. 4. Higher number of lesion derived MSCs associates with higher celluar proliferation in the lesions. Summary Our study demonstrated MSCs could migrate to pre-malignant leukoplakia lesions prior to tumor establishment. Further, MSCs play an important role in leukoplakia malignant transformation induced by chemicals, which via its strong immunomodulatory activities. Citation Format: Yichen Chen, Bailin He, Da Ma, Jingjing Song, Xi Wang, Bin Cheng, Zhi Wang. Mesenchymal stem cell correlates oral leukoplakia malignant transformation through regulate T cell response [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 2015. doi:10.1158/1538-7445.AM2017-2015
Abstract 1790: Evaluation of UCK2 protein expression as a potential predictive biomarker of RX-3117
Authors: Young Bok B. Lee, Deog J. Kim, Christina George, Chang-ho Ahn, Julie Frank, Reza Mazhari, Lisa M. Dauffenbach, Eric P. Olsen
Journal: Cancer Research (2017)

Abstract Background: A novel, orally bioavailable nucleoside analogue, RX-3117, is a prodrug activated intracellularly by Uridine Cytidine Kinase 2 (UCK2) that is thought to be expressed predominantly in tumor tissue. RX-3117 is currently being evaluated in a Phase Ib/IIa multi-center, open-label clinical study in patients with advanced pancreatic and bladder cancer. In this study, we aimed to determine the relation between UCK2 tissue protein expression and the efficacy of RX-3117 in mice xenograft models and also UCK2 protein expression in a panel of human cancer tissues relative to normal tissue. Methods: The UCK2 protein expression in tumor tissues was analyzed by immunoblotting using clone 22-1 rabbit monoclonal antibody. The validated procedure for the immunohistochemistry (IHC) of UCK2 with clone 22-1 was performed in a panel of human formalin-fixed paraffin-embedded (FFPE) cancer and normal tissues. Results: The immunoblotting protein level of UCK2 normalized to β-actin and corresponding tumor growth inhibition (oral RX-3117 dose of 500mg/kg, TIWK) were 57 and 67% in MiaPaCa2, 30 and -5% in BxPC3, 199 and 92% in Colo-205, 21 and 90% in Caki-1, 2 and 39% in A549, and 146 and 79% in H460, respectively. This data indicates an anti-tumor efficacy trend in a UCK2-dependent manner. The IHC of UCK2 showed that positive staining of UCK2 in cancer tissues was observed in 20/20 bladder cancer tissues (100% frequency), 19/20 CRC tissues (95% frequency), 18/20 NSCLC tissues (90% frequency), and 19/20 pancreatic cancer tissues (95% frequency). Average H-Scores of UCK2 in cancer tissues vs. normal tissues were 104 vs. 9 in lung, 97 vs. 20 in bladder, 67 vs. 41 in pancreas and 39 vs. 21 in colon, respectively. Conclusions: The current data showed a correlation trend between UCK2 protein expression level and degree of antitumor activity of RX-3117 in xenograft models. It also supports a higher UCK2 protein expression level in human cancer tissues compared to their normal tissues. This suggests that RX-3117 activity may be specific to tumor tissue, and quantification of UCK2 expression in human cancer tissues may be useful as a predictive biomarker to select patients for their sensitivity to RX-3117 in future clinical studies. Citation Format: Young Bok B. Lee, Deog J. Kim, Christina George, Chang-ho Ahn, Julie Frank, Reza Mazhari, Lisa M. Dauffenbach, Eric P. Olsen. Evaluation of UCK2 protein expression as a potential predictive biomarker of RX-3117 [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 1790. doi:10.1158/1538-7445.AM2017-1790
Abstract 3089: Combining MEK and HDAC inhibitors as a therapeutic strategy to promote differentiation of colorectal cancer
Authors: Laura J. Jenkins, Ian Y. Luk, Janson W. Tse, Jennifer Mooi, Amardeep S. Dhillon, John M. Mariadason
Journal: Cancer Research (2017)

Abstract The five-year survival rate for patients with metastatic colorectal cancer is less than 15%, necessitating an urgent need to develop novel therapeutic strategies for this disease. Loss of differentiation is associated with worse overall survival in colorectal cancer, suggesting that strategies to re-induce differentiation may provide clinical benefit. Differentiation therapy is effective in the treatment of acute promyelocytic leukemia but whether this approach can be efficacious in treating colorectal cancer is unknown. Inhibitors of the MAPK signaling pathway including the MEK inhibitor Trametinib can induce markers of differentiation in colorectal cancer cells. Trametinib also induces expression of Cdx-2, a known driver of colonic cell differentiation. Similarly, histone deacetylase inhibitors (HDACi) induce markers of differentiation in multiple tumor cell lines, including colon cancer cells. The aim of this study was to assess the potential therapeutic benefit of combining MEK (Trametinib) and HDAC (Panobinostat) inhibitors to further promote differentiation in colorectal cancer cells, and to elucidate the mechanistic basis for this effect. Combination treatment of HT29 and T84 cells with Trametinib and Panobinostat significantly enhanced mRNA and protein expression of the differentiation markers Cadherin 17 (CDH17) and Keratin 20 (KRT20), compared to either agent alone. Trametinib also induced expression of Cdx-2, an effect that was enhanced upon combination treatment with Panobinostat. Notably, Cdx-2 knockdown attenuated CDH17 and KRT20 induction by the combination, establishing a direct role for Cdx-2 in differentiation induction by the Trametinib/Panobinostat combination. Concomitant with inducing differentiation, the drug combination also invoked more apoptosis than either agent alone. To validate these findings in vivo, HT29 cells grown as xenografts were treated with Trametinib and Panobinostat alone and in combination. Mice treated with the combination had significantly smaller tumours than mice treated with vehicle or either agent alone. Consistent with the in vitro findings, immunostaining of the tumour xenografts demonstrated a strong increase in CDH17, KRT20 and Cdx2 expression upon treatment with the drug combination. Collectively, this study highlights a drug combination strategy to re-induce differentiation for the treatment of colorectal cancers. Citation Format: Laura J. Jenkins, Ian Y. Luk, Janson W. Tse, Jennifer Mooi, Amardeep S. Dhillon, John M. Mariadason. Combining MEK and HDAC inhibitors as a therapeutic strategy to promote differentiation of colorectal 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 3089. doi:10.1158/1538-7445.AM2017-3089
Protein and vitamin B6 intake are associated with liver steatosis assessed by transient elastography, especially in obese individuals
Authors: Yvelise Ferro, Ilaria Carè, Elisa Mazza, Francesco Provenzano, Carmela Colica, Carlo Torti, Stefano Romeo, Arturo Pujia, Tiziana Montalcini
Journal: Clinical and Molecular Hepatology (2017)

Background/Aims Although the detrimental effects of several dietary components on the promotion of nonalcoholic fatty liver disease are well known, no studies have assessed the role of dietary vitamin B6. Moreover, studies on the associations between dietary components or body composition indices and liver steatosis assessed by transient elastography are rare. Our aim was to identify the nutritional factors and anthropometric parameters associated with liver steatosis. Methods In this cross-sectional study, we enrolled 168 individuals (35% obese) who underwent a liver steatosis assessment by Controlled Attenuation Parameter measurement and nutritional assessment. Results Tertiles of vitamin B6 intake were positively associated with hepatic steatosis (B=1.89, P=0.026, confidence interval [CI] 0.03-0.80) as well as with triglycerides, glucose, alanine aminotransferase (ALT), and body mass index . In obese individuals, after multivariable analysis, the Controlled Attenuation Parameter score was still associated with triglycerides, ALT, and total protein intake (B=0.56, P=0.01, CI 0.10-1.02). Participants in tertile I (low intake) had a lower Controlled Attenuation Parameter than those in tertile III (P=0.01). Conclusions We found a positive association between hepatic steatosis or Controlled Attenuation Parameter score and vitamin B6/total protein intake, probably related to the high intake of meat. Vitamin B6 might have a pathogenic role related to the increase of hepatic steatosis. Keywords: Obesity; Fatty liver; Elastography; Vitamin B6; Proteins