tbuckley/cabot-search huggingface dataset:
Abstract 4321: TNF receptor 2 is essential for RIP1-dependent cell death in refractory leukemia
Authors: Julia Aguadé-Gorgorio, Scott McComb, Cornelia Eckert, Maria Pamela Dobay, Gunnar Cario, Caterina Mezzatesta, Arend Von Stackelberg, Martin Stanulla, Schrappe Martin, Jean-Pierre Bourquin, Beat C. Bornhauser
Journal: Cancer Research (2017)

Abstract The identification of molecular determinants that regulate sensitivity to specific agents is essential for the development of new therapeutic approaches in cancer. We have earlier shown that a subset of refractory acute lymphoblastic leukaemia (ALL) samples respond to SMAC-mimetic (SM) induced IAP depletion by concurrently inducing RIP1-dependent apoptosis and necroptosis. Comparative gene expression profiling indicated a correlation of sensitivity to SM with the expression of TNF receptor 2 (TNFR2) in primary ALL. Using an independent cohort of primary chemotherapy-resistant ALL samples, we found that presence of high TNFR2 expression identified by qPCR predicted ex vivo-sensitivity to SM. High TNFR2 levels also correlated with higher expression of TNFR1. Deletion of either TNFR1 or TNFR2 using CRISPR/Cas9 in primary ALL conferred resistance to treatment with SM, indicating that TNFR1 and 2 are both functionally required for cell death. Concomitant with an important role for TNFR2 in the response to SM, the overexpression of TNFR2 leads to increased sensitivity to TNF through increased activation of the TNFR1/RIP1 death axis. On the mechanistic level, SM induced recruitment of RIP1 to TNFR1, which was abolished in cells deficient for TNFR2. Taken together, our data reveal a novel function of TNFR2 in cell death signalling, as TNFR2 predicts sensitivity to SMAC mimetics and plays a key role in modulating a switch from RIP1-controlled cell survival to cell death. Citation Format: Julia Aguadé-Gorgorio, Scott McComb, Cornelia Eckert, Maria Pamela Dobay, Gunnar Cario, Caterina Mezzatesta, Arend Von Stackelberg, Martin Stanulla, Schrappe Martin, Jean-Pierre Bourquin, Beat C. Bornhauser. TNF receptor 2 is essential for RIP1-dependent cell death in refractory leukemia [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 4321. doi:10.1158/1538-7445.AM2017-4321
Abstract 844: PPARD downregulation in cancer cells suppresses metastases by inhibiting tumor angiogenesis and EMT
Authors: Xiangsheng Zuo, Weiguo Xu, Min Xu, Rui Tian, Micheline J. Moussalli J. Moussalli, Fei Mao, Mihai Gagea, Daoyan Wei, Anil K. Sood, Imad Shureiqi
Journal: Cancer Research (2017)

Abstract PPARD is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity to metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer. Citation Format: Xiangsheng Zuo, Weiguo Xu, Min Xu, Rui Tian, Micheline J. Moussalli J. Moussalli, Fei Mao, Mihai Gagea, Daoyan Wei, Anil K. Sood, Imad Shureiqi. PPARD downregulation in cancer cells suppresses metastases by inhibiting tumor angiogenesis and EMT [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 844. doi:10.1158/1538-7445.AM2017-844
Multitarget Therapy for Maintenance Treatment of Lupus Nephritis
Authors: Haitao Zhang, Zhengzhao Liu, Minlin Zhou, Zhangsuo Liu, Jianghua Chen, Changying Xing, Hongli Lin, Zhaohui Ni, Ping Fu, Fuyou Liu, Nan Chen, Yongcheng He, Jianshe Liu, Caihong Zeng, Zhihong Liu
Journal: Journal of the American Society of Nephrology (2017)

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2–3 mg/d; mycophenolate mofetil, 0.50–0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; P= 0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; P &lt;0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; P =0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.
Abstract 2413: SIRT1 regulatesMxd1throughout melanoma progression
Authors: Fabiana M. Meliso, Danilo Micali, Camila T. Silva, Thais S. Sabedot, Simon G. Coetzee, Adrian Koch, Fabian B. Fahlbusch, Houtan Noushmehr, Regine Schneider-Stock, Miriam G. Jasiulionis
Journal: Cancer Research (2017)

Abstract In a murine melanoma model of malignant transformation promoted by sustained stress, increased levels of reactive oxygen species were found to result in DNA damage and were related to massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found down-regulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to up-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, the upregulation of which is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression. Citation Format: Fabiana M. Meliso, Danilo Micali, Camila T. Silva, Thais S. Sabedot, Simon G. Coetzee, Adrian Koch, Fabian B. Fahlbusch, Houtan Noushmehr, Regine Schneider-Stock, Miriam G. Jasiulionis. SIRT1 regulates Mxd1 throughout melanoma progression [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 2413. doi:10.1158/1538-7445.AM2017-2413
Abstract 2557: Role of microRNAs in breast cancer
Authors: Hesham Abbas El-Mahdy, Ossama Abdelmotaal Mansour, Mohamed Mohamed Badr, Reham Aly Elshimy
Journal: Cancer Research (2017)

Abstract Background: Breast cancer (BC) is one of the most common cancer in women around the world and the second leading cause of death worldwide. MicroRNAs (miRNAs) expression participates in breast cancer. Objectives: The purpose of this study is to investigate the expression of miR-133a and miR-155 in breast cancer serum and study their correlation with tumor suppressor protein (p53), carcinoembryonic antigen (CEA) and cancer antigen-15.3 (CA-15.3) concentrations in serum of breast cancer patients and also study their correlations with clinicopathological features. Material and methods: In this study the expression of miR-133a and miR-155 in serum were measured using quantitative real-time polymerase chain reaction (qRT-PCR), P53 concentration was measured by enzyme-linked immunosorbent assays (ELISA), CEA and CA-15.3 concentration were measured using ARCHITECT immunoassay in women with breast cancer (n=60) and controls (n = 80). Results: In this study miRNA-155 was significantly overexpressed (P&amp;lt;0.001) while miR-133a had significant down expression (P&amp;lt;0.001) in the serum of breast cancer patients compared to control serum. P53 had no significant correlations with any of the studied miRNAs. Carcinoembryonic antigen and CA-15.3 have significant higher concentration in the serum of breast cancer patients compared to control serum. A significant association was observed between miR-133a with tumor grade (P&amp;lt;0.05) and miR-155 with lymph node involvement (P&amp;lt;0.05). A significant correlation between miR-155 and CEA (P&amp;lt;0.05). No correlations between miR-133a and P53, CEA, CA-15.3. By using receiver operating characteristic (ROC) curve, the two miRNAs showed higher sensitivity, specificity, positive predictive value and negative predictive value than routine markers. Our Conclusion: These miRNAs have a significant signature in the pathogenesis of breast cancer and can be used as non-invasive potential biomarkers for breast cancer detection. Note: This abstract was not presented at the meeting. Citation Format: Hesham Abbas El-Mahdy, Ossama Abdelmotaal Mansour, Mohamed Mohamed Badr, Reham Aly Elshimy. Role of microRNAs in 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 2557. doi:10.1158/1538-7445.AM2017-2557
A biallelic mutation in <i>IL6ST</i> encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis
Authors: Tobias Schwerd, Stephen R.F. Twigg, Dominik Aschenbrenner, Santiago Manrique, Kerry A. Miller, Indira B. Taylor, Melania Capitani, Simon J. McGowan, Elizabeth Sweeney, Astrid Weber, Liye Chen, Paul Bowness, Andrew Riordan, Andrew Cant, Alexandra F. Freeman, Joshua D. Milner, Steven M. Holland, Natalie Frede, Miryam Müller, Dirk Schmidt-Arras, Bodo Grimbacher, Steven A. Wall, E. Yvonne Jones, Andrew O.M. Wilkie, Holm H. Uhlig
Journal: The Journal of Experimental Medicine (2017)

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.
Abstract 5922: Cellular interaction between pancreatic cancer cells and MSC as tumor microenvironment
Authors: Eisaku Kondo, Ken Saito
Journal: Cancer Research (2017)

Abstract Tumor microenvironment such as neoangiogenesis, stroma and tumor immunity has recently gained much attention because it is significantly involved in tumor progression. Pancreatic adenocarcinoma (PAC; pancreatic invasive ductal carcinoma) is recognized as one of the most intractable malignancies and required to disclose a key biological characteristics to provide a clue for its diagnosis and therapeutics. Here we focus on the biological role of bone marrow-derived human mesenchymal stem cells (MSCs) in PAC, which were reported to be accumulated in various cancer tissues such as colon, breast cancers. We detected small numbers of MSCs in the stroma of PAC in human pathological tissues using double immunofluorescence in combination with several MSC markers including CD73, 105, 34, 45, SMA and so on. Then, in in vitro coculture system, we found that MSCs significantly facilitated invasion of BxPC3 cells, a human PAC cell line, in comparison with the culture of BxPC3 cell alone by transwell chamber assay. Proteome profiling of the cocultured supernatant revealed augmented production of soluble molecules including CXCL7, CCL7 as a cytokine, integrin beta1, transferrin R, ALCAM, and Amphiregulin (AREG) as a soluble receptor and ligand, metalloprotease (MMP), ADAMTS-1 as a soluble protease-related molecule, all which were significantly increased comparing to the culture sup. of BxPC3 alone or MSC alone. Based on the result of proteome profiling, we further examined mRNA upreguttion on the cells of each culture by real-time PCR (qPCR) to identify which molecule would be more specifically upregulated by the coculture sample of PAC cells and MSCs. Consequently, upregutaion of AREG and MMP-3, in addition to downregulation of MMP-9 was observed by qPCR, and knockdown of AREG using the specific siRNA on the cocultured cells corroborated marked decrease of PAC invasion in transwell chamber assay. Interestingly, AREG expression on the tumor cells of tissue specimens of the patient with PAC was observed especially on the cells at invasive front, which suggests stromal MSCs may interact with PAC cells and facilitate invasion of cancer cells by regulating expression of the specific genes such as AREG and MMPs. Note: This abstract was not presented at the meeting. Citation Format: Eisaku Kondo, Ken Saito. Cellular interaction between pancreatic cancer cells and MSC as tumor microenvironment [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 5922. doi:10.1158/1538-7445.AM2017-5922
Abstract 2913: Emergence of <i>RAS</i> or <i>EGFR</i> mutant clones affects duration of response to EGFR blockade in colorectal cancers
Authors: Sabrina Arena, Beth Van Emburgh, Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Giorgio Corti, Benedetta Mussolin, Federica Baldi, Michela Buscarino, Alice Bartolini, Emanuele Valtorta, Joana Vidal, Beatriz Bellosillo, Giovanni Germano, Filippo Pietrantonio, Agostino Ponzetti, Joan Albanell, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Clara Montagut, Alberto Bardelli
Journal: Cancer Research (2017)

Abstract Cetuximab and panitumumab are monoclonal anti-EGFR antibodies (moAbs) currently used for the treatment of advanced RAS wild type colorectal cancers (CRC). Emergence of acquired resistance invariably limits the efficacy of these agents, and the dynamics of clonal evolution during anti-EGFR blockade are poorly understood. At progression, RAS mutations represent the most common genetic alterations, while EGFR extracellular domain (ECD) mutations are acquired by a smaller cohort of patients. We found that the mutation profile correlates with the clinical outcome of patients; in particular those who develop RAS mutations upon EGFR blockade achieve reduced tumor shrinkage and shorter duration of response respect to patients in which EGFR ECD mutations emerge during therapy. We investigated in preclinical models the potential role of RAS and EGFR ECD mutations during the emergence of acquired resistance, by tracking the evolution of clones in a genetically barcoded population of CRC cells chronically treated with cetuximab. We observed that therapeutic (target therapy, chemotherapy) and environmental (reduced nutrient condition) pressures differentially shape the clonal composition of CRC cell populations, leading to the emergence of clones with the highest fitness in presence of the external pressure. In conclusion, a multistep clonal evolution process characterizes the development of drug resistance and is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies. Citation Format: Sabrina Arena, Beth Van Emburgh, Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Giorgio Corti, Benedetta Mussolin, Federica Baldi, Michela Buscarino, Alice Bartolini, Emanuele Valtorta, Joana Vidal, Beatriz Bellosillo, Giovanni Germano, Filippo Pietrantonio, Agostino Ponzetti, Joan Albanell, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Clara Montagut, Alberto Bardelli. Emergence of RAS or EGFR mutant clones affects duration of response to EGFR blockade in colorectal cancers [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 2913. doi:10.1158/1538-7445.AM2017-2913
Abstract 5556: Widespread protein interactome network rewiring in human cancer
Authors: Song Yi, Nidhi Sahni
Journal: Cancer Research (2017)

Abstract In the past decade, genome and exome sequencing projects have identified thousands of genetic variants in patients across a large number of cancer types. However, the explosion of genomic information has left many fundamental questions regarding genotype-phenotype relationships unresolved. One critical challenge is to distinguish causal disease mutations from non-pathogenic polymorphisms. Even when causal mutations are identified, the functional consequence of such mutations is often elusive. Classical “one gene, one function, one disease” models can not reconcile with the complexity that different mutations of the same gene often lead to different phenotypes. The extent to which network perturbations are involved in disease malfunction and how distinct interaction perturbation patterns can distinguish cancer mutations are largely unknown. Here we report a systematic approach to investigate genetic variant-specific effects on molecular interactions at large scale across diverse human cancers. Remarkably, in comparison to non-disease polymorphisms, disease mutations are more likely to associate with interaction perturbations. A large fraction of missense disease mutations are found to cause protein interaction alterations. While some result in loss of all their interactions, many exhibit selective elimination of specific interactions (“edgetic”). Different mutations of the same gene give rise to different interaction profiles, accounting for distinct disease outcomes. Edgetic mutations perturb interactions through disrupting specific interaction interfaces, and the perturbed partners are more likely expressed in relevant disease tissue. Together, our approach is insightful in prioritizing disease-causing variants, and uncovering patient mutation-specific disease mechanisms at a base-pair resolution, a critical step towards personalized precision medicine. Furthermore, our results suggest distinct interaction perturbations as a widespread mechanism underlying genetic heterogeneity, providing a fundamental link between genotype and phenotype in cancer. Citation Format: Song Yi, Nidhi Sahni. Widespread protein interactome network rewiring in human 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 5556. doi:10.1158/1538-7445.AM2017-5556
Abstract 5029: Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial
Authors: David Jamieson, Beatrice Seddon, Katja Kuever, Hakim-Moulay Dehbi, Sandra Strauss, Sandy Beare, Gareth Veal
Journal: Cancer Research (2017)

Abstract Introduction The treatment of locally advanced or metastatic soft tissue sarcoma remains a significant clinical challenge, with overall survival rates of approximately 12 months observed with current first line palliative chemotherapy. A recently completed randomised phase III clinical trial entitled GeDDiS (ISRCTN07742377), was designed to compare first line treatment with gemcitabine in combination with docetaxel (GemDoc) versus current standard treatment with doxorubicin. A pharmacogenetic sub-study was incorporated into the trial to assess potential impact of single nucleotide polymorphisms (SNPs) in genes associated with the pharmacology of the three drugs. Methods A total of 240 patients were recruited to the sub-study with 119 on the doxorubicin arm and 121 on the GemDoc arm. A 4 ml blood sample was taken from each participant and genomic DNA extracted. Individual candidate SNPs were assessed by Taqman PCR in 7 genes associated with doxorubicin pharmacology, 7 genes associated with gemcitabine and 5 genes associated with the pharmacology of docetaxel. Association between the SNPs and efficacy and toxicity was assessed. Results SNPs within the solute transporter SLC22A16, associated with the intracellular influx of doxorubicin, were associated with worse PFS (HR = 1.72, p=0.04) and decreased frequency of grade 3/4 adverse events (71% vs 48%, p=0.04) in the doxorubicin arm of the study but not in the GemDoc arm. Conclusions The association of genetic variants of SLC22A16 with decreased efficacy and decreased incidence of toxicity is consistent with a loss of function in the transporter and previous observation of increased AUC in pharmacokinetic studies assuming that distribution of the drug into target and collateral tissues is restricted. Citation Format: David Jamieson, Beatrice Seddon, Katja Kuever, Hakim-Moulay Dehbi, Sandra Strauss, Sandy Beare, Gareth Veal. Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial [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 5029. doi:10.1158/1538-7445.AM2017-5029