tbuckley/cabot-search huggingface dataset:
Association Between Genomic Metrics and Immune Infiltration in Triple-Negative Breast Cancer
Authors: Thomas Karn, Tingting Jiang, Christos Hatzis, Nicole Sänger, Ahmed El-Balat, Achim Rody, Uwe Holtrich, Sven Becker, Giampaolo Bianchini, Lajos Pusztai
Journal: JAMA Oncology (2017)

<h3>Importance</h3> Why some triple-negative breast cancers (TNBCs) have high and others have low immune cell infiltration is unknown. Understanding how immune surveillance shapes the cancer genome could help in the selection of patients and the development of more effective immunotherapy strategies. <h3>Objective</h3> To examine the association between genomic metrics and the extent of immune infiltration in TNBCs. <h3>Design, Setting, and Participants</h3> This study, performed from June 1, 2015, through January 31, 2017, used DNA and RNA sequencing data and messenger RNA expression results from The Cancer Genome Atlas (TCGA) breast cancer data set (n = 1215) to calculate previously described immune metagene expression values and histologic lymphocyte counts to quantify immune infiltration and assign prognostic categories to TNBCs. It used the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set as an independent validation cohort. The study compared clonal heterogeneity, somatic total mutational load, neoantigen load, and somatic copy number alteration levels between immune-rich TNBC cohorts with good prognosis and immune-poor TNBC cohorts with poor prognosis. The study also compared the distribution of mutations in 119 canonical cancer genes. <h3>Main Outcomes and Measures</h3> Correlation between immune prognostic category and genomic metrics of the cancer. <h3>Results</h3> This study of 193 TNBC samples with patient survival information found an inverse association between clonal heterogeneity and immune metagene expression (ρ = −0.395,<i>P</i>= 2 × 10<sup>−8</sup>). The study also found an inverse association between immune metagene expression and somatic copy number alteration levels (ρ = −0.484,<i>P</i>= 2 × 10<sup>−10</sup>). Lymphocyte-rich TNBCs with good prognosis had significantly lower mutation and neoantigen counts than did lymphocyte-poor TNBCs with poor prognosis. The robustness of the study results was confirmed by using various immune metagenes in the same TCGA data set and in the independent METABRIC data set. <h3>Conclusions and Relevance</h3> This study suggests that immune-rich TNBCs may be under an immune surveillance that continuously eliminates many immunogenic clones, resulting in lower clonal heterogeneity. These cancers may also represent the subset of TNBCs that could derive benefit from immune checkpoint inhibitor therapy to tilt the balance in favor of the immune system.
Abstract 4028: Analysis and recovery of functionally defined single immune cell clones through opto-electro-positioning technology
Authors: Xiaohua Wang, Yelena Bronevetsky, Kristin Beaumont, Guido Stadler, Xiaoyan R. Bao, Duane Smith, Peter Beemiller, Kevin Chapman
Journal: Cancer Research (2017)

Abstract Cancer patients mount protective innate and adaptive immune responses against tumor cells. Such responses are able to control or even eliminate tumor burden if harnessed properly. Identifying clonal adaptive immune cells targeting tumor cells with designated function is extremely valuable as these cells are able to either fight the tumor directly or provide tumor targeting immune receptors to engineer other effector cells like autologous CD8 T cells or NK cells. The process of isolating cancer specific immune cells and their receptors, however, remains technically challenging and labor intensive. Opto-Electro-Positioning (OEP) technology employs a light actuated dielectrophoretic force to maneuver live cells in their culture environment. We have combined OEP with a nanofluidic cell culture system to produce an integrated microfluidic platform that enables multi-dimensional investigation of lymphocyte specificity and function. The system is able to 1) deterministically capture designated lymphocytes, 2) actively maintain and observe colony growth, and 3) conduct cytokine release assays, all in a single enclosed microfluidic chip. The new platform is suitable for high throughput screening to identify and harvest antigen specific and/or functionally defined T cells. We have successfully applied it to isolate primary human T cells targeting either EBV/Tetanus toxin antigens or tumor associated antigens such as MART-1 through tetramer staining or a proliferation assay. The system is also exceptionally efficient for investigating immune cells from clinical specimens typically of low cellularity. From tumor biopsies, we are able to capture tumor infiltrating T cells, stimulate proliferation, investigate their TNF-α secretion on chip, and obtain full transcriptomic analysis after export. Overall, our data suggest the OEP nano-fluidic environment provides a powerful high throughput screening tool to identify rare lymphocytes against tumor associate antigens or neo-antigens and to investigate precious clinical samples for biomarker discovery. Citation Format: Xiaohua Wang, Yelena Bronevetsky, Kristin Beaumont, Guido Stadler, Xiaoyan R. Bao, Duane Smith, Peter Beemiller, Kevin Chapman. Analysis and recovery of functionally defined single immune cell clones through opto-electro-positioning technology [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 4028. doi:10.1158/1538-7445.AM2017-4028
Abstract 1933: Discovery of first-in-class small molecule CD99 inhibitors for targeted therapy of Ewing sarcoma
Authors: Haydar Celik, Marika Sciandra, Bess Flashner, Elif Gelmez, Neslihan Kayraklıoğlu, David V. Allegakoen, Jeff R. Petro, Erin J. Conn, Sarah Hour, Jenny Han, Lalehan Oktay, Purushottam B. Tiwari, Mutlu Hayran, Maria Cristina Manara, Jeffrey A. Toretsky, Katia Scotlandi, Aykut Uren
Journal: Cancer Research (2017)

Abstract Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy that affects predominantly children and adolescents with a high propensity to metastasize and poor prognosis. CD99 is a transmembrane cell surface protein that is highly expressed on ES cells, and routinely used as a marker for histological diagnosis of ES. We screened small molecule libraries for their binding to recombinant CD99 protein and subsequent selective inhibition of ES cell growth. We identified two structurally similar FDA-approved nucleoside analogues, clofarabine and cladribine that selectively inhibited the growth of ES cells in a panel of 14 ES vs. 28 non-ES cell lines. A significant negative correlation was found in human cell lines between CD99 expression and IC50 values for clofarabine and cladribine. Both drugs inhibited CD99 dimerization and its interaction with downstream signaling components cyclophilin A and PKA-RIIα as well as led to reduced ROCK2 protein expression and migration in ES cells. A membrane-impermeable analog of clofarabine showed similar cytotoxicity in ES cells, suggesting that it can function through inhibiting CD99 alone without any effect on DNA metabolism. Clofarabine and cladribine led to a significant increase in hypodiploid DNA content of ES cells, which was diminished by suppression of CD99 expression. Both drugs drastically inhibited anchorage-independent growth of ES cells, but clofarabine was more effective in inhibiting ES xenografts. Finally, the screening of a set of chemotherapy drugs revealed a synergy for the combination of anti-CD99 drugs and dasatinib in ES cells, which may translate into increased survival and reduced toxicity. Overall, our findings suggest that clofarabine is a good candidate for early phase clinical trials in children with ES. Citation Format: Haydar Celik, Marika Sciandra, Bess Flashner, Elif Gelmez, Neslihan Kayraklıoğlu, David V. Allegakoen, Jeff R. Petro, Erin J. Conn, Sarah Hour, Jenny Han, Lalehan Oktay, Purushottam B. Tiwari, Mutlu Hayran, Maria Cristina Manara, Jeffrey A. Toretsky, Katia Scotlandi, Aykut Uren. Discovery of first-in-class small molecule CD99 inhibitors for targeted therapy of Ewing sarcoma [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 1933. doi:10.1158/1538-7445.AM2017-1933
Abstract LB-126: PPARgamma agonists sensitize PTEN-deficient lung cancer cells resistant to EGFR tyrosine kinase inhibitors
Authors: Kenneth KW To, Wing Sum Tong, William KK Wu, Herbert HF Loong
Journal: Cancer Research (2017)

Abstract We aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of lung cancer. EGFR TKIs are approved for treating advanced lung cancer that harbors the sensitizing EGFR mutations. However, resistance to EGFR TKIs is almost inevitable for all patients due to multifactorial mechanisms. The PI3K/Akt/mTOR pathway is a major signaling pathway regulated by EGFR to drive cancer survival. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates PTEN to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to intrinsic resistance to EGFR TKIs. Therefore, PPARγ agonists are hypothesized to overcome EGFR TKI resistance. Using well defined human non-small cell lung cancer (NSCLC) cell model with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARγ agonists was demonstrated. PPARγ agonists were found to upregulate PTEN, subsequently inhibit the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI). Specific PPARγ inhibitor (GW9662) and genetic silencing of PPARγ were shown to prevent this potentiation of anticancer activity by PPARγ agonists, thus confirming the crucial role played by PPARγ activation. Interestingly, the tested PPARγ agonists were also found to induce autophagy, as evidenced by the increased expression of an autophagy marker LC3-II and the autophagic degradation of p62/SQSTM1. PPARγ agonists-induced autophagic cell death was believed to contribute to the circumvention of resistance in PTEN-deficient cells because the genetic silencing of ATG5 (an autophagy mediator) was found to eliminate the drug potentiation effect by the PPARγ agonists. Our findings thus provide the basis for the rational and personalized use of PPARγ agonists in combination with EGFR TKIs in lung cancer patients with specific resistance mechanism. Citation Format: Kenneth KW To, Wing Sum Tong, William KK Wu, Herbert HF Loong. PPARgamma agonists sensitize PTEN-deficient lung cancer cells resistant to EGFR tyrosine kinase 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 LB-126. doi:10.1158/1538-7445.AM2017-LB-126
Improved sarcoma management in a national network of reference centers: Analysis of the NetSarc network on 13,454 patients treated between 2010 and 2014.
Authors: Jean-Yves Blay, Axel Le Cesne, Nicolas Penel, Emmanuelle Bompas, Florence Duffaud, Christine Chevreau, Maria Rios, Pierre Kerbrat, Didier Cupissol, Philippe Anract, Jean-Emmanuel Kurtz, Celeste Lebbe, Nicolas Isambert, Francois Bertucci, Antoine Thyss, Sophie Piperno-Neumann, Pascale Dubray-Longeras, Francoise Ducimetiere, Jean-Michel Coindre, Antoine Italiano
Journal: Journal of Clinical Oncology (2016)

11013 Background: Since 2009 a network of 26 reference multidisciplinary centers aiming to improve the quality of care for sarcoma patients (pts) in France was granted by the French National Cancer Institute. We report here on the results of this network on patient management after 5 years. Methods: Data of the NetSarc network database include pts characteristics, previous treatment and diagnosis procedures, medical decision, survival and progression. From Jan 2010 to Dec 2014, 13454 newly diagnosed pts were included, soft tissue and visceral representing 10427 (77%) and 3027 (23%) respectively. These represent an estimated 78% of sarcoma case in France in 5 years. Individual Netsarc enters managed a median of 325 (range 39-1529) pts in 5 years. Results: 6955 women (52%) and 6499 men (48%), with a median age of 60y (range 0-101) were included. Soft tissue and visceral represented 10427 (77%) and 3027 (23%) pts respectively. LMS (12%), GIST (8.2%), DDLPS (7.3%) and UPS (11%) were the most frequent histotypes. 12% pts had metastases at diagnosis. Between 2010 and 2015, the proportion of pts reviewed in Netsarc reference centers prior to surgery increased from 41% to 48%. A higher number of pts managed in Netsarc centers had proper imaging of the primary tumor prior to surgery (86% vs 59%, p<0.0001), and had biopsy prior the first resection (80% vs 36%, p<0.0001). 10265 (76%) pts had a surgery, 4304 (42%) within the Netsarc network and 4639 (45%) outside the network, and unknown in 1322 (13%) pts). Patients whose primary surgery was performed in Netsarc centers had R0, R1, R2, and R (unknown or non evaluable) surgery in 49%, 27%, 7%, 16% vs 24%, 31%, 21%, 23% in centers outside Netsarc (p<0.000001). 865 (19%) pts had secondary resection after primary surgery in non NetSarc centers vs 252 (6%) in NetSARC centers (p<0.0001). Progression free survival (PFS) was better in patients managed in Netsarc reference centers (p=0.0008). Conclusions: Sarcoma pts managed in reference centers have a significantly higher rate of management according to CPGs, R0 surgery, less reoperations, and better PFS. The number of patients managed prior to surgery in reference centers increases slightly overtime.
Abstract 5739: Nicotine promotes stemness-related properties and cell migration/metastasis through IGF-1R regulation in triple negative breast cancer
Authors: Yung-Che Kuo, Jan-Show Chu, Kha-Liang Lee, Victor James Drew, Wei-Zhan Zhuang, Chi-Long Chen, Yuan-Soon Ho, Yen-Hua Huang
Journal: Cancer Research (2017)

Abstract Purpose: To determine the role of insulin-like growth factor (IGF)-I receptor (IGF-IR) in alpha 9 nicotinic acetylcholine receptor (α9-nAChR)-induced stemness-related properties and to assess the therapeutic potential for preventing early tumor relapse and metastasis of TNBCs. Experimental Design: Expression levels of stemness-related genes, α9-nAChR and IGF-IR in tissues (n = 67) were analyzed by real-time Q-PCR and the correlation of different gene levels were calculated by the Pearson correlation analysis. The effects of either α9-nAChR activation or IGF-1R transactivation on stemness expression in TNBC were examined using ALDEFLUOR assay with flow cytometry, RNA interference, wound closure/migration/invasion assay, and animal models. The α9-nAChR, OCT4 and IGF-1R protein, p-IGF-1R in tissues were detected by immunohistochemical staining. Results: A high positive correlation between the gene expression levels of OCT4/NANOG/CD24/CD44 and α9-nAChR/IGF-IR in human breast cancer tissues was observed. Nicotine induced α9-nAChR activation trans-activates an IGF-IR expression and a phosphorylation of STAT3, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of either α9-nAChR or IGF-IR activation by RNA interference significantly suppressed the nicotine-induced stemness-related properties and cell metastasis both in vitro and in vivo. Conclusions: IGF-1R signal regulates the nicotine/α9-nAChR-induced stemness properties and cell metastasis therefore convene poor prognosis in TNBCs. Citation Format: Yung-Che Kuo, Jan-Show Chu, Kha-Liang Lee, Victor James Drew, Wei-Zhan Zhuang, Chi-Long Chen, Yuan-Soon Ho, Yen-Hua Huang. Nicotine promotes stemness-related properties and cell migration/metastasis through IGF-1R regulation 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 5739. doi:10.1158/1538-7445.AM2017-5739
Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomised, outcome assessor-blinded EAT-ICU trial
Authors: Matilde Jo Allingstrup, Jens Kondrup, Jørgen Wiis, Casper Claudius, Ulf Gøttrup Pedersen, Rikke Hein-Rasmussen, Mads Rye Bjerregaard, Morten Steensen, Tom Hartvig Jensen, Theis Lange, Martin Bruun Madsen, Morten Hylander Møller, Anders Perner
Journal: Intensive Care Medicine (2017)
Abstract 1964: Identification of a novel molecule target for the detection, prediction, and treatment of peritoneal metastasis of gastric cancer
Authors: Mitsuro Kanda, Haruyoshi Tanaka, Dai Shimizu, Daisuke Kobayashi, Chie Tanaka, Hideki Takami, Masamichi Hayashi, Naoki Iwata, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Cancer Research (2017)

Abstract Background: Advanced gastric cancer (GC) frequently recurs because of undetected micrometastases even when disease is localized and patients undergo curative resection. Moreover, peritoneal metastasis is fatal. We aimed to develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of GC to improve management. Methods: We conducted a metastatic pathway-specific transcriptome analysis to identify candidate biomarkers comprising 340 patients allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value. The mRNA and protein levels in primary GC tissues were compared with patients’ clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. Results: Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. SYT8 levels were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. High SYT8 levels were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between high and low SYT8 levels was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. Conclusions: SYT8 expression represents a promising diagnostic and predictive biomarker for peritoneal metastasis of GC. Citation Format: Mitsuro Kanda, Haruyoshi Tanaka, Dai Shimizu, Daisuke Kobayashi, Chie Tanaka, Hideki Takami, Masamichi Hayashi, Naoki Iwata, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera. Identification of a novel molecule target for the detection, prediction, and treatment of peritoneal metastasis of gastric 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 1964. doi:10.1158/1538-7445.AM2017-1964
Abstract 5143: Fusogenic targeted liposomes: novel nanotherapy for specific treatment of prostate cancer
Authors: Jihane Mriouah, Rae Lynn Nesbitt, Susan Richter, Melinda Wuest, Desmond Pink, Deborah Sosnowski, Roy Duncan, Frank Wuest, Andries Zijlstra, John Lewis
Journal: Cancer Research (2017)

Abstract Metastatic or castrate-resistant prostate cancer is the second-leading cause of cancer mortality in males. In the past 3 years, chemotherapies have extended survival, but efficacy is limited by dose-limiting toxicities due to suboptimal biodistribution. Here, we have addressed the lack of specificity and accumulation in Castrate Resistant Prostate Cancer (CRPC) by developing a unique nano-carrier for drug delivery: molecular targeted fusogenic liposomes. Previously, we have developed a platform whereby lipid nanoparticles are formulated with fusion associated small transmembrane (FAST) protein p14. The p14 protein catalyzes mixing of the nanoparticle lipids with target plasma membrane to deliver the cargo directly into the cytoplasm. In this study, we have engineered the p14 protein to incorporate the prostate cancer targeting ligand bombesin, which binds specifically to the Gastrin-releasing Peptide (GRPR) that is overexpressed in prostate cancer. We hypothesized that this novel targeted fusogenic liposome formulation would significantly improve the biodistribution and efficacy of chemotherapy. A clinical liposomal doxorubicin formulation (DOXIL) was modified to incorporate targeted fusogenic p14 protein, and the efficacy and biodistribution of these new formulations was evaluated using in vitro and in vivo models of CRPC. In PC3 cells, compared to conventional liposomes, intracellular levels of doxorubicin are increased by 15 and 25 times when p14 or p14-bombesin liposomes are used. Additionally, the IC50 is reduced from 85mM to 2mM. In mice bearing PC3 tumors treated with targeted fusogenic liposomal doxorubicin, we observed improved tumor growth inhibition by 57% (vs control) and 1.5 fold increased accumulation in tumors within 24h after administration. These proof of concept experiments indicate that molecular targeted fusogenic nanomedicines can improve both the intracellular delivery and tumor accumulation of chemotherapy, improving outcomes in this preclinical model. This highlights the potential for improved outcomes in patients with CRPC through the enhancement of approved drugs. Note: This abstract was not presented at the meeting. Citation Format: Jihane Mriouah, Rae Lynn Nesbitt, Susan Richter, Melinda Wuest, Desmond Pink, Deborah Sosnowski, Roy Duncan, Frank Wuest, Andries Zijlstra, John Lewis. Fusogenic targeted liposomes: novel nanotherapy for specific treatment of prostate 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 5143. doi:10.1158/1538-7445.AM2017-5143