tbuckley/cabot-search huggingface dataset:
Abstract 4693: Mechanism-based combination strategies for BET inhibitors in NUT midline carcinoma
Authors: Anastasia Wyce, Peter Soden, Daniel J. Felitsky, Jeanne J. Matteo, Susan Korenchuk, Gary Thripp, Kathryn Keenan, Charles F. McHugh, Rab Prinjha, Christopher Carpenter, Nicholas Smithers, Olena Barbash
Journal: Cancer Research (2016)

Abstract NUT midline carcinoma (NMC) is a highly aggressive squamous cell cancer that responds poorly to standard chemotherapuetic approaches. NMC is characterized by translocations involving the NUT (nuclear protein in testes) protein, which in a majority of cases is fused to the BET (bromodomain and extra-terminal) protein family members BRD3 or BRD4. BET proteins (BRD2, BRD3, BRD4, BRDT) are epigenetic readers that modulate expression of genes involved in cell growth and oncogenesis. Selective small molecule inhibitors of BET proteins, such as the GSK I-BETs (I-BET762, I-BET151), abrogate binding of BET proteins to acetylated chromatin and inhibit the expression of BET target genes. Here we describe the activity in I-BET762 and other BET inhibitors in pre-clinical models of NMC. Consistent with previous reports, we observe profound growth inhibition and cytotoxicity in NMC cell lines in vitro, as well as significant tumor growth inhibition or tumor regression in cell line xenografts of NMC. I-BET762 treatment in NMC cell lines results in transcriptional changes affecting MYC and other pathways critical for cancer cell growth. We explore the contribution of these changes to the anti-proliferative effects observed in NMC models, and identify rational combinations to improve upon the efficacy of I-BET762 as a monotherapy. Taken together, our data highlight novel mechanisms through which BET inhibitors impact NMC cell growth and survival, and suggest potential treatment strategies to improve response in this highly aggressive disease. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed by the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Citation Format: Anastasia Wyce, Peter Soden, Daniel J. Felitsky, Jeanne J. Matteo, Susan Korenchuk, Gary Thripp, Kathryn Keenan, Charles F. McHugh, Rab Prinjha, Christopher Carpenter, Nicholas Smithers, Olena Barbash. Mechanism-based combination strategies for BET inhibitors in NUT midline carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4693.
Association Between Rosacea and Parkinson Disease
Authors: Alice He, Ronald J. Sweren, Shawn G. Kwatra
Journal: JAMA Neurology (2016)

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Abstract 2968: A novel bispecific CD3/CDH19 antibody construct (CDH19 BiTE) directs potent killing of melanoma cellsin vitroandin vivoand is enhanced by blockade of PD-L1
Authors: Gordon E. Moody, Jodi Moriguchi, Shyun Li, Fei Lee, Brendon Frank, Amy Gilbert, Ryan Case, Khue Dang, Beth Hinkle, Suzanne Coberly, James Rottman, Kim Merriam, Julie Bailis, Pedro J. Beltran
Journal: Cancer Research (2016)

Abstract CDH19 is an unconventional type 2 cadherin widely expressed in malignant melanoma with limited expression in normal tissues. RNAseq and immunohistochemical analysis of CDH19 in human samples confirmed its over-expression in &amp;gt;60% of melanoma, whereas normal expression primarily occurred in tissues derived from the neural crest such as nerve fibers and autonomic ganglia. CD3 based bi-specific T-cell engagers (BiTEs) were used to determine if redirected lysis of T-cells against CDH19 would drive anti-tumor efficacy. In vitro, the CDH19 BiTEs were high affinity binders to both human and cyno CDH19, and were able to induce specific T-cell activation and cytotoxicity against a panel of melanoma cell lines. In addition, soluble CDH19 levels were detected in human serum and the effects of BiTE cytotoxicity toward melanoma cells in the presence of soluble CDH19 was investigated. In vivo studies were conducted to confirm the specificity and activity of CDH19 BiTEs in xenograft models of melanoma. The CDH19 BiTE AMG-CDH19X was able to cause tumor growth inhibition in models expressing as few as 250 receptors per cell, and inhibition of tumor growth was enhanced by the addition of a blocking antibody against PD-L1. Immunohistochemical analysis of post-treatment xenograft samples suggested that anti-PD-L1 the persistence of tumor reactive T cells, and provided rationale for combining a BiTE against CDH19 with a PD-1 or PD-L1 blocking antibody in melanoma. In summary, targeting CDH19 presents a promising novel opportunity for BiTEs in the treatment of melanoma, both alone and in combination with current standard of care. Citation Format: Gordon E. Moody, Jodi Moriguchi, Shyun Li, Fei Lee, Brendon Frank, Amy Gilbert, Ryan Case, Khue Dang, Beth Hinkle, Suzanne Coberly, James Rottman, Kim Merriam, Julie Bailis, Pedro J. Beltran. A novel bispecific CD3/CDH19 antibody construct (CDH19 BiTE) directs potent killing of melanoma cells in vitro and in vivo and is enhanced by blockade of PD-L1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2968.
Abstract LB-165: Multiple mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma
Authors: John T. Powers, Kaloyan Tsanov, Frederik Roels, Catherine Spina, Richard Ebright, Marc Seligson, Yvanka de Soysa, Patrick Cahan, Daniel Pearson, Jessica Theißen, Ho-Chou Tu, Grace LaPier, Jihan Osborne, Samantha Ross, James Collins, Frank Berthold, George Daley
Journal: Cancer Research (2016)

Abstract The let-7 microRNA family are known tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma, a neural crest derived tumor, is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has recently been implicated as a critical regulator of MYCN, but through CRISPR-mediated gene disruption we show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN-amplified neuroblastoma cell lines despite robust de-repression of let-7, prompting us to explore additional mechanisms for let-7 disruption. Consequently, we have found a novel non-coding role for amplified MYCN mRNA as a potent let-7 sponge that through exceptionally high expression defines a sub-class of self-sponging amplified-competing-endogenous-RNA (aceRNA) and reconciling the dispensability of LIN28B in neuroblastoma cell lines. Furthermore, by analyzing a large cohort of tumor samples from patients, we observe frequent genomic loss of let-7 that inversely associates with MYCN-amplification, providing a functional explanation for the known MYCN-amplification-independent pattern of chromosome 3p and 11q loss, which harbor let-7g and let-7a2, respectively. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN-amplified tumors marks decreased survival, further underscoring its importance. The inverse selective relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis. Citation Format: John T. Powers, Kaloyan Tsanov, Frederik Roels, Catherine Spina, Richard Ebright, Marc Seligson, Yvanka de Soysa, Patrick Cahan, Daniel Pearson, Jessica Theißen, Ho-Chou Tu, Grace LaPier, Jihan Osborne, Samantha Ross, James Collins, Frank Berthold, George Daley. Multiple mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-165.
A phase II, randomized trial of standard of care with or without midostaurin to prevent relapse following allogeneic stem cell transplantation in patients with FLT3-ITD mutated acute myeloid leukemia.
Authors: Richard T. Maziarz, Bart L Scott, Sanjay Ram Mohan, Abhinav Deol, Mrinal M. Patnaik, Kelly Haines, Brian Elliott, Carole S. Paley, Hugo Francisco Fernandez
Journal: Journal of Clinical Oncology (2015)

TPS7094 Background: Midostaurin, an orally administered multitarget kinase inhibitor, potently inhibits the FLT3 and c-Kit tyrosine kinases. Prior phase 1/2 and 1b clinical trials of the drug have demonstrated tolerable safety profiles and clinical activity in pts with AML (Fischer, J Clin Oncol, 2010; Stone, Leukemia, 2012), and it is currently in development in advanced mastocytosis (phase 2; Gotlib, ASH 2014) and AML (phase 3; Stone, ASCO 2011). In the phase 3 randomized trial in pts with newly diagnosed, FLT3-mutated AML aged < 60 years, midostaurin 50 mg BID or placebo was administered sequentially with standard induction and consolidation therapy, followed by 1 year of maintenance. Results are pending from this primary therapy trial (RATIFY; NCT00651261). Overall, pts with FLT3-ITD–mutated AML have a poor prognosis and are generally considered for curative alloHSCT in first clinical remission (CR1). However, an EBMT retrospective analysis of outcomes for pts who underwent alloHSCT in CR1 demonstrated a high rate of early relapse, with very poor long-term survival (Brunet, J Clin Oncol, 2012). There is interest in the use of post-transplant adjuvant maintenance therapy with hypomethylating agents or TKIs in pts with high-risk AML to potentially increase long-term relapse-free and overall survival (OS). Methods: This randomized, open-label phase 2 study is investigating the efficacy and safety of midostaurin 50 mg BID in pts with FLT3-ITD–mutated AML who underwent alloHSCT in CR1 to determine whether the addition of study drug will reduce relapse at 18 mo post-HSCT. Secondary endpoints are disease-free survival, nonrelapse mortality, OS, safety, and pharmacokinetics. Key inclusion criteria include a documented FLT3-ITD mutation, age 18 to 60 years, 8/8 or single-allele mismatch 7/8 donor, and CR1 status. Pts may enroll after the date of engraftment and hematologic recovery to an ANC > 1000/μL and platelets ≥ 20,000/μL without platelet transfusion. Status: The trial is open at 18 centers, and 22 of the planned 60 pts have been enrolled. ClinicalTrials.gov no. NCT01883362. Clinical trial information: NCT01883362.
Elevation of PFKFB3 and TIGAR levels in pancreatic cancer.
Authors: S. D. Kotiah, J. Caro
Journal: Journal of Clinical Oncology (2010)

e14679 Background: In 1930, Otto Warburg noted that some cancer cells had increased glycolysis even under normoxic conditions (Warburg effect). Glycolysis becomes essential for energy production in these tumors versus normal aerobic metabolism. The rate limiting step of glycolysis is determined by the phosphofructokinase bisphosphatase (PFKFB) enzymes in the third irreversible reaction. PFKFB has four known isoforms (PFKFB1-4) that increase in response to hypoxia by HIF related mechanisms. High glycolytic flux and lactic acidosis has been linked to tumor progression, invasiveness, metastatic potential and mortality. The recently discovered p53-inducible TIGAR gene functions as a fructuose2, 6-bisphosphatase, promoting the pentose phosphate pathway and preventing reactive oxygen species (ROS) accumulation and apoptosis. Our study evaluates the expression of PFKFB3, PFKFB4 and TIGAR in PET avid tumors, such as pancreatic cancer. PET scans are based on a glucose analog tracer taken up by cancer cells that have rapid and increased glucose uptake. Methods: 21 matched normal and pancreatic tumor tissues were obtained prospectively and frozen in liquid nitrogen. RNA extraction was performed using the Qiagen RNAeasy Mini Kit. The RNA was measured using the NanoDrop 2000. 3 ug of RNA was used for cDNA preparation with the SuperScript First Strand Synthesis for RT PCR (Invitrogen). Approximately 10 ng of cDNA was used for genes of interest and 10 picograms was used for 18s RNA for Taqman real time PCR analysis. Results: Overexpression of PFKFB3, PFKFB4 and TIGAR were found in the pancreatic samples. Interestingly, TIGAR was not induced by hypoxia when studied in vivo. However, this elevation was more significant for PFKFB3 and TIGAR. About 61.9% of the tumors had PFKFB3 elevation and 52.3% had at least a 2-fold increase versus matched normal. About 52.38% of the tumors had at least a 2 fold elevation in TIGAR expression versus the matched normal. The majority of the samples had concurrent elevation of PFKFB3 and TIGAR. Conclusions: The key glycolytic enzyme, PFKFB3 appears to be significantly elevated in pancreatic tumors and is a potential therapeutic target. Surprisingly, TIGAR was overexpressed in these samples and its function deserves further investigation. No significant financial relationships to disclose.
Management of Adverse Events Associated with Dasatinib during Early Periods of Therapy in the Treatment of Chronic Myeloid Leukemia -a Clinical Report of Daria-01 Study
Authors: Shuichi Mizuta, Hisashi Tsurumi, Masashi Sawa, Kana Matsumoto, Kotaro Miyao, Takeshi Hara, Takeshi Takahashi, Reona Sakemura, Akio Kohno, Mari Oba, Satoshi Morita, Junichi Sakamoto, Nobuhiko Emi
Journal: Blood (2014)
Abstract 2164: Tenascin-C binding peptides for cancer targeting
Authors: Prakash Lingasamy, Allan Tobi, Hedi Hunt, Pille Säälik, Markko Salumäe, Tambet Teesalu, Tambet Teesalu
Journal: Cancer Research (2016)

Abstract Extracellular matrix protein tenascin C (TNC) is strongly overexpressed in the stroma of many solid tumors. TNC expression is upregulated at the invasive front of tumors while being nearly undetectable in normal adult tissues. TNC-targeted humanized antibodies are undergoing clinical development for targeting compounds to solid tumors. Compared to antibodies, homing peptides may have more favorable extravasation and tumor penetration properties. We used in vitro T7 peptide display to identify peptides that bind to the alternatively spliced domain C of the large isoform of Tenascin-C (TNC FnIIIC). The selected phage pool showed 500-fold increase in binding to immobilized TNC FnIIIC. Candidate TNC FnIIIC-binding peptides (designated PL1- 3) were found to bind to TNC FnIII C protein, to the extracellular matrix extracted from PC3 prostate tumors and to cultured tumor cells known to overexpress TNC. To evaluate candidate peptides in vivo, we used mice bearing patient-derived xenografts of P3 glioma (R. Bjerkvig, Bergen, Norway), 4T1 breast tumors, and PC-3prostate carcinoma. A pool of the phages displaying TNC FnIIIC binding peptides, and a panel of phages displaying published tumor homing and control peptides was injected intravenously in tumor-bearing mice, and relative tumor homing and background in control tissues was determined for each phage using high-throughput sequencing (HTS) of phage genomic DNA. These studies demonstrated that among TNC FnIIIC targeting peptides, the PL3 peptide showed the best tumor homing and specificity profile. To evaluate the potential of the synthetic PL3 peptide for tumor targeting of nanoparticles, we coupled PL3 peptide to iron oxide nanoworms (IONW) - paramagnetic nanoparticles that are PEGylated to extend blood half-life, and have because of their elongated shape more effective targeting properties than spherical nanoparticles. 5 hours after intravenous administration of 7.5mg/kg of IONW in mice bearing PC3 prostate cancer xenografts, PL3-IONW but not control IONW showed a robust accumulation in tumor vasculature, and some extravasation into extravascular tumor tissue. Our data suggests that the newly identified TNC FnIIIC targeting peptide, PL3, may be used for payload delivery into tumor stroma. Currently, we are evaluating PL3-targeted IONWs as a MRI contrast agent and as carriers for cytotoxic compounds to TNC expressing tumors. Citation Format: Prakash Lingasamy, Allan Tobi, Hedi Hunt, Pille Säälik, Markko Salumäe, Tambet Teesalu, Tambet Teesalu. Tenascin-C binding peptides for cancer targeting. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2164.
Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy
Authors: Nicolas Weiss, Pierre Barbier Saint Hilaire, Benoit Colsch, Foucauld Isnard, Suleiman Attala, Augustin Schaefer, Maria del Mar Amador, Marika Rudler, Foudil Lamari, Frédéric Sedel, Dominique Thabut, Christophe Junot
Journal: Journal of Hepatology (2016)
Abstract 4195: Targeting the immune microenvironment to improve colorectal cancer anti-angiogenic therapy
Authors: Keehoon Jung, Takahiro Heishi, Andy Yun, Timothy P. Padera, Rakesh K. Jain, Dai Fukumura
Journal: Cancer Research (2016)

Abstract Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Anti-angiogenic therapy with bevacizumab has been proven efficacious in metastatic CRC. However, the improvement in overall survival has been modest and rather disappointing. Thus, there is an urgent need to identify the underlying mechanisms responsible for the resistance to anti-angiogenic therapy and develop strategies to overcome it. Clinical and preclinical interest in tumor immunotherapy has been renewed in a significant manner recently. However, the role of the immune microenvironment in colorectal cancer resistance to anti-angiogenic therapy is not well understood. We have developed miniaturized confocal endomicroscopy technique for spontaneous CRC models in mice. We also established a novel cecum window recently. These unique systems enable us to monitor the CRC and its immune microenvironment longitudinally with a video-rate intravital multi-photon microscope. Using these CRC models and in vivo imaging methods, we found that anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody increases infiltration of Gr1+ myeloid-derived suppressor cells (MDSCs) and they alter the tumor microenvironment toward an immune-suppressive condition to avoid attack of the host immune system. We also found that the Gr1+ MDSCs express CXCR4, which has important roles in cell-autonomous survival and chemotaxis, through its downstream signaling pathways. When we treat the VEGF signaling blocker together with a CXCR4-specific inhibitor, the level of the Gr1+ MDSC infiltration is dramatically decreased nearly to that of control group, and subsequently, tumor growth is significantly delayed compared to separate treatment of each inhibitor. Taken together, we identified Gr1+ MDSCs as key players in tumor resistance to anti-angiogenic therapy in CRCs, and the blockade of CXCR4 signaling has a synergistic effect with anti-VEGF therapy, proven by state-of-the-art in vivo imaging modalities. Citation Format: Keehoon Jung, Takahiro Heishi, Andy Yun, Timothy P. Padera, Rakesh K. Jain, Dai Fukumura. Targeting the immune microenvironment to improve colorectal cancer anti-angiogenic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4195.
An Exploratory Study of the Effects of Strenuous Exercise On Markers of Activation of Coagulation, Inflammation and Endothelial Activation: Possible Implications for Exercise-Related Morbidity in Sickle Cell Trait
Authors: Micah J. Mooberry, Robert Bradford, Robin Kellerman, Eric Sobolewski, Harry C. Stafford, Robert G. McMurray, Eric D. Ryan, Nigel S Key
Journal: Blood (2012)
Circulating protein and antibody biomarker for personalized cancer immunotherapy
Authors: Jianda Yuan
Journal: Journal for ImmunoTherapy of Cancer (2016)

Immune checkpoint blockade therapies are revolutionizing standard cancer treatments. Immune checkpoint inhibitors likely function to enhance the tumor specific antigen response in order to achieve favorable clinical outcomes. Thus, continuous efforts to identify the common tumor-specific antigens are essential for the broad clinical application of these therapies. Several immunoproteomics approaches have been used in order to screen for this specificity. In a recent article from Jhaveri and colleagues published in the February issue of Cancer Immunology Research, antibody biomarkers were screened in pancreatic cancer patients who received allogeneic, granulocyte-macrophage colony stimulating factor-secreting pancreatic cancer vaccine (GVAX) by using a serum antibody-based SILAC immunoprecipitation (SASI) approach. Using this assay, several new tumor antigens (MYPT1, PSMC5 and TRFR) were identified that were found to have significantly different expression in tumors compared with normal tissue. Moreover, patients with detectable antibodies showed improved disease-free survival after GVAX therapy. These targets need to be further validated to determine the full spectrum of tumor antigen immunogencity and their potential clinical application. In addition to antibodies, circulating protein, DNA and RNA in peripheral blood are under clinical investigation as liquid biopsies and have the potential to provide guidance for future personalized cancer immunotherapy.
Novel 3rd Generation Humanized Type II CD20 Antibody with Glycoengineered Fc and Modified Elbow Hinge for Enhanced ADCC and Superior Apoptosis Induction.
Authors: Pablo Umana, Ekkehard Moessner, Peter Bruenker, Gabriele Unsin, Ursula Puentener, Tobias Suter, Roger Grau, Carla Schmidt, Christian Gerdes, Adam Nopora, Monika Patre, Samuel Moser, Peter Sondermann, Luise Wheat, Martin J.S. Dyer, Sibrand Poppema, Sabine Bauer, Pamela Strein, Thomas Friess, Christian Klein
Journal: Blood (2006)
Assessment of a rapid liquid-based cytology method for measuring sputum cell counts
Authors: M J Martin, H Lee, G Meakin, A Green, R L Simms, C Reynolds, S Winters, D E Shaw, I Soomro, T W Harrison
Journal: Thorax (2016)

Differential sputum cell counting is not widely available despite proven clinical utility in the management of asthma. We compared eosinophil counts obtained using liquid-based cytology (LBC), a routine histopathological processing method, and the current standard method. Eosinophil counts obtained using LBC were a strong predictor of sputum eosinophilia (≥3%) determined by the standard method suggesting LBC could be used in the management of asthma.
Production of infectious dromedary camel hepatitis E virus by a reverse genetic system: Potential for zoonotic infection
Authors: Tian-Cheng Li, Xianfeng Zhou, Sayaka Yoshizaki, Yasushi Ami, Yuriko Suzaki, Tomofumi Nakamura, Naokazu Takeda, Takaji Wakita
Journal: Journal of Hepatology (2016)