tbuckley/cabot-search huggingface dataset:
415. First-In-Patient Proof of Safety and Efficacy of a 4th Generation Chimeric Antigen Receptor-Modified T Cells for the Treatment of Relapsed or Refractory CD30 Positive Lymphomas
Authors: Zhi-Tao Ying, Lung-Ji Chang, Hao-Hsiang Kuo, Yu-Chen Liu, Yu-Qin Song, Xiao-Pei Wang, Wei-Ping Liu, Wen Zheng, Yan Xie, Ning-Jing Lin, Mei-Feng Tu, Ling-Yang Ping, Chen Zhang, Hui-Ying Huang, Jun Zhu
Journal: Molecular Therapy (2015)

Many lymphoma patients cannot be cured by standard chemo-radiotherapy. CD30 is expressed in Hodgkin's lymphoma (HL), anaplastic large cell lymphoma (ALCL), diffuse large B cell lymphoma, and peripheral T/NK cell lymphoma. Brentuximab (SGN-35), an antibody-drug against CD30, has been approved by U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory classical HL and systemic ALCL. However, SGN-35 is not available or approved in many countries. Nevertheless, CD30 represents an attractive target for chimeric antigen receptor (CAR)-based immune cell therapy. This study reports the safety and efficacy of a 4th generation CAR T cell treatment for the management of relapsed and refractory CD30 positive lymphomas (www.clinicaltrials.gov; #NCT02274584). Lymphoma patients with relapsed or progressive CD30 positive disease are recruited. T cells are transduced with lentiviral CAR containing anti-CD30-scFv and T cell signaling domains including CD28/CD137/CD27 and CD3zeta. The CAR is fused with an apoptosis-inducing gene, FKBP-caspase 9 (iCasp9), to establish a safety-improved CAR (4S-CAR). CAR T cells and cytokines in blood are detected by quantitative PCR and ELISA, respectively. A 22-year-old male, diagnosed with stage III HL (Nodular Sclerosis, NS) in December 2011, had been heavily treated with three lines of chemotherapy and auto-transplantation. The patient relapsed in May 2014 and has been enrolled in this study. He received a conditioning regimen of three daily doses of fludarabine 25mg/m^2 and cyclophosphamide 250mg/m^2 one week before CAR T infusion. The total cell number infused was 3.2×10^8, of which 5% were CAR-positive. There were no infusion-related toxicities. 35 days and 2.5 months after infusion, CT scan showed resolution of multiple tumor nodules, which indicated partial remission. However, 5 months after infusion, disease slowly progressed based on CT scan. The CAR T cells peaked on day 45 accounting for >20% of circulating lymphocytes. Peak levels of interferon-γ and interleukin-6 were detected around day 40 coincided with peak CAR T detection. We demonstrate for the first time the safety and efficacy of CD30 4S-CAR T cells in a heavily-treated, relapsed late-stage CD30 positive HL patient. Compared with leukemia and other subtypes of lymphoma, HL has unique pathological characteristics. The NS subtype is the most common HL characterized by dense bands of collagen fibrosis and an overt immunosuppressive tumor niche. Such feature may result in the difficulty of CAR T cells to penetrate into the tumor mass. We are designing new treatment regimens to overcome this obstacle. Expansion of patient cohort and long term follow-up are in progress.
Abstract 5320: Targeting HER3 and EGFR in NRG1 positive and HER3 mutated lung squamous cell carcinoma
Authors: Maria C. Pinzon-Ortiz, Xianhui Rong, Richard Versace, Qing Sheng, Z. Alexander Cao
Journal: Cancer Research (2015)

Abstract HER3 is a member of the ErbB family of receptor tyrosine kinases. Aberrant activation of HER3 as a result of HER2 amplification or neuregulin 1 (NRG1) over-expression has been demonstrated to mediate constitutive activation of downstream oncogenic signals. LJM716 is a fully human IgG1 anti-HER3 monoclonal antibody. It locks HER3 in an inactive conformation and prevents HER3 dimerization with other ErbB family members. This unique mode of action enables LJM716 to block both ligand dependent and ligand independent HER3 activation. In search of new indications that may benefit from anti-HER3 therapies, we noted that squamous cell carcinomas (SCC) tend to have relatively higher NRG1 expression as compared to their adenocarcinoma counterparts. Highest NRG1 expression was observed in the lung SCC cell lines in cell line encyclopedia (CLE). A subset of the lung SCC cell lines with high NRG1 expression are moderately sensitive to LJM716, with HER3 activation detected in all of the sensitive lines. Additionally, EGFR activation is consistently observed in our panel of squamous lung carcinoma models. In some cases, activation of HER2 and/or HER3 is also noted. We hypothesize that squamous lung carcinomas may be dependent on signaling through EGFR, HER2 and HER3. To completely block EGFR, HER2-HER3 signaling, we set to test the treatment of LJM716 and Cetixumab in a number of NGR 1 positive squamous lung carcinomas tumor models. Enhanced anti tumor activity of LJM716 and Cetixumab is observed in four out nine tumor models. Analysis of broad activation status of receptor tyrosine kinases (RTK) reveals that a subset of responsive models have activated pEGFR, pHER2 and pHER3. These data suggest that activated HER3 signaling may be important in a subset of lung squamous cell carcinoma. Combination of anti-HER3 and anti EGFR treatment is effective at inhibiting growth in these tumors. Note: This abstract was not presented at the meeting. Citation Format: Maria C. Pinzon-Ortiz, Xianhui Rong, Richard Versace, Qing Sheng, Z. Alexander Cao. Targeting HER3 and EGFR in NRG1 positive and HER3 mutated lung squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5320. doi:10.1158/1538-7445.AM2015-5320
Investigation of a Novel Cyclin-Dependent-Kinase (CDK) Inhibitor Cdki-73 As an Effective Treatment Option for MLL-AML
Authors: Ka Leung Li, Sarah C Bray, Diana Iarossi, Julian Adams, Longjin Zhong, Ben Noll, Muhammed H Rahaman, Jennifer Richmond, Luen Bik To, Ian D Lewis, Richard B Lock, Shudong Wang, Richard J D'Andrea
Journal: Blood (2015)
Abstract 2199: Evaluation of critical residues in the C-terminal binding protein (CtBP) dehydrogenase domain contributing to substrate binding, catalysis, and oncogenic activity
Authors: Benjamin L. Morris, Priyadarshan Damle, Zaid Nawaz, Steven R. Grossman
Journal: Cancer Research (2015)

Abstract C-terminal binding proteins (CtBP) 1 and 2 are transcriptional coregulators that are upregulated in several cancers, including a majority of studied breast, colorectal, and ovarian tumor samples. CtBPs drive many cellular oncogenic properties, including migration, invasion, proliferation, and survival, in part through repression of tumor suppressor genes, such as E-cadherin, PTEN, BRCA1, and p16. CtBPs encode an intrinsic dehydrogenase activity regulated by both intracellular NADH concentration and the putative substrate 4-methylthio-2-oxobutyric acid (MTOB). NADH binding induces CtBP dimerization, which regulates the recruitment of transcriptional regulatory complexes. High levels of MTOB appear to inhibit CtBP dehydrogenase function and induce cytotoxicity among cancer cells in a CtBP-dependent manner. However, the function of the substrate-binding domain has yet to be examined with regard to CtBP's oncogenic activity. To this end, we have created several point mutations in the substrate-binding pocket of CtBP and have determined key residues for CtBP's enzymatic activity using an in vitro dehydrogenase assay. We have found that a conserved tryptophan in the catalytic domain, and specifically its aromatic moiety, is imperative for enzyme activity. This tryptophan is unique to CtBP family proteins and distinguishes the CtBP substrate-binding domain from that of all other families of dehydrogenases. Additionally, we found arginine and histidine residues lining the substrate pocket that are necessary for CtBP dehydrogenase function. Knowledge of these residues allows the directed synthesis of drugs with increased potency and higher CtBP specificity. Moreover, to investigate the importance of the catalytic domain on CtBP's oncogenic potential, we have transfected human cancer cell lines with several CtBP substrate-binding domain mutants and observed the effects on cellular processes, including growth, survival, migration, and recruitment of key components of the transcriptional repressor complex. From this work we have investigated the utility of CtBP, and specifically the CtBP substrate-binding domain, as a target for cancer therapeutics. We also provide preliminary insights into the function of this domain in cellular models of cancer. Citation Format: Benjamin L. Morris, Priyadarshan Damle, Zaid Nawaz, Steven R. Grossman. Evaluation of critical residues in the C-terminal binding protein (CtBP) dehydrogenase domain contributing to substrate binding, catalysis, and oncogenic activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2199. doi:10.1158/1538-7445.AM2015-2199
Altered Collagen Production by Dysfunctional Mesenchymal Stem Cells Is Linked to T Cell Large Granular Lymphocyte Leukemia Pathophysiology.
Authors: Adam W. Mailloux, Fanqi Bai, Ling Zhang, Eric Padron, Lili Yang, Cody Wei, Amber Schmidt, Lubomir Sokol, Dung-Tsa Chen, Thomas P. Loughran, Alan F. List, P. K. Epling-Burnette
Journal: Blood (2010)
666. A Phase-1 Safety Study Protocol for Lentiviral-Mediated COL7A1 Gene-Modified Autologous Fibroblasts in Recessive Dystrophic Epidermolysis Bullosa
Authors: Farhatullah Syed, Wei-Li Di, Anastasia Petrova, Alya Abdul-Wahab, Christos Georgiadis, Su M. Lwin, Adrian Thrasher, John McGrath, Waseem Qasim
Journal: Molecular Therapy (2015)

Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genodermatosis caused by loss-of-function mutations in COL7A1, the gene encoding type VII collagen (C7), a protein central to anchoring fibril formation at the dermal-epidermal junction (DEJ). Presently there are no curative treatments for this condition. We have been developing the gene therapy protocol for locally injection of lentiviral mediated COL7A1 gene-modified autologous fibroblasts into the patients with RDEB. Primary fibroblasts were isolated from a 6mm skin biopsy. Cells are expanded and transduced with a GMP compliant lenti-viral vector containing codon optimised COL7A1 gene cDNA under the control of the human PGK promoter. Transduced cells were further expended to reach appropriate cell numbers and cryopreserved until patients are ready. Scale up studies carried out in our GMP compliance laboratory showed C7 expression and stable integration of vector into cells. In-situ immunostaining and western blot analysis confirmed the expression of collagen VII protein (C7) not only in transduced RDEB fibroblasts but also in the culture media, indicating there is secreted C7 from transduced cells. The primary objective of our proposed Phase-I study is to determine the safety and tolerability of treatment with autologous gene modified cells administered to RDEB patients. Fibroblasts expressing codon-optimised COL7A1 will be injected intra-dermally in 5-10 adults with RDEB. The secondary objectives are to assess the efficacy of this treatment and its impact on skin and reversion of gene expression. Each study participant will receive three intradermal injections of ex-vivo transduced autologous fibroblasts expressing codon-optimised COL7A1 as the IMP and three intradermal injections of non-transduced autologous fibroblasts as control. Each injection (both IMP and control) will be administered into separate 1cm2 areas of intact skin sites. Participants will be followed up with study interventions for a total of 36-month period at various time points. If successful, a similar approach could be used to modify autologous epidermal sheets for localised treatment of blisters as well as systemic cell therapies.
Sofosbuvir + simeprevir +/-ribavirin treatment is efficient in genotype 4 chronic hepatitis C patients: results of a large international cohort.
Authors: C Moreno, M Derbala, E Nguyen-Khac, M Babatin, I Rosa, M Alzaabi, B Hanslik, A Mangia, T Asselah, P Buggisch, S Mauss, T Sersté, Jean Delwaide, S Alkaabi, A Pariente, A Remy, A Alghamdi, JF Cadranel, S Mohiuddin, D Degré
Journal: Hepatology (2016)
The Combination of PEITC (Phenehyl Isothiocyanate) with a Histone Deacetylase Inhibitor (HDACi) Has Synergistic Antileukemia Activity by Overcoming a Redox-Mediated Resistance Pathway.
Authors: Yumin Hu, Gang Chen, Yu Jia, Hui Zhang, Peng Huang, Kapil N. Bhalla, Michael Keating, Guillermo Garcia-Manero
Journal: Blood (2009)
Abstract 1140: PI3K/Akt inhibition decreases oxygen consumption In tumor cells by phosphorylating and inactivating pyruvate dehydrogenase PDH E1α subunit
Authors: George John Cerniglia, Souvik Day, Shannon M. Gallagher-Colombo, Natalie Daurio, Stephen Tuttle, Theresa M. Busch, Theresa M. Busch, Alexander Lin, Tatiana V. Esipova, Sergei A. Vinogradov, Constantinos Koumenis, Amit Maity
Journal: Cancer Research (2015)

Abstract The PI3K/mTOR pathway plays a central role in coupling metabolic processes to the cellular proliferative state. Pharmacologic inhibitors of the PI3K/mTOR pathway or genetic inhibition of Akt/PI3K decreased the oxygen consumption rate (OCR) in transformed cell lines in vitro by 30-40%. Pharmacologic inhibition of this pathway increased phosphorylation of the E1α subunit of the pyruvate dehydrogenase (PDH) complex on Ser293, an inhibitory modification of this critical gatekeeper of mitochondrial respiration. Expressing wild type PTEN in a doxycycline-inducible manner in a glioblastoma cell line with mutant PTEN led to an increase in PDH E1α phosphorylation and a decrease in OCR. The decrease in OCR with PI3K/Akt/mTOR inhibition was recapitulated by knocking down PDH E1α expression using siRNA. Pre-treatment with dichloroacetate (DCA), a known inhibitor of the pyruvate dehydrogenase kinases (PDKs) that phosphorylate PDH E1α, prevented the upregulation in PDH E1α phosphorylation, induced by inhibition of the pathway and also blunted the decrease in OCR. Likewise, introduction of exogenous PDH-E1α that contains serine to alanine mutations, which can no longer be regulated by phosphorylation, also blunted the decrease in OCR seen with PI3K/mTOR inhibition. Our findings highlight an association between the PI3K/mTOR pathway and tumor cell oxygen consumption that is regulated in part by PDH phosphorylation. These results have important implications for understanding the effects PI3K pathway activation in tumor metabolism and also in designing cancer therapy trials that use inhibitors of this pathway. Citation Format: George John Cerniglia, Souvik Day, Shannon M. Gallagher-Colombo, Natalie Daurio, Stephen Tuttle, Theresa M. Busch, Theresa M. Busch, Alexander Lin, Tatiana V. Esipova, Sergei A. Vinogradov, Constantinos Koumenis, Amit Maity. PI3K/Akt inhibition decreases oxygen consumption In tumor cells by phosphorylating and inactivating pyruvate dehydrogenase PDH E1α subunit. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1140. doi:10.1158/1538-7445.AM2015-1140
594. Exosome-Associated AAV Enhances Retinal Transduction Following Intravitreal Injection
Authors: Bence György, Sarah Wassmer, Livia Carvalho, Casey Maguire, Luk H. Vandenberghe
Journal: Molecular Therapy (2016)

Introduction Adeno-associated virus (AAV) has been shown to be associated with cell derived exosomes (exo-AAV). Exo-AAV outperforms regular AAV in transduction efficacy and evades neutralizing anti-AAV antibodies. Here we investigate the retinal transduction profile of exo-AAV vectors when administered intravitreally in BL6 adult mice. Methods Exo-AAV vectors were isolated from the culture media of triple-transfected 293T cells (AAV2 rep/cap, GFP transgene and adenovirus helper plasmid) by differential centrifugation. Regular AAV vectors were isolated from the cell lysate by iodixanol density gradient ultracentrifugation. To assess the transduction ability of the regular AAV2 and exo-AAV2 , we performed intravitreal injections into mice (n= 12 eyes, 1×1012 VG/mL), using AAV2 as the control (n=14 eyes, 1×1012 VG/mL). Fundus imaging was performed at 2 and 4 weeks post-injection, at which point the eyes were collected for immunohistological processing. Results We found that the exo-AAV2 showed an early onset of robust GFP expression via fundus imaging at 2 weeks post injection, as compared to regular AAV2. This was further enhanced by larger spread and brightness of GFP expression at 4 weeks. Histological processing of retinal sections shows GFP expression after exo-AAV2 expression in the nerve fiber layer, retinal ganglion cell layer, inner nuclear layer, outer nuclear layer and photoreceptor inner and outer segments. Staining with ganglion cell and bipolar cell markers show co-localization of GFP in these cell types. AAV2 injected animals show GFP expression mostly restricted to the nerve fiber and ganglion cell layers. Conclusion Intravitreal injections are an ideal delivery route to the retina in humans as it is minimally invasive and performed routinely in the clinic. Repeated pre-clinical work by others and us using AAV2 shows that an intravitreal injection is limited to targeting the nerve fiber layer (consequently, optic nerve) and retinal ganglion cells. Here, we demonstrate that exo-AAV2 targets all cell layers of the retina at robust levels and successfully targets retinal bipolar cells. As a result, an intravitreal injection of exo-AAV with a cell specific promoter may be the vector of choice for future gene therapy.
The Correlation Analysis of Venous Thromboembolism and Acute Myocardial Infarction with the Levels and Polymorphisms of Coagulation and Anticoagulation Factors.
Authors: Linhua Yang, Xuanmao Han, Zhenhua Qiao, Jinfang Ren, Xiue Liu, Lihong Hou, Xuefeng Wang, Qiulan Ding
Journal: Blood (2007)
Abstract 1224: Identification of novel p53 targets by RNA sequencing in mice liver tissues
Authors: Tomoyuki Koguchi, Chizu Tanikawa, Yoshiyuki Kojima, Hidewaki Nakagawa, Yusuke Nakamura, Koichi Matsuda
Journal: Cancer Research (2015)

Abstract In response to various type of cellular stress such as X-ray irradiation, ultraviolet exposure, and oxidative stress, the p53 protein is activated and regulates its target genes that induce cell cycle arrest, senescence, DNA repair, and apoptosis. Inactivation of the p53 gene is the most common alterations observed in human cancers. Therefore, identification of p53-target genes would help us to understand molecular carcinogenesis. However, an entire picture of the p53 signaling pathway has not been disclosed yet. To elucidate the mechanism whereby p53 suppress tumor development, we purified RNA of 19 organs from p53+/+ or p53-/- mice with or without 10 Gy of X-ray irradiation. RNA sequence analysis of 228 tissues provided expression profile of 23813 genes. Then we screened genes which satisfy the following criteria at least one organ; median FPKM value after radiation in p53WT mice is more than two-fold higher than that of those in other groups with p-value of 0.05 by t-test; median FPKM value after radiation in p53WT mice is more than one. Among 119 previously identified p53 targets with functional p53 binding motifs, 70 targets were induced by DNA damage in at least one mice tissues. Then we selected 16 candidates those were induced in mice liver. Quantitative PCR analysis using HepG2 human hepatocellular carcinoma cells revealed that four genes were induced by adriamycin treatment in a p53-dependent manner. Through these screening, here we identified p53-dependent inositol phosphate converting enzyme (PICE) as a direct target of p53. p53 induced PICE protein and mRNA in both human and mice. In addition we identified p53 binding sequence within its promoter region and exon 7 of the PICE gene. p53 also increased an inositol isomer synthesis in response to DNA damage. Our findings revealed the novel role of p53 in inositol phosphate metabolism. Citation Format: Tomoyuki Koguchi, Chizu Tanikawa, Yoshiyuki Kojima, Hidewaki Nakagawa, Yusuke Nakamura, Koichi Matsuda. Identification of novel p53 targets by RNA sequencing in mice liver tissues. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1224. doi:10.1158/1538-7445.AM2015-1224
Abstract 3520: Small molecule inhibitors of ring1B-Bmi1 E3 ligase target polycomb repressive complex 1 activity and regulate cell proliferation
Authors: Shirish Shukla, Qingjie Zhao, Weijang Ying, Felicia Gray, Kelly Vandenberg, George Lund, Bohdan Boytsov, Shihan He, Jolanta Grembecka, Tomasz Cierpicki
Journal: Cancer Research (2015)

Abstract Emerging evidence implicates the role of Ring1B and Bmi1 in the maintenance of embryonic stem cells and regulating adult stem cells self-renewal. Both Ring1B and Bmi1 are part of Poly-comb Repressive Complex 1(PRC1) and execute gene silencing through histone H2A lysine119 ubiquitination (UbH2A K119). In addition, Bmi1 is also required for the self-renewal capacity of leukemic stem cells, suggesting that Poly-comb Group proteins may contribute to oncogenic transformation by regulating stem cell self-renewal. Targeting cancer stem cell self-renewal has been proposed as a therapeutic goal and could be an effective approach to control tumor growth. In this study, we report the development and characterization of small molecule inhibitors against Ring1B-Bmi1 complex which interfere with its E3 ligase function. We developed ligands binding to Ring1B-Bmi1 employing NMR fragment-based screening. We further performed extensive medicinal chemistry optimization and synthesized over 80 analogs of the initial fragment hit and improved its binding affinity to Ring1B-Bmi1 complex by more than 1000-fold. The activity of developed small molecule inhibitors was analyzed by cellular and biochemical studies including in vitro ubiquitination assay and quantitative analysis of p16 expression. Mechanistically, we found that our most potent compounds inhibit E3 ligase activity of Ring1B-Bmi1 at low micromolar concentrations. As expected, treatment of HeLa and leukemic cell lines with these compounds demonstrated reduced UbH2A K119 levels and increased expression of p16. In addition, presence of the lead compounds also reduces leukemic cell proliferation as determined by MTT assays. Furthermore, the comparison between knockdown effects of Ring1B/Bmi1 with small molecule inhibitors revealed on target effect of the lead compounds. To our knowledge, these compounds represent the first small molecule inhibitors that directly bind to Ring1B-Bmi1 and inhibit its E3 ubiquitin ligase activity and have a strong potential for further development into potent anticancer agents. Citation Format: Shirish Shukla, Qingjie Zhao, Weijang Ying, Felicia Gray, Kelly Vandenberg, George Lund, Bohdan Boytsov, Shihan He, Jolanta Grembecka, Tomasz Cierpicki. Small molecule inhibitors of ring1B-Bmi1 E3 ligase target polycomb repressive complex 1 activity and regulate cell proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3520. doi:10.1158/1538-7445.AM2015-3520