tbuckley/cabot-search huggingface dataset:
Abstract 2046: Structural analysis of VEGFR2 function blocking antibodies
Authors: Anita Wary
Journal: Cancer Research (2018)

Abstract The vascular endothelial growth factor receptor-2 (VEGFR2) is a receptor tyrosine kinase that is expressed highly in endothelial cells (ECs). By binding to VEGF165 (VEGF-A) VEGFR2 signals in ECs mediate the formation of new blood vessels, a process known as angiogenesis. Growth of tumor and metastasis depends on angiogenic activities of ECs. Thus, an agent that blocks VEGFR2 signaling specifically in tumor ECs could inhibit tumor growth and metastasis. The IMC-1121B is an antiangiogenic agent that inhibits the VEGFR2 signaling. Here we modeled the structure of the 1121B Fab fragment in complex with domain-3 of VEGFR2, and the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain-3. The two Fab fragments interact at opposite ends of VEGFR2 domain-3; 1121B blocks VEGF binding, whereas 6.64 appears to prevent receptor dimerization by perturbing the domain-3:domain-4 interface. Blocking of VEGFR2 signaling activities by two different antibodies could be a powerful approach to block angiogenesis, thereby inhibiting growth of tumor and metastasis. Key reference: Franklin MC et al., Structure 2011;19:1097-1107. Citation Format: Anita Wary. Structural analysis of VEGFR2 function blocking antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2046.
Abstract 15623: Effect of Pemafibrate (k-877), a Novel Selective Peroxisome Proliferator-activated Receptor α Modulator (spparmα), in Atherosclerosis Model Using Low Density Lipoprotein Receptor Knock-out Swine With Balloon Injury
Authors: Hirokazu Konishi, Katsumi Miyauchi, Hideki Wada, Ryo Naito, Shuta Tsuboi, Manabu Ogita, Tomotaka Dohi, Takatoshi Kasai, Hiroyuki Daida
Journal: Circulation (2017)

Background: Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that has key roles of lipid and inflammation. The PPARα affects the initiation and progression of atherosclero...
Abstract 14639: Long-term Clinical Outcomes After Treatment With Excimer Laser Coronary Atherectomy for In-Stent Restenosis of Drug-Eluting Stent
Authors: Eiji Ichimoto, Tadayuki Kadohira, Joseph De Gregorio
Journal: Circulation (2016)

Introduction: Excimer laser coronary atherectomy (ELCA) has been used for the treatment of complex percutaneous coronary intervention (PCI) such as in-stent restenosis (ISR). However, there was little information about the long-term outcomes after treatment with ELCA. Hypothesis: We assessed the long-term clinical outcomes after treatment with ELCA for ISR of DES. Methods: A total of 81 consecutive patients with 87 lesions who underwent PCI for ISR of DES between January 2012 and March 2015 were included. According to the use of ELCA, patients were classified into PCI with ELCA group (23 patients with 24 lesions) or PCI without ELCA group (58 patients with 63 lesions). The major adverse cardiac events (MACE) including all-cause death, myocardial infarction and target lesion revascularization (TLR) were evaluated. Results: The mean duration of clinical follow-up was 29.8 ± 11.6 months. Diffuse restenosis and AHA/ACC type B2 or C lesion in PCI with ELCA group were higher than in PCI without ELCA group. Quan...
Abstract 3706: Novel therapeutic strategy for pancreatic cancer with lectin drug conjugate (LDC): The efficacy and pilot safety test
Authors: Osamu Shimomura, Tatsuya Oda, Hiroaki Tateno, Yusuke Ozawa, Sota Kimura, Jun Hirabayashi, Nobuhiro Ohkohchi
Journal: Cancer Research (2018)

Abstract Background: We recently developed lectin-drug conjugate (LDC) for targeting pancreatic cancer specific glycan and showed potent anti-cancer effect both in vitro and in vivo (Osamu Shimomura et al., Molecular Cancer Therapeutics 2017). The additional evaluation of anti-cancer effects and the toxicity studies of LDC need to be clarified. Methods: LDC, rBC2LC-N lectin fused with 38 kDa of pseudomonas exotoxin (PE) A, was used in this study. We confirmed of the anti-cancer effect of LDC in orthotopic mouse models and developed dissemination mouse models to make sure of the survival benefits in LDC by both intra-peritoneally and intra-venously injection by log-rank test. We checked the damage of all organs pathologically after injection of the minimal or maximal tolerance doses and performed the blood sample analyses. Results: We have already validated the cytotoxic effect of LDC for PDAC cell lines in vitro i.e., IC50= 1.04 pico g/ml. Intraperitoneal and intravenous injection of LDC reduced tumor weight from 390 mg in normal saline group to 130.8 mg and 203 mg, respectively in the orthotopic models (P=0.001 and P=0.007, respectively), and improved median survival duration from 62 days to 105 and 90 days in the peritoneal dissemination models, respectively (P&amp;lt;0.0001 and P&amp;lt;0.0001, respectively). Intravenous injection of LDC conferred comparable therapeutic effects to intraperitoneal injection. Inconsistent with the apprehension that all lectins mediate harmful hemagglutination, the rBC2LC-N never caused hemagglutination with human erythrocytes in every blood types. The laboratory test after injection of therapeutic dose (1µg/mouse) of LDC showed no obvious abnormality except slightly elevation of aspartate and alanine aminotransferase. Surprisingly, no adverse event were observed after administration of rBC2LC-N lectins without PE up to 15 µg/mouse in wild type mice. Although some epithelial desquamations were revealed in the mucosa of the gut after fatal dose of LDC injection, we could not figure out the organ damage after the therapeutic dose of LDC injection pathologically. Conclusions: We show the successful in vivo application of a lectin for cancer treatment. Lectin itself did not cause severe adverse events and could be a potential candidate of a drug carrier, providing a new insight into anti-cancer drug development. Citation Format: Osamu Shimomura, Tatsuya Oda, Hiroaki Tateno, Yusuke Ozawa, Sota Kimura, Jun Hirabayashi, Nobuhiro Ohkohchi. Novel therapeutic strategy for pancreatic cancer with lectin drug conjugate (LDC): The efficacy and pilot safety test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3706.
Abstract 2220: Autoantibody detection of high-grade serous ovarian cancer with paraneoplastic antigens
Authors: Laura C. Hurley, Nancy K. Levin, Madhumita Chatterjee, Michael A. Tainsky
Journal: Cancer Research (2018)

Abstract Improved early detection methods for ovarian cancer are necessary as the majority of cases present at late stage metastatic disease with a poor prognosis. Early stages of tumor development initiate an immune response, eliciting antibodies that target tumor associated antigens. Paraneoplastic neurological syndromes are rare autoimmune disorders that develop when the unregulated immune response against a tumor also targets healthy cells, due to shared tumor antigen expression with nervous system and muscle tissue. As these syndromes generally precede detection of a tumor, paraneoplastic antibodies are previously unexplored candidate biomarkers for early diagnosis of ovarian cancer. We have detected paraneoplastic antibodies in serum samples from patients with high-grade serous ovarian cancer (HGSOC) that did not present with paraneoplastic neurological syndrome symptoms using paraneoplastic diagnostic line blots. Ovarian cancer specific epitopes discovered previously in our laboratory by phage-display biopanning were evaluated for both homology to paraneoplastic antigens and for reactivity with paraneoplastic neurological syndrome patient sera. Western blot screening revealed a panel of paraneoplastic antigens that distinguished HGSOC patient sera autoantibody reactivity from healthy and benign sera. An indirect ELISA for measuring patient serum autoantibody reactivity was developed and correlated with western blot results. A panel consisting of 8 antigens: 5 paraneoplastic antigens, 2 well-characterized tumor associated antigens, and a non-reactive control was selected for screening on ELISA against patient serum samples representing each group of HGSOC early stage, HGSOC late stage, healthy, and benign. Biomarkers identified can contribute to an autoantibody diagnostic panel for early clinical diagnosis of ovarian cancer, which would allow for timely therapeutic intervention with potential to improve patient outcome. Citation Format: Laura C. Hurley, Nancy K. Levin, Madhumita Chatterjee, Michael A. Tainsky. Autoantibody detection of high-grade serous ovarian cancer with paraneoplastic antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2220.
Abstract 5097: Knock-in of a human tumor suppressor (25-kilobase pairs) by traditional and CRISPR/<i>Cas9</i>-stimulated homologous recombination
Authors: Tiffany Leidy-Davis, Kai Cheng, Leslie Goodwin, Judith Morgan, Wen Chun Juan, Xavier Roca, Sin-Tiong Ong, David E. Bergstrom
Journal: Cancer Research (2018)

Abstract Here we describe an expansion of the DNA size limitations associated with CRISPR knock-in technology, more specifically, the physical extent to which mouse genomic DNA can be replaced with donor (in this case, human) DNA at an orthologous locus. Driving our efforts was the desire to create a whole animal model inserting a 25-kbp segment of a human tumor-suppressor gene in place of 17 kbp of its corresponding mouse orthologue. Included within the human fragment is a conditionally removable (by Cre-loxP) segment of the gene's second intron, a cryptic exon immediately 3' of this, and a native exon some 20 kbp downstream. Using two methods, we first carried out the replacement by employing a combination of bacterial artificial chromosome recombineering, classic ES cell targeting, dual selection, and recombinase-driven cassette removal (traditional approach). Using a unique second method, we employed the same vector (devoid of its selectable marker cassettes), microinjecting it along with CRISPR RNA guides and Cas9 into mouse zygotes (CRISPR approach). In both instances, we were able to achieve humanization of the tumor suppressor to the extent designed, remove all selection cassettes, and demonstrate the functionality of the conditionally removable, loxP-flanked, intronic segment. Citation Format: Tiffany Leidy-Davis, Kai Cheng, Leslie Goodwin, Judith Morgan, Wen Chun Juan, Xavier Roca, Sin-Tiong Ong, David E. Bergstrom. Knock-in of a human tumor suppressor (25-kilobase pairs) by traditional and CRISPR/Cas9-stimulated homologous recombination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5097.
A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML
Authors: Samuel John, Heyu Chen, Mi Deng, Xun Gui, Guojin Wu, Weina Chen, Zunling Li, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang
Journal: Molecular Therapy (2018)

To effectively improve treatment for acute myeloid leukemia (AML), new molecular targets and therapeutic approaches need to be identified. Chimeric antigen receptor (CAR)-modified T cells targeting tumor-associated antigens have shown promise in the treatment of some malignancies. However, CAR-T cell development for AML has been limited by lack of an antigen with high specificity for AML cells that is not present on normal hematopoietic stem cells, and thus will not result in myelotoxicity. Here we demonstrate that leukocyte immunoglobulin-like receptor-B4 (LILRB4) is a tumor-associated antigen highly expressed on monocytic AML cells. We generated a novel anti-LILRB4 CAR-T cell that displays high antigen affinity and specificity. These CAR-T cells display efficient effector function in vitro and in vivo against LILRB4+ AML cells. Furthermore, we demonstrate anti-LILRB4 CAR-T cells are not toxic to normal CD34+ umbilical cord blood cells in colony-forming unit assays, nor in a humanized hematopoietic-reconstituted mouse model. Our data demonstrate that anti-LILRB4 CAR-T cells specifically target monocytic AML cells with no toxicity to normal hematopoietic progenitors. This work thus offers a new treatment strategy to improve outcomes for monocytic AML, with the potential for elimination of leukemic disease while minimizing the risk for on-target off-tumor toxicity.
Bone Marrow–Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload
Authors: JinEndo, MotoakiSano, JunFujita, KentaroHayashida, ShinsukeYuasa, NaokiAoyama, YujiTakehara, OsamuKato, ShinjiMakino, SatoshiOgawa, KeiichiFukuda
Journal: Circulation (2007)

Background— Bone marrow (BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role. Methods and Results— Lethally irradiated wild-type mice were transplanted with BM cells from enhanced green fluorescent protein–transgenic mice. The chimeric mice were subjected to either prolonged hypoxia or transverse aortic constriction. BM-derived enhanced green fluorescent protein–expressing cardiomyocytes increased in number over time, emerging predominantly in the pressure-overloaded ventricular myocardium, although they constituted <0.01% of recipient cardiomyocytes. To determine whether BM-derived cardiomyocytes were derived from cell fusion or transdifferentiation at the single-cell level, lethally irradiated Cre mice were transplanted with BM cells from the double-condit...
No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients
Authors: Christoph Sarrazin, Curtis L. Cooper, Michael P. Manns, K. Rajender Reddy, Kris V. Kowdley, Stuart K. Roberts, Hadas Dvory-Sobol, Evguenia Svarovskia, Ross Martin, Gregory Camus, Brian P. Doehle, Luisa M. Stamm, Robert H. Hyland, Diana M. Brainard, Hongmei Mo, Stuart C. Gordon, Marc Bourliere, Stefan Zeuzem, Steven L. Flamm
Journal: Journal of Hepatology (2018)
Abstract 2591: Role of EGFR-AS1 lncRNA in growth factor addiction and treatment response in squamous cell cancers
Authors: Daniel SW Tan, Fui-Teen Chong, Hui-Sun Leong, Shen Yon Toh, Dawn P. Lau, Xue Lin Kwang, Xiaoqian Zhang, Gek San Tan, Anders J. Skanderup, Tony KH Lim, Ramanuj Dasgupta, N Gopalakrishna Iyer
Journal: Cancer Research (2018)

Abstract Squamous-cell cancers (SCCs) represent one of the commonest lethal malignancy worldwide. Despite evidence demonstrating that majority are addicted to Epidermal Growth Factor Receptor (EGFR)-signaling, targeting with monoclonal antibodies or tyrosine-kinase inhibitors (TKIs) has been met with limited success. We recently demonstrated that TKI-sensitivity is modulated by a long non-coding RNA (lncRNA) situated in the antisense strand of EGFR (EGFR-AS1). ‘Synonymous' alterations in EGFR-AS1 affected TKI-response in patient-derived models, and could be used to predict response in a small patient cohort. The lncRNA likely functions in cis by altering EGFR splicing, favouring expression of a truncated EGFR isoform (isoform D), with previously unknown function. Importantly, mediation of this effect requires EGFR ligand derived from paracrine or autocrine sources. Remarkably, even modest EGFR-AS1 knockdown showed profound effects on TKI sensitivity and tumor growth in vivo; the latter suggesting lncRNA-addiction. TKI-resistance models were established from patient-derived lines, through serial passaging with sub-lethal drug doses. Detailed analyses of four of these models demonstrate alterations that affect each of the steps involved in this addiction pathway: ligand binding, EGFR-AS1 expression/amplification and isoform D expression. Based on our mechanistic insights, we propose that patient-response to EGFR inhibitors is contingent on establishing a comprehensive suite of inter-related biomarkers as delineated here. This data also supports a novel therapeutic approach that involves modulating a lncRNA and/or splice variants of a well-established oncogenic driver. Citation Format: Daniel SW Tan, Fui-Teen Chong, Hui-Sun Leong, Shen Yon Toh, Dawn P. Lau, Xue Lin Kwang, Xiaoqian Zhang, Gek San Tan, Anders J. Skanderup, Tony KH Lim, Ramanuj Dasgupta, N Gopalakrishna Iyer. Role of EGFR-AS1 lncRNA in growth factor addiction and treatment response in squamous cell cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2591.
Abstract 2803: Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity
Authors: Philip N. Moquist, Tim D. Bovee, Andrew B. Waight, Sarah Owen, Jamie A. Mitchell, Margo Zaval, Marsha Quick, Sharsti Sandall, Kim K. Emmerton, Nicole Blesie, Robert P. Lyon, Peter Senter, Svetlana Doronina
Journal: Cancer Research (2018)

Abstract Auristatins are a class of clinically validated antimitotic agents utilized as payloads in antibody-drug conjugates (ADCs). Auristatins display many of the desirable properties necessary for ADC cytotoxins, such as low nanomolar potency, cell permeability, and activity across multidrug-resistant (MDR+) cell lines. Herein, we report the development of novel auristatins, which have a unique combination of these favorable properties. The hydrophilic monomethyl auristatin F (MMAF) was chosen as the parent structure, and a medicinal chemistry campaign was undertaken to functionalize various sites of the auristatin with hydrophobic moieties in an effort to improve membrane permeability. The structure-activity relationships (SAR) of the new auristatins demonstrated clear trends correlating hydrophobicity, structure, and polarity with permeability and in vitro cytotoxicity. The highest-performing molecules showed a preference for hydrophobic functionalization at the N-terminal dolavaline. The payloads were linked to the C-terminal position of the auristatin with a lysosomally cleavable maleimido-dipeptide linker. Examination of the ADCs revealed low ng/mL activity in CD30+ and CD19+ cell lines in vitro. Anti-CD70 ADCs demonstrated high in vivo efficacy in a 786-O xenograft and complete remissions (CRs) in the efflux-positive renal cell carcinoma model. Anti-CD30 ADCs were dosed in a CD30+ and CD30- admixed Karpas/Karpas-35R xenograft model to demonstrate proof-of-concept in vivo bystander activity. In summary, these novel auristatins showed potential across multiple indications as ADC payloads. Citation Format: Philip N. Moquist, Tim D. Bovee, Andrew B. Waight, Sarah Owen, Jamie A. Mitchell, Margo Zaval, Marsha Quick, Sharsti Sandall, Kim K. Emmerton, Nicole Blesie, Robert P. Lyon, Peter Senter, Svetlana Doronina. Novel auristatins with high activity on efflux-positive models and demonstrable bystander activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2803.
A possible new pathway in natural killer cell activation also reveals the difficulty in determining human NK cell function in cancer
Authors: Robert J. Canter, William J. Murphy
Journal: Journal for ImmunoTherapy of Cancer (2018)

Immunotherapy is rapidly becoming the fourth arm of cancer treatment, and breakthrough successes have been observed in multiple malignancies. However, despite the potential for impressive anti-tumor effects, on average, only 25% of patients respond, and barriers clearly remain. Hence, uncovering innovative ways to apply immunotherapy and overcome immune resistance remains an unmet need in immuno-oncology. Natural killer (NK) cells are an attractive candidate for extending the promise of immunotherapy, although success to date has been largely limited to hematological cancers. An important study has identified novel ways in which NK cells sense and respond to tumors, and these findings may impact clinical translation of NK cells in cancer immunotherapy. Using the activating receptor NKp44, NK cells were shown to bind platelet-derived growth factor DD (PDGF-DD) which was secreted by tumors. Using transgenic mice, NKp44 binding of tumor-expressed PDGF-DD was able to limit tumor growth, and expression of natural cytotoxicity receptor-associated gene signatures (of which NKp44 is a member) was correlated to clinical outcomes. This study highlights the potential for effector-target interactions to impact immune homeostasis in previously unrecognized ways, while at the same time, underscoring the complexities inherent in pre-clinical/ translational experimental design which may confound clinical application of these interesting results.