tbuckley/cabot-search huggingface dataset:
Abstract 2878: CRISPR-Cas9 screens identify the nuclear export factor NXT1 as a novel therapeutic target in <i>MYCN-</i>amplified neuroblastoma
Authors: Clare F. Malone, Neekesh V. Dharia, Guillaume Kugener, Brenton Paolella, Michael Rothberg, Mai Abdusamad, Alfredo Gonzalez, Nancy Dumont, Scott Younger, David Root, Francisca Vazquez, Kimberly Stegmaier
Journal: Cancer Research (2019)

Abstract Pediatric cancers, such as neuroblastoma, have a relative lack of oncogenic mutations and the known drivers of these cancers are largely transcription factors, a target class notoriously difficult to “drug.” In order to identify novel therapeutic targets for high-risk, MYCN-amplified neuroblastoma, we employed functional genomic screening using a CRISPR-Cas9 approach. We generated genome-scale CRISPR dependency data to identify a candidate gene list of 197 putative genetic dependencies in neuroblastoma. We next created a focused sgRNA library targeting these genes and performed time-course dropout screens using CRISPR and CRISPRi and Annexin-V-based positive-selection cell death screens in four MYCN-amplified neuroblastoma cell lines. We also screened this library in vivo in two xenograft models of MYCN-amplified neuroblastoma. At the intersection of these screens, we identified the nuclear export factor NXT1 as a top candidate for therapeutic development in neuroblastoma. NXT1 scores as a strong dependency using both CRISPR and CRISPRi, is strongly enriched in our Annexin-V based positive selection cell death screen and scores in our in vivo screen. We have validated that NXT1 is indeed a genetic dependency in neuroblastoma in low-throughput and that NXT1 loss induces apoptosis in these cell lines. We were next interested in identifying biomarkers of dependency on NXT1, and by integrating RNAseq data with CRISPR dependency data, we identified low expression of NXT2, a paralog of NXT1, as the top predictive feature of NXT1 dependency. Importantly, while NXT1 itself is not currently druggable, inhibitors against another nuclear export protein, CRM1, are currently in Phase II clinical trials, demonstrating this class of proteins has the potential to be effectively drugged. Together, we show that CRISPR-Cas9 functional screens can be used to identify new therapeutic targets, particularly in diseases that lack “druggable” oncogenic drivers, such as many pediatric cancers. Citation Format: Clare F. Malone, Neekesh V. Dharia, Guillaume Kugener, Brenton Paolella, Michael Rothberg, Mai Abdusamad, Alfredo Gonzalez, Nancy Dumont, Scott Younger, David Root, Francisca Vazquez, Kimberly Stegmaier. CRISPR-Cas9 screens identify the nuclear export factor NXT1 as a novel therapeutic target in MYCN-amplified neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2878.
Abstract 4519: The reciprocal interaction between neutrophil extracellular traps and cancer cells impacts on their malignant potentials
Authors: Hiroki Kajioka, Shunsuke Kagawa, Atene Ito, Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2019)

Although the neutrophil extracellular traps (NETs) are first recognized to function to trap invading microorganisms and eliminate them as a defense mechanism, the involvement of NETs in cancer metastasis is being elucidated. The mechanism of interaction between NET and cancer cells, however, remains to be fully understood. Here, we investigated the direct and indirect interaction between NETs and cancer. NETs were detected in surgically resected metastatic liver cancer tissue specimens. In direct co-culture, NETs actually attracted cancer cells with their web-like structure. Of note, indirect transwell co-culture of neutrophils and pancreatic cancer cells provoked NETs without the other stimuli. In addition, conditioned media derived from cancer cells also induced NETs. The co-culture of NETs and cancer cells dramatically accelerated their migration and invasion abilities. Further investigation revealed that NETs induced mesenchymal markers in cancer cells which was associated with upregulated epithelial to mesenchymal transition (EMT)-related transcriptional factors. Finally, the accelerated cancer migration and overexpression of mesenchymal markers induced via NETs were inhibited by pharmacological blockade of NETs including NADPH oxidase inhibitor, peptidylarginine deiminase inhibitor, and neutrophil elastase inhibitor. These results suggested that cancer cells and neutrophils reciprocally interact when they coexist and NETs drive malignant potentials via EMT, implicating NETs as a candidate therapeutic target.   Citation Format:  Hiroki Kajioka, Shunsuke Kagawa, Atene Ito, Kazuya Kuwada, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara. The reciprocal interaction between neutrophil extracellular traps and cancer cells impacts on their malignant potentials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4519.
Synergistic Activity of IDH1 Inhibitor Bay-1436032 with Azacitidine in IDH1 Mutant Acute Myeloid Leukemia
Authors: Anuhar Chaturvedi, Charu Gupta, Ramya Goparaju, Razif Gabdoulline, Stefan Kaulfuss, Kerstin Görlich, Renate Schottmann, Olaf Panknin, Markus Wagner, Robert Geffers, Arnold Ganser, Felicitas Thol, Michael Jeffers, Andrea Haegebarth, Michael Heuser
Journal: Blood (2017)
Baseline 18F-FDG-PET and Dynamic Contrast Enhanced (DCE)-MRI for assessment of lymph node metastatic potential of oesophageal adenocarcinoma
Authors: K. Owczarczyk, S. Withey, R. Kozarski, J. Winfield, M. Siddique, N. Maisey, J. Gossage, A. Davies, G. Cook, V. Goh
Journal: Annals of Oncology (2019)
Clare Gerada: Thriving in medicine
Authors: Clare Gerada
Journal: BMJ (2019)

I recently interviewed two retired doctors, Michael and Bernadette Modell, both in their 80s, who taught me when I was a medical student.

I remember their lectures vividly, as well as my attachment at Kentish Town Health Centre, where Michael was a partner. They were giants of their respective specialties: Michael was professor of general practice, and Bernadette, his wife, forged a career creating the specialty that we now know as clinical genetics. They inspired not just me but a generation of students and young doctors who trained at University College Hospital.

I asked them both …
Abstract 235: Preclinical activity of an antibody drug conjugate targeting tumor specificmuc1 structural peptide-glycotope
Authors: Marc Trombe, Anne Caron, Alexia Tellier, Chantal Carrez, Stephane Guérif, Severine Clavier, Nathalie Karst, Juhani Saarinen, Tero Satomaa, Virve Pitkänen, Olli Aitio, Annamari Heiskanen, Matteo Fassan, Jan Pinkas, Raffaele Baffa, Veronique Blanc, Celine Nicolazzi
Journal: Cancer Research (2019)

Abstract SAR566658 antibody drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative DM4 that has been evaluated in the clinical setting. The purpose of our work was; 1) characterize the epitope targeted by anti DS6 on mucin1, 2) determine the prevalence of antigen expression in a patient population and 3) further explore preclinical activities of the ADC. Murine DS6 monoclonal antibody (muDS6) was generated from serous ovary adenocarcinoma immunization of immunocompetent mice. It specifically recognizes a MUC-1 tandem repeat domain in the context of cancer associated glycosylation. CA6-positive MUC-1 carries mucin-type O-linked glycans with α2,3-sialylated and β1,4-galactosylated termini, and antibody binding was abrogated by treating MUC-1 with specific glycosidases that remove either one of these glycan structures. However, the antibody did not bind to synthetic glycans modeled according to the major O-glycans of MUC-1. Our characterization of the peptide-glycotope leads us to conclude that tumor associated glycosylation is essential for the formation of the epitope on the peptide sequence of the MUC-1 tandem repeat domain. CA6 expression was evaluated by immunohistochemistry in paraffin embedded tumor tissue samples: 35.2% of breast cancer patients, 70,1% of ovarian cancer patients and 58,5% of bladder cancer patients have at least 30% of CA6 positive cells with an intensity of 2+/3+ in a multinational population-based study. In pre-clinical in vivo models, SAR566658 induced anti-tumor activity against CA6 positive tumor models of human pancreas, cervix and bladder cancer as well as and 3 Breast Patient-Derived Xenografts (PDX). Efficacy was correlated with MUC1-CA6 expression levels. In 3 additional models, SAR566658 showed anti-tumor activity that was more potent when compared to 3 conventional tubulin cytotoxic agents, docetaxel, vinorelbine and vinblastine. Citation Format: Marc Trombe, Anne Caron, Alexia Tellier, Chantal Carrez, Stephane Guérif, Severine Clavier, Nathalie Karst, Juhani Saarinen, Tero Satomaa, Virve Pitkänen, Olli Aitio, Annamari Heiskanen, Matteo Fassan, Jan Pinkas, Raffaele Baffa, Veronique Blanc, Celine Nicolazzi. Preclinical activity of an antibody drug conjugate targeting tumor specificmuc1 structural peptide-glycotope [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 235.
Abstract 208: Transcriptional profiling of the microenvironment in pediatric osteosarcoma
Authors: Laurie Sorenson, Troy A. McEachron
Journal: Cancer Research (2019)

Abstract Osteosarcoma (OS) is the most common bone tumor in pediatric and adolescent/young adult patients. Over the past three decades, significant improvements in the survival rates or therapeutic approaches for these patients have not been made, especially in the context of metastatic disease. While immune checkpoint blockade has revolutionized the therapeutic landscape in various adult malignancies, its impact in OS has been largely underwhelming. Currently, it is unknown whether the lack of therapeutic benefit of immune checkpoint inhibition observed in patients with OS is truly due to treatment inefficacy rather than a limited understanding of the tumor microenvironment that supports this aggressive disease. To address this knowledge gap, we have performed targeted gene expression profiling of metastatic and non-metastatic osteosarcoma specimens. Our profiling experiments have revealed that metastatic OS specimens are immunologically “colder” than non-metastatic OS specimens. Our data also demonstrates that T cells are largely excluded from the metastatic specimens and that this exclusion significantly correlates with markers of vascular instability. In a pathological setting, such as that of cancer, VEGF and ANG2 signaling promote vascular instability which limits leukocyte extravasation and subsequent tumor infiltration. Our data suggests that vascular destabilization mediated by VEGF/ANG2 signaling impedes T cell infiltration specifically in metastatic OS and identifies these molecules as potential targets for therapeutic intervention. Citation Format: Laurie Sorenson, Troy A. McEachron. Transcriptional profiling of the microenvironment in pediatric osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 208.
The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell–mediated resistance to metastasis
Authors: Irene Mattiola, Federica Tomay, Maria De Pizzol, Rita Silva-Gomes, Benedetta Savino, Tamara Gulic, Andrea Doni, Silvia Lonardi, Marie Astrid Boutet, Alessandra Nerviani, Roberta Carriero, Martina Molgora, Matteo Stravalaci, Diego Morone, Irina N. Shalova, Yunquin Lee, Subhra K. Biswas, Giovanna Mantovani, Marina Sironi, Costantino Pitzalis, William Vermi, Barbara Bottazzi, Alberto Mantovani, Massimo Locati
Journal: Nature Immunology (2019)
Mitochondrial Homeostasis in AML and Gasping for Response in Resistance to BCL2 Blockade
Authors: Michael R. Savona, Jeffrey C. Rathmell
Journal: Cancer Discovery (2019)

Abstract Summary: Understanding resistance to BCL2 inhibition is a critical scientific and clinical challenge. In this issue of Cancer Discovery, two laboratories use unbiased approaches of large loss-of-function CRISPR/Cas 9 screens to discover targetable liabilities in cell signaling and metabolism to acute myeloid leukemia resistant to BCL2 inhibition. See related article by Chen et al., p. 890. See related article by Nechiporuk et al., p. 910.
Abstract 2758: Domain swapping and SMYD1 interactions with the PWWP domain of human hepatoma-derived growth factor
Authors: Chun-Jung Chen, Li-Jin Hsu
Journal: Cancer Research (2019)

Abstract The human hepatoma-derived growth factor (HDGF), containing the chromatin-associated N-terminal PWWP domain capable of binding the SMYD1 promoter, participates in various cellular processes and is involved in human cancers, including hepatocellular carcinoma, pancreatic cancer, oral cancer, breast cancer and non-small cell lung cancer. However, the functional mechanisms of human HDGF had been puzzling because of a lack of essential knowledge of its intact structure in complex with DNA. We present the first crystal structures of the human HDGF PWWP domain (residues 1 - 100) in a complex with SMYD1 of 10 bp at 2.84 Å resolution and its apo form at 3.3 Å, respectively. The structure of the apo PWWP domain comprises mainly four β-strands and two α-helices. The PWWP domain undergoes domain swapping to dramatically transform its secondary structures, altering the overall conformation from monomeric globular folding into an extended dimeric structure upon DNA binding. The flexible loop2, as a hinge loop with the partially built structure in the apo PWWP domain, notably refolds into a visible and stable α-helix in the DNA complex. The swapped PWWP domain interacts with the minor grooves of the DNA through residues Lys19, Gly22, Arg79 and Lys80 in varied ways on loops 1 and 4 of the two chains, and the structure becomes more rigid than the apo form. These novel structural findings, together with physiological and activity assays of HDGF and the PWWP domain, provide new insights into the DNA-binding mechanism of HDGF during nucleosomal functions. Note: This abstract was not presented at the meeting. Citation Format: Chun-Jung Chen, Li-Jin Hsu. Domain swapping and SMYD1 interactions with the PWWP domain of human hepatoma-derived growth factor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2758.
Abstract LB-265: ARAF activates RAS by antagonizing its interaction with NF1
Authors: Wenjing Su, Rona Yaeger, Na Na, Jaclyn Hechtman, Viktoriya Paroder, Sandra Misale, Sae-Won Han, Omar I. Abdel-Wahab, Frank McCormick, Neal Rosen, Zhan Yao
Journal: Cancer Research (2019)

Abstract ARAF, BRAF and CRAF protein kinases are RAS effectors required for activation of ERK signaling. ARAF has relatively modest kinase activity and its biological functions are largely unknown. Here, we show that ectopic expression of ARAF but not B- or CRAF, leads to induction of RAS activation in cells with WT RAS. This phenomenon requires the binding of ARAF to RAS but not its kinase activity. ARAF was found to reduce inactivation of RAS by antagonizing its binding to the major RAS-GAP NF1. By this mechanism, the abundance of ARAF in cells determines cellular RAS-GTP levels, the dynamics of RTK-induced RAS activation and the biological consequences of RAS signaling. We find that a certain expression level of ARAF is required for growth factors induced proliferating or neural differentiation in PC12 cells. In RTK-dependent tumor cells, knocking down of ARAF leads to a reduction of RAS-GTP, thus impairs RAS signaling and the tumor growth. Furthermore, by investigating the tumor samples from MSK patients who are diagnosed with progressing disease after EGFR inhibitor treatment, we find the up-regulation of ARAF (including the ARAF gene amplification) is associated with EGFR inhibitor resistance in the lung cancer patients. We confirmed in cell line and xenograft models that a 5-fold elevation of ARAF expression is sufficient to eliminate RAS inhibition by EGFR inhibition and to cause resistance. Resistance in these cells could be overcome by combining EGFR and SHP2 inhibitors. The latter prevents EGFR activation of RAS-GTP exchange and thus would be expected with weaking the effects of NF1 inhibition by ARAF. Taken together, our work shows that ARAF directly activates RAS by antagonizing its interaction with NF1 and thus affects the duration and cellular response of growth factor activation and sensitivity of tumors to pharmacological inhibition of RTK-RAS signaling. Citation Format: Wenjing Su, Rona Yaeger, Na Na, Jaclyn Hechtman, Viktoriya Paroder, Sandra Misale, Sae-Won Han, Omar I. Abdel-Wahab, Frank McCormick, Neal Rosen, Zhan Yao. ARAF activates RAS by antagonizing its interaction with NF1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-265.
Abstract 4787: New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor
Authors: Ferah Comert Onder, Mehmet Ay, Serdar Durdagi, Bulent Ozpolat, isik Kantarcioglu
Journal: Cancer Research (2019)

Abstract Triple-negative breast cancer (TNBC) which constitutes 15-20% of breast cancers, is the most aggressive and chemo-resistant subtype of breast cancer and associated with the highest mortality rates of mortality among all breast cancer subtypes. TNBC is characterized by a lack of molecular targets (e.g., estrogen, progesterone, and HER2 receptors. Current treatment options for TNBC are still limited to conventional chemotherapies such as anthracyclines (e.g., doxorubicin) and taxane-based therapeutics. Identification of new molecular targets is critical for development of novel targeted treatments to improve poor patient prognosis and survival. We recently found that expression of eukaryotic elongation factor-2 kinase (EF2K), an unusual alpha kinase, is commonly upregulated in the majority of TNBC patients and associated with poor prognosis. We showed that EF2K is a potential molecular driver by promoting cell proliferation motility and invasion and drug resistance and validated it as a molecular target by RNA based therapeutic (i.e, siRNA and microRNA) in various TNBC models in mice (Tekedereli 2012, Hamurcu 2017, Bayraktar 2017). Several inhibitors of eEF2K have been described in the previous studies. However, these inhibitors have been neither specific nor potent. Small molecule inhibitor was synthesized in many steps by using different synthesis methods and also performed all of the structural analysis (FT-IR, 1H-NMR, 13C-NMR and LC-MS-MS). Computational studies were performed by using Schrödinger 2015 programme to investigate of in vitro activity of the compounds. By performing in vitro assays we identified a potent inhibitor of EF2K which inhibited p-EF2 at 1 μM (2 hours) detected by Western blots. Treatment of TNBC cells with this compound starts to inhibits cell proliferation and colony formation at 5-10 μM concentrations. The further studies are still ongoing. In conclusion, our results suggest that our newly designed small molecule may be potent EF2K inhibitor and can be used for targeting EF2K in TNBC. Note: This abstract was not presented at the meeting. Citation Format: Ferah Comert Onder, Mehmet Ay, Serdar Durdagi, Bulent Ozpolat, isik Kantarcioglu. New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4787.
Abstract 17203: Postnatal Management of Fetuses With Ebstein Anomaly or Tricuspid Valve Dysplasia in the Current Era: A Multi-center Study
Authors: Lindsay R Freud, Brian T Kalish, Maria C Escobar-Diaz, Rukmini Komarlu, Michael D Puchalski, Edgar T Jaeggi, Anita L Szwast, Grace Freire, Stephanie M Levasseur, Ann Kavanaugh-McHugh, Erik C Michelfelder, Anita J Moon-Grady, Mary T Donofrio, Lisa W Howley, Elif Seda Selamet Tierney, Bettina F Cuneo, Shaine A Morris, Jay D Pruetz, Mary E van der Velde, John P Kovalchin, Catherine M Ikemba, Margaret M Vernon, Cyrus Samai, Gary M Satou, Nina L Gotteiner, Colin K Phoon, Norman H Silverman, Doff B McElhinney, Wayne Tworetzky
Journal: Circulation (2015)

Background: A recent multi-center study of perinatal outcome in fetuses with Ebstein anomaly or tricuspid valve dysplasia (EA/TVD) found that 1/3rd of live-born patients (pts) died prior to hospital discharge. The purpose of this study was to explore differences in postnatal management and the relationship to outcome. Methods: This 23-center, retrospective study included 243 fetuses with EA/TVD from 2005 to 2011. Neonatal procedure (NP) was defined as surgery or interventional catheterization (cath) prior to discharge. Associations between postnatal management and outcome at discharge were explored. Results: Of 176 live-born pts, 7 received comfort care only, 11 died &lt;24 hrs of life, and 4 had insufficient data. Among 154 remaining pts, 38 (25%) did not survive to discharge. Pts who required ECMO at any point (n=18) had 83% mortality. More than half of pts (54%) did not have an NP, 34% had surgery, 8% had interventional cath, and 4% had both. The median age at 1st NP was 6 days (quartiles: 1-11). Survival did not differ between pts who had an NP and those who did not (70% vs. 80%; p=0.19) or between pts who had surgery and those who did not (68% vs. 80%; p=0.09). However, mortality differed by NP performed and whether pulmonary regurgitation, an indicator of high risk, was present prenatally (Figure). No pts with a right ventricular exclusion (RVE) died. Of 49 surviving neonates with ≥1 procedure, 28 (57%) were palliated with a shunt or RVE and 21 (43%) had a biventricular circulation. Thus, in total, 86 of 154 live-born pts (56%) survived with a biventricular circulation: 65 with medical management only and 21 with ≥1 NP. Conclusion: Among live-born pts diagnosed with EA/TVD in utero, a variety of postnatal management strategies were employed with overall poor outcomes. If surgery beyond PDA ligation is necessary, then RVE or other palliative procedure may need to be considered. A prospective, multi-center study utilizing a management algorithm would help elucidate the optimal strategy.