tbuckley/cabot-search huggingface dataset:
Establishment of patient-derived orthotopic xenograft model of 1q+ posterior fossa group A ependymoma
Authors: Angela M Pierce, Davis A Witt, Andrew M Donson, Ahmed Gilani, Bridget Sanford, Martin Sill, Benjamin Van Court, Ayman Oweida, Eric W Prince, Jenna Steiner, Etienne Danis, Kathleen Dorris, Todd Hankinson, Michael H Handler, Kenneth L Jones, Sana D Karam, Natalie J Serkova, Rajeev Vibhakar, Nicholas K Foreman, Andrea M Griesinger
Journal: Neuro-Oncology (2019)

Treatment for pediatric posterior fossa group A (PFA) ependymoma with gain of chromosome 1q (1q+) has not improved over the past decade owing partially to lack of clinically relevant models. We described the first 2 1q+ PFA cell lines, which have significantly enhanced our understanding of PFA tumor biology and provided a tool to identify specific 1q+ PFA therapies. However, cell lines do not accurately replicate the tumor microenvironment. Our present goal is to establish patient-derived xenograft (PDX) mouse models.Disaggregated tumors from 2 1q+ PFA patients were injected into the flanks of NSG mice. Flank tumors were then transplanted into the fourth ventricle or lateral ventricle of NSG mice. Characterization of intracranial tumors was performed using imaging, histology, and bioinformatics.MAF-811_XC and MAF-928_XC established intracranially within the fourth ventricle and retained histological, methylomic, and transcriptomic features of primary patient tumors. We tested the feasibility of treating PDX mice with fractionated radiation or chemotherapy. Mice tolerated radiation despite significant tumor burden, and follow-up imaging confirmed radiation can reduce tumor size. Treatment with fluorouracil reduced tumor size but did not appear to prolong survival.MAF-811_XC and MAF-928_XC are novel, authentic, and reliable models for studying 1q+ PFA in vivo. Given the successful response to radiation, these models will be advantageous for testing clinically relevant combination therapies to develop future clinical trials for this high-risk subgroup of pediatric ependymoma.
Abstract 3500: Highly potent and selective ATM kinase inhibitor M4076: A clinical candidate drug with strong anti-tumor activity in combination therapies
Authors: Thomas Fuchss, Ulrich Graedler, Kai Schiemann, Daniel Kuhn, Holger Kubas, Heike Dahmen, Astrid Zimmermann, Frank Zenke, Andree Blaukat
Journal: Cancer Research (2019)

Abstract M4076 is an ATP-competitive inhibitor of the Ataxia telangiectasia mutated (ATM) kinase (IC50 &amp;lt; 1 nM), which targets tumor cell survival and growth by inhibiting double-strand break (DSB) repair as well as checkpoint control. DSB repair is crucial for survival of malignant tumor cells, especially under treatment with DNA damaging chemo- and radiotherapy. As such, the rationale of pharmacological inhibition of ATM is to increase and maintain the extent of unrepaired DNA damage generated by radio-, chemotherapy, and targeted therapies to drive tumor cells into cell death. We have developed an orally administered, sub-nanomolar potent &amp; selective kinase inhibitor of ATM, M4076, for cancer therapy in combination with DNA damaging modalities. Here, we present its structure-activity relationship, its chemical structure (first-time disclosure) &amp; physicochemical profile as well as its preclinical characterization using biochemical, cellular &amp; human tumor xenograft models. M4076 sensitizes tumor cell lines to radiation therapy in vitro and strongly enhances the anti-tumor activity of ionizing radiation in vivo. These effects are due to the inhibition of ATM kinase activity as demonstrated by the inhibition of radiotherapy induced ATM autophosphorylation and CHK2 phosphorylation in xenograft lysates. Citation Format: Thomas Fuchss, Ulrich Graedler, Kai Schiemann, Daniel Kuhn, Holger Kubas, Heike Dahmen, Astrid Zimmermann, Frank Zenke, Andree Blaukat. Highly potent and selective ATM kinase inhibitor M4076: A clinical candidate drug with strong anti-tumor activity in combination therapies [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 3500.
Role of the Aryl Hydrocarbon Receptor/ARNT/Cytochrome P450 System in Pulmonary Vascular Diseases
Authors: Grazyna Kwapiszewska, Anne Katrine Z. Johansen, Jose Gomez-Arroyo, Norbert F. Voelkel
Journal: Circulation Research (2019)

CYPs (cytochrome p450) are critically involved in the metabolism of xenobiotics and toxins. Given that pulmonary hypertension is strongly associated with environmental exposure, we hypothesize that CYPs play a role in the development and maintenance of pathological vascular remodeling.We sought to identify key CYPs that could link drug or hormone metabolism to the development of pulmonary hypertension.We searched in Medline (PubMed) database, as well as http://www.clinicaltrials.gov, for CYPs associated with many key aspects of pulmonary arterial hypertension including, but not limited to, severe pulmonary hypertension, estrogen metabolism, inflammation mechanisms, quasi-malignant cell growth, drug susceptibility, and metabolism of the pulmonary arterial hypertension-specific drugs.We postulate a hypothesis where the AhR (aryl hydrocarbon receptor) mediates aberrant cell growth via expression of different CYPs associated with estrogen metabolism and inflammation.
Abstract 3629: Development of Combrestatin loaded vascular cell modified CLENS for targeting cellular models of tumor vascular endothelia in vitro
Authors: Kanchi S. Sanghvi, Robert Campbell, Guang Yan
Journal: Cancer Research (2019)

Abstract Purpose: The American Cancer Society predicts that about 0.6 million people would die of cancer and about 1.7 million new cases will be diagnosed in the year 2018. One important goal of cancer treatment is to minimize uptake of the cytotoxic drug agent by normal tissues. CLENs (cell membrane lipid-extracted nanoliposomes) have been developed to enhance targeted delivery of drugs to cancer cells located in the tumor interstitial matrix environment. The purpose of this study was to evaluate the use of CLENs for tumor vascular targeting. Methods: We expanded tumor endothelial cells derived from the pancreas followed by membrane extraction and the development of MS1-VEGF CLENs for vascular targeting. We evaluated the benefits of the additional inclusion of conventional liposome components (DOPC/Chol/DPPE-PEG5000) in various ratios, including the synthetic cationic lipid DOTAP (50 mol%), known for its vascular targeting characteristics when employed with conventional liposome components. We performed cellular uptake studies to determine relative level of selectivity in connection with the inclusion of LE (lipid extract) material. We determined also the effect of the additional inclusion of DOTAP in CLENs for targeting. We separated free drug from drug incorporated in CLENs using dialysis cassettes with MWCO of 10 kD. We evaluated the efficiency of Combrestatin A4 Phosphate (a microtubule-destabilizing agent) loading in CLENs by HPLC. Results: The addition of (50 mol%) cationic lipid DOTAP content in CLENs increased the overall zeta potential of the preparation from -14.26 ± 3.65 mV to 10.24 ± 4.23 mV. The average particle size for MS1-VEGF CLENs was approximately 137 ± 7 nm. The cellular uptake studies revealed that CLENs consisting of 70 mol% LE demonstrated the greatest selectivity towards MS1 VEGF cells, when compared to minimal uptake observed for non-target human glioblastoma (U87-MG) cell control. However, the data suggest also an overwhelming cationic lipid effect when DOTAP was included in the CLENs. Where overall cellular uptake increased, the selectivity afforded by LE decreased. Preliminary drug loading studies (between 20 and 45%) suggested that LE inclusion in nanoliposomes influenced the capacity for drug loading. Conclusion: The inclusion of MS1-VEGF lipid extract material in nanoliposomes improved vascular selectivity. The additional inclusion of DOTAP enhanced targeting, but the preference for target versus non-target cells had diminished. Additional studies are currently underway. Citation Format: Kanchi S. Sanghvi, Robert Campbell, Guang Yan. Development of Combrestatin loaded vascular cell modified CLENS for targeting cellular models of tumor vascular endothelia in vitro [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 3629.
Abstract 3180: Targeting peptide-loaded-DC CIK cells induce a specific antitumor response
Authors: Yimin Zhu, Xueyuan Cui, Cuijuan Liu
Journal: Cancer Research (2019)

Abstract Currently, immunotherapy has become an effective alternative therapeutic approach for cancers. Cytokine-induced killer (CIK) cells have a higher proliferation rate, increased efficacy with few side-effects, and non- MHC-restricted killing after co-culturing with dendritic cells (DCs). However, the specificity and efficacy of DC-CIK treatment still need to be improved. In our study, the antitumor effects of CIK cells co-culturing with DCs pulsed with non-cell derived targeting peptides, which could specifically bind to certain tumor cells, were evaluated. Our results indicated that targeting peptide-loaded DCs could enhance the differentiation and cytotoxicity of CIK cells. CIK cells, which were treated with specific targeting peptide-loaded DCs, could effectively and specifically kill tumor cells in vitro and in vivo, as long as tumor cells were pre-treated with these targeting peptides. Moreover, the CIK cytotoxic effect of this type acquired a certain properties of memory and resistance to the tolerance. In conclusion, targeting peptides could guide DC-CIK more effectively and specifically kill tumor cells and this non-cell derived targeting peptide-loaded-DC CIK may work as a novel means for cancer therapy. Citation Format: Yimin Zhu, Xueyuan Cui, Cuijuan Liu. Targeting peptide-loaded-DC CIK cells induce a specific antitumor response [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 3180.
Effectiveness of CA 19.9 in predicting prognosis in metastatic pancreatic cancer patients treated with nab-paclitaxel plus gemcitabine
Authors: S. Mariani, P. Soro, N. Liscia, F. Balconi, S. Camera, C. Donisi, V. Impera, F. Musio, M. Persano, A. Pireddu, A. Pretta, S. Tolu, V. Pusceddu, E. Lai, L. Faloppi, L. Demurtas, P. Ziranu, M. Puzzoni, M. Scartozzi
Journal: Annals of Oncology (2019)
Abstract 3974: In vivo CRISPR-Cas9 library screen for liver cancer therapeutic targets essential for T cell killing
Authors: Haixin Zhao, Chenlu Geng, Wenrong Zhou, Zhengang Peng, Qunsheng Ji, Yong Cang
Journal: Cancer Research (2019)

Abstract T-cell checkpoint inhibition by antibodies blocking programmed cell death protein 1 (PD1) has been a major breakthrough in cancer therapeutic development. However, anti-PD1 drugs approved by FDA are ineffective in treating all cancer types or in all patients in a responsive cancer type. Therefore, it is important to stratify responsive patient population and identify synergistically effective combination therapies. Primary hepatocellular carcinoma (HCC) is a human malignancy with a high incidence, mortality and recurrence rate worldwide. We established a syngeneic mouse HCC model using a murine hepatoma cell line, Hepa1-6, which, interestingly, shrunk in volume shortly after reaching up to 400 mm3. The tumor failed to resume growth unless treated with anti-CD4/CD8 antibodies to deplete endogenous T cells, suggesting that an adaptive T cell immunity suppresses the late-stage tumor growth. To identify the genetic regulators of the cancer elimination, we employed CRISPR-Cas9 based genome-wide knockout screening strategy to identify the potential targets essential for cancer cell sensitivity to the T cell immunity. Mouse xenograft models derived from hepa1-6 cells infected with the library were treated with anti-CD4/CD8 antibodies or anti-mPD1 antibody. Deep sequencing of the tumors revealed T cell-dependent enrichment of guide RNAs targeting 241 genes with variable functions. We have performed a second round of in vivo screen with a CRISPR library focused on these candidate genes. We will discuss the technical challenges of the in vivo screen as well as the broad application of the technology for discovery of immune oncology targets. Citation Format: Haixin Zhao, Chenlu Geng, Wenrong Zhou, Zhengang Peng, Qunsheng Ji, Yong Cang. In vivo CRISPR-Cas9 library screen for liver cancer therapeutic targets essential for T cell killing [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 3974.
Abstract 3056: Development of an integrated CRISPR interference system targeting ΔNp63 to treat lung and esophageal squamous cell carcinoma
Authors: Masakazu Yoshida, Etsuko Yokota, Tetsushi Sakuma, Nagio Takigawa, Toshikazu Ushijima, Takashi Yamamoto, Yoshio Naomoto, Takuya Fukazawa, Tomoki Yamatsuji
Journal: Cancer Research (2019)

Abstract TP63 encodes two different transcripts that have opposite functions in transcriptional control. One transcript encodes TAp63 that is functionally similar to the tumor suppressor TP53. The other transcript, ΔNp63, lacks the transcription-activating domain of TAp63 and has been proposed to function as a potent oncogene in squamous cell carcinomas. In this study, we have developed an integrated CRISPR interference system to selectively suppress ΔNp63 and we have termed this system CRISPRiΔNp63. We engineered the CRISPRi using tandemized guide RNA expression cassettes to target the 50 to 100 bp downstream region of the transcription start site of ΔNp63 and we used inactivated Cas9 linked to the transcription repression module Krüppel-associated box repressor domain. The plasmid vector harboring CRISPRiΔNp63 repressed ΔNp63 transcriptional activity in lung and esophageal squamous cell carcinoma cells that express ΔNp63. Moreover, an all-in-one adenoviral vector containing tandemized gRNAs and the dCas9/KRAB expression cassette, Ad-CRISPRiΔNp63, suppressed ΔNp63 expression in squamous cell carcinomas cells. Ad-CRISPRiΔNp63 effectively decreased cell proliferation and colony formation and induced apoptosis in lung and esophageal squamous cell carcinoma cells in vitro. Moreover, the all-in-one vector significantly inhibited tumor growth in a lung squamous cell carcinoma xenograft mouse model in vivo. These results indicate that ΔNp63 suppression by CRISPRiΔNp63 might be an effective strategy for the treatment of lung and esophageal squamous cell carcinoma. Citation Format: Masakazu Yoshida, Etsuko Yokota, Tetsushi Sakuma, Nagio Takigawa, Toshikazu Ushijima, Takashi Yamamoto, Yoshio Naomoto, Takuya Fukazawa, Tomoki Yamatsuji. Development of an integrated CRISPR interference system targeting ΔNp63 to treat lung and esophageal squamous cell carcinoma [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 3056.
5-year overall survival in patients with lung cancer eligible or ineligible for screening according to US Preventive Services Task Force criteria: a prospective, observational cohort study
Authors: Yung-Hung Luo, Lei Luo, Jason A Wampfler, Yi Wang, Dan Liu, Yuh-Min Chen, Alex A Adjei, David E Midthun, Ping Yang
Journal: The Lancet Oncology (2019)
Abstract LB-163: Comparing clinical value scores (NCCN, ASCO and ESMO) for TTFields treatment in glioblastoma
Authors: Justin Kelly, Christina Proescholdt, Nicholas A. Blondin
Journal: Cancer Research (2019)

Abstract Objective: To compare the tools of the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) for the assessment of the clinical value for Tumor treating fields (TTFields) in newly diagnosed Glioblastoma (GBM). Background: The effectiveness and safety of TTFields in newly diagnosed GBM was demonstrated by the final analysis of the randomized controlled EF-14 Trial (n=695). NCCN, ASCO and ESMO have developed tools to help inform physicians and policymakers about the clinical value of new cancer treatments in a standardized way. We report on the results of the tools for scoring the EF-14 trial data and comparatively discuss the results. Materials/Methods: The EF-14 Trial proved the effect of adding TTFields to maintenance temozolomide (TMZ) for newly diagnosed glioblastoma patients. The ESMO Magnitude of Clinical Benefit Scale (MCBS) and the ASCO Net Health Benefit (NHB) frameworks calculate a score for the clinical value of a cancer treatment. We applied both classifications to the EF-14 trial data. Quality of life data from the EF-14 Trial was also published and is included in the scoring. NCCN self reports “evidence blocks” which are assessed by clinician panels and were recently published for the first line treatment of newly diagnosed GBM. Results: Applying the ASCO framework to the EF-14 data resulted in a NHB score of 56. This scores is among the highest identified in the literature search. Applying the ESMO framework resulted in MCBS scores of A/5, these being the highest achievable scores for this framework. The ESMO framework valued the Health Related Quality of Life (HRQoL) gain during deterioration-free survival time with TTFields. The NCCN CNS panel designated TTFields as a category 1 recommendation in newly diagnosed GBM; the related NCCN evidence blocks support this recommendation. Conclusions: While the frameworks used by ASCO and ESMO focus on different aspects and definition of clinical value both suggest that adding TTFields to maintenance TMZ for newly diagnosed glioblastoma patients provides patients with significant clinical benefits. The high ESMO and ASCO scores are reflecting the fact, that treatment with TTFields extended progression free and overall survival without additional systemic toxicities. The NCCN evidence blocks together with the NCCN category 1 recommendation strongly support the use of Optune in newly diagnosed GBM Citation Format: Justin Kelly, Christina Proescholdt, Nicholas A. Blondin. Comparing clinical value scores (NCCN, ASCO and ESMO) for TTFields treatment in glioblastoma [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-163.
Inching towards precision medicine for multiple myeloma with causal network models.
Authors: Jun Zhu, Yu Liu, Li Wang, Haocheng Yu, Seungyeul Yoo, Eunjee Lee, Eric E. Schadt
Journal: Journal of Clinical Oncology (2019)

e19526 Background: Multiple myeloma (MM) is the 2 nd most prevalent blood cancer. For each molecular subtype of MM defined by molecular profiles, mechanisms underlying prognosis and drug response are largely unknown. Elucidating the mechanisms underlying differences in prognosis and drug response will enable a more personalized, precision medicine (PM) approach to treating patients. Methods: Big multiomics data are now widely available and contain the ingredients necessary to build causal models to uncover mechanisms of prognosis and drug response. However, data from resources like the MM Research Consortium (MMRC) dataset may contain errors (eg, sample mislabeling) that diminish modeling accuracy. We developed a probabilistic data matching method ( proMODMatcher) to correct such errors and applied it to the MMRC data. We identified labeling errors in 10 patients, including swaps in RNA and CNV profiles. Given the corrected MMRC data, we characterized recurrent genomic aberrations in MM. We found &gt; 8000 genes significantly associated (FDR &lt; 0.01) with CNVs spanning the gene locations. To distinguish expression correlations driven by causal biological relationships from those driven by coincident CNV influence, we constructed a causal MM network based on the MMRC dataset. Results: Overlaps among multiomic prognostic or drug response biomarkers are sparse. To identify common mechanisms of different biomarkers, we projected them onto our MM network to define the causal context in which they occur. Prognostic biomarkers were enriched in subnetworks associated with mitotic regulation and lipid metabolism, and predicted by our network to be regulated by ZWINT, BUB1B, DTL, TPX2 and NOP16. Proteasome inhibitor and immunomodulating drug responses were mediated by amino acid biosynthesis and cell surface protein complex subnetworks, respectively, with MTHFD2 and TMC8 inferred as the master regulators of these subnetworks, respectively. Regulators include genes (eg, BUB1B and MTHFD2) known to associate with tumor growth and drug response and novel therapeutic control points. Conclusions: Causal models can elucidate the molecular mechanisms underlying prognosis and drug response, enabling the design of more personalized MM treatments.
Abstract 15588: Folic Acid Attenuates Acute Doxorubicin-Induced Cardiomyopathy by Modulating Endothelial Nitric Oxide Synthase and Mitochondrial Integrity
Authors: Yanti Octavia, Georgios Kararigas, Martine de Boer, Rinrada Kietadisorn, Melissa Swinnen, Hans Duimel, Fons K Verheyen, Stefan Janssens, Dirk J Duncker, An L Moens
Journal: Circulation (2015)

Aims: In the pathogenesis of doxorubicin (DOXO)-induced cardiomyopathy, endothelial nitric oxide synthase (eNOS) has a pivotal role. Here we tested the hypothesis that folic acid (FA), as an eNOS modulator, attenuates DOXO-induced cardiomyopathy and mortality. Methods: Male C57BL/6 mice (n=265) received DOXO (1x 20 mg/kg, ip) or saline (sham). FA (10 mg/d po) or placebo was administered from 7d before DOXO administration until the end of the experiment (10d). Left ventricular (LV) function was measured by echocardiography; atrophy, fibrosis and apoptosis by hematoxylin-eosin, Picro-sirius Red and TUNEL staining, respectively; eNOS uncoupling, activity and S-glutathionylation by co-immunoprecipitation and immunoblotting; superoxide (O2-) production by lucigenin-enhanced chemiluminescence, with or without L-NAME (NOS inhibitor); cardiac NO by Griess reaction; mitochondrial function and morphology by mitochondrial oxygen consumption measurements and electron microscopy, respectively. Results: DOXO produced 70% mortality (P&lt;0.01 vs sham), while mice receiving DOXO and FA (DOXOFA) had significantly lower mortality (45%; P&lt;0.01). FA ameliorated DOXO-induced LV dysfunction, atrophy, fibrosis, and apoptosis (Table 1). Uncoupling, activity and S-glutathionylation levels of eNOS were restored in DOXOFA, and subsequently lead to a reduction in O2- production, which mainly NOS-dependent, and an increase in cardiac NO. Furthermore, FA attenuated mitochondrial dysfunction and morphological changes. Conclusion: FA as eNOS modulator might be a new and immediate therapeutic approach to reduce DOXO-induced cardiomyopathy.