tbuckley/cabot-search huggingface dataset:
Abstract LB-056: A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma
Authors: YI P. HU, Yinghua M. Wang, Daniel Lee, Yi Ren
Journal: Cancer Research (2020)

Abstract The Hippo signaling pathway plays an important role in organ size control. Dysregulations of this pathway have been implicated in human cancer. Oncoprotein YAP is a major downstream effector molecule for Hippo pathway and has no intrinsic DNA binding domain. The functionality of YAP depends on the interaction of YAP with transcription factor TEAD in cell nucleus. Inhibitors targeting YAP-TEAD PPI could rectify abnormal Hippo pathway, leading to tumor remission. Screening through a carefully designed peptide library derived from the YAP protein, we have successfully identified potent YAP inhibiting peptides (YIP). Surface plasmon resonance (SPR) showed that the YIP bind to TEAD with high affinity in the nM-pM (KD) range. Subsequently, the binding interaction was confirmed by Pull-down experiments. In cell-based assays, YIP inhibited cell proliferation in various cancer cell lines at low µM (IC50) range. Furthermore, cellular nuclear tests indicated that YIP could penetrate into the nucleus and inhibited YAP-TEAD interaction by TEAD-luciferase assay in a dose dependent manner. In several s.c. xenograft animal models, a lead YIP strongly suppressed the tumour growth including NF-2 mutant mesothelioma cells. The lead YIP has good drug-like pharmacological properties and represents a promising candidate targeting the Hippo pathway as an effective treatment for cancers. Citation Format: YI P. HU, Yinghua M. Wang, Daniel Lee, Yi Ren. A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-056.
Abstract 1671: Deregulation of mTOR signaling contributes to chemoradiation resistance in lung squamous cell carcinoma
Authors: Changxian Shen, Duan-Liang Shyu, Min Xu, Linlin Yang, Wenrui Duan, Terence M. Williams
Journal: Cancer Research (2020)

Abstract Non-small cell lung carcinoma (NSCLC) represents ~ 85% of lung cancer, and ~1/3 of these patients present with locally-advanced, unresectable/medically-inoperable disease. Patients who present with locally-advanced NSCLC are commonly treated with definitive chemoradiation. Even though an initial response to concurrent chemoradiation is commonly observed, disease relapse in the radiation fields occurs in 1/3 of cases, likely driven by therapy-resistant tumor cells. However, the underlying molecular mechanisms of chemoradiation resistance of NSCLC remains largely unknown. We herein report that upregulation of mTOR signaling plays an important role in the chemoradiation resistance of NSCLC. Patient-derived xenograft (PDX) models of lung squamous cell carcinoma (LUSC) were established in the flanks of NOD-SCID gamma (NSG) mice. Chemoradiation resistant tumor models were developed by treating the tumors with a regimen of 2-4 weeks of chemoradiation (20, 30 or 40 Gy at 2 Gy per day, concurrent with cisplatin). Recurrent tumor models were collected and subjected to functional proteomics using reverse phase protein analysis (RPPA). Several LUSC tumors recurred in the 20 Gy+cisplatin, and 40 Gy+cisplatin groups. RPPA analysis of the recurrent and parental (untreated) PDX tumors showed that there were enhanced mTOR signaling in the chemoradiation resistant 20 Gy+cisplatin and 40 Gy+cisplatin tumors compared to that in the control tumors. Of note, phospho-AKT-S473, phospho-AKT-S308, phospho-S6-S235/6 and phospho-GSK3β-S9/21 were the highest upregulated signaling and were validated by immunoblotting. Consistently, pharmacological inhibition of mTOR kinase by Torin2 significantly sensitized LUSC cell lines to ionizing radiation. Our results demonstrate that utilization of PDX models is a useful method to elucidate the molecular mechanisms of chemoradiation resistance of NSCLC and deregulation of mTOR signaling contributes to the chemoradiation resistance of NSCLC. Our findings suggest that clonal selection of subpopulations with high mTOR signaling in heterogeneous NSCLC tumors might contribute to the relapse of NSCLC after chemoradiation and that mTOR kinase inhibitors are promising agents for the upfront treatment of NSCLC patients in combination with chemoradiation. Citation Format: Changxian Shen, Duan-Liang Shyu, Min Xu, Linlin Yang, Wenrui Duan, Terence M. Williams. Deregulation of mTOR signaling contributes to chemoradiation resistance in lung squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1671.
Abstract 891: CRISPR-Cas9-gRNA RNP mediated gene knockout of TGFBR2 and CISH enhances CD19-CAR NK cell function and provides resistance to TGFβ
Authors: Chao Guo, Ivan H. Chan, Luxuan Buren, Yanying Fan, Alexander Aronov, James B. Trager
Journal: Cancer Research (2020)

Abstract Natural killer (NK) cells, known for their ability to kill tumor cells, represent a promising ‘off the shelf' therapeutic for cell-based cancer immunotherapy. One of the major challenges with NK cell-based therapies includes their lack of persistence and expansion after adoptive transfer. In addition, the presence of inhibitory signals within the tumor microenvironment and mediated by tumor cells also contributes to the poor infiltration and activation of NK cells at the tumor site. To improve NK cell function, we developed an optimized CRISPR-Cas9 system utilizing electroporation of CRISPR-gRNA ribonucleoproteins (RNPs) to disrupt important regulatory genes to enhance and/or protect primary human NK cell function. This method allowed efficient knockout of the TGFBR2 and CISH genes in NK cells, genes that have a functional impact on NK cells. FACS and Amplicon NGS Sequencing data confirmed both genes were successfully disrupted. Furthermore, we were able to transduce and expand CRISPR/Cas9 edited NK cells to express a CD19-CAR construct and membrane bound IL-15. Cytotoxicity assays demonstrated that TGFBR2 knockout CD19-CAR NK cells were resistant to TGFβ inhibition of cytotoxicity. We also showed that CISH gene-edited CD19-CAR NK cells have significantly improved proliferation, survival, cytokine production, and cancer cell cytotoxicity. In summary, this data demonstrates that this platform enables effective primary human NK cell gene knockout to enhance NK function and provide resistance to tumor microenvironment inhibition. Citation Format: Chao Guo, Ivan H. Chan, Luxuan Buren, Yanying Fan, Alexander Aronov, James B. Trager. CRISPR-Cas9-gRNA RNP mediated gene knockout of TGFBR2 and CISH enhances CD19-CAR NK cell function and provides resistance to TGFβ [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 891.
Abstract 6680: Inclusion of inhibitory neoantigens can abolish efficacy of otherwise protective therapeutic anti-tumor vaccines
Authors: Victoria L. DeVault, Hanna Starobinets, Sanmit Adhikari, Simran Singh, Stephanie Rinaldi, Brendan Classon, Jessica B. Flechtner, Hubert Lam
Journal: Cancer Research (2020)

Abstract Identification of neoantigens that can elicit strong anti-tumor responses has become critical to vaccine design for cancer immunotherapy. Conventional methods for in silico neoantigen identification have yielded poor predictive value, highlighting the need for methods that identify bona fide neoantigen targets. The Genocea ATLAS™ platform uses autologous antigen presenting cells and T cells to identify pre-existing CD4+ and/or CD8+ T cell responses to patient-specific mutations and therefore selects confirmed neoantigens that can be used for vaccines and cell therapies. Screened neoantigens are characterized as stimulatory or inhibitory based on up- or downregulation of inflammatory cytokine secretion compared to baseline controls. In the mouse B16F10 melanoma model, therapeutic immunization with stimulatory neoantigen peptides arrested tumor growth whereas in contrast, inhibitory antigen immunization (henceforth referred to as inhibigens) resulted in accelerated tumor progression. The presence of an inhibigen in an otherwise protective vaccine formulation completely abolished protection. Global IFNγ responses to neoantigens were abrogated in these mice as measured by ELISpot suggesting that inhibigen pro-tumor responses can be immunodominant. Analysis of tumor-infiltrating lymphocytes (TILs) from mice immunized with ATLAS-identified neoantigen ± inhibigen peptide vaccines revealed significant alterations in the tumor microenvironment. Inclusion of inhibigens resulted in low T cell infiltration into tumors and increased expression of TIL inhibitory surface markers (e.g. PD-1, LAG-3). Immunological mechanisms of the inhibitory phenomenon are currently being explored. These data promote rational methods for neoantigen identification and highlight the potential advantages of excluding deleterious inhibigens from cancer vaccines and immunotherapies. GEN-009, a personalized cancer vaccine filtered for inclusion of only ATLAS-identified neoantigens (excluding inhibigens) is currently being evaluated in a Phase 1/2a clinical trial (NCT03633110). Citation Format: Victoria L. DeVault, Hanna Starobinets, Sanmit Adhikari, Simran Singh, Stephanie Rinaldi, Brendan Classon, Jessica B. Flechtner, Hubert Lam. Inclusion of inhibitory neoantigens can abolish efficacy of otherwise protective therapeutic anti-tumor vaccines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6680.
Abstract 4518: Pre-clinical development of NL-201: A <i>de novo</i> α-independent IL-2/IL-15 agonist
Authors: Carl D. Walkey, Paul Hara, Laurie Tatalick, Umut Ulge, Jonathan Drachman, Daniel-Adriano Silva
Journal: Cancer Research (2020)

Abstract Interleukin-2 (IL-2) and interleukin-15 (IL-15) promote anti-tumor immune activity by stimulating effector T and NK cells expressing the β and γ subunits of the IL-2 and IL-15 receptors. However, preferential activation of off-target cell populations expressing the high-affinity α subunit (including regulatory T cells, eosinophils, and endothelial cells) has limited the safety, therapeutic benefit, and widespread clinical use of these cytokines. Recently, we used sophisticated computational methods to create Neoleukin-2/15 (Neo-2/15), an entirely de novo α-independent agonist of both the IL-2 and IL-15 receptors. Unlike strategies that attempt to sterically inhibit or mutate the α-binding region of IL-2 or IL-15, Neo-2/15 was computationally designed to have no α-binding interface, while also having increased affinity for the β and γ signaling subunits. As a result, Neo-2/15 stimulates effector T and NK cells more potently and selectively than IL-2 or IL-15. Here, we report on the preclinical development and pharmacology of NL-201, a long-circulating variant of Neo-2/15 that is intended for clinical applications. NL-201 was derived from Neo-2/15 via the site-specific conjugation of a single PEG molecule and is manufactured using a simple and scalable process. NL-201 has a prolonged blood half-life and a sustained pharmacodynamic effect while retaining the high potency, selectivity, and thermodynamic stability of Neo-2/15. Preclinical studies demonstrate the robust antitumor activity of NL-201 as a single agent across a wide range of syngeneic murine tumor models, including those that do not respond well to checkpoint inhibitors. Due to its stability, high potency, and selectivity, NL-201 may overcome the long-standing challenges associated with the clinical use of IL-2 and IL-15 for cancer immunotherapy. Citation Format: Carl D. Walkey, Paul Hara, Laurie Tatalick, Umut Ulge, Jonathan Drachman, Daniel-Adriano Silva. Pre-clinical development of NL-201: A de novo α-independent IL-2/IL-15 agonist [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4518.
Factors Associated With Detection and Survival of T1 Hepatocellular Carcinoma in the United States: National Cancer Database Analysis
Authors: Ju Dong Yang, Michael Luu, Amit G. Singal, Mazen Noureddin, Alexander Kuo, Walid S. Ayoub, Vinay Sundaram, Honore Kotler, Irene K. Kim, Tsuyoshi Todo, Georgios Voidonikolas, Todd V. Brennan, Kambiz Kosari, Andrew S. Klein, Andrew Hendifar, Shelly C. Lu, Nicholas N. Nissen, Jun Gong
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: It remains unknown to what extent hepatocellular carcinomas (HCCs) are detected very early (T1 stage; ie, unifocal &lt;2 cm) in the United States. The aim of this study was to investigate the trends and factors associated with very early detection of HCC and resultant outcomes. Methods: Patients with HCC diagnosed from 2004 through 2014 were identified from the National Cancer Database. Logistic regression was used to identify factors associated with T1 HCC detection, and Cox proportional hazard analyses identified factors associated with overall survival among patients with T1 HCC. Results: Of 110,182 eligible patients, the proportion with T1 HCC increased from 2.6% in 2004 to 6.8% in 2014 ( P &lt;.01). The strongest correlate of T1 HCC detection was receipt of care at an academic institution (odds ratio, 3.51; 95% CI, 2.31–5.34). Older age, lack of insurance, high Model for End-Stage Liver Disease (MELD) score, high alpha-fetoprotein, increased Charlson-Deyo comorbidity score, and nonsurgical treatment were associated with increased mortality, and care at an academic center (hazard ratio [HR], 0.27; 95% CI, 0.15–0.48) was associated with reduced mortality in patients with T1 HCC. Liver transplantation (HR, 0.27; 95% CI, 0.20–0.37) and surgical resection (HR, 0.67; 95% CI, 0.48–0.93) were independently associated with improved survival compared with ablation. This is the first study to examine the trend of T1 HCC using the National Cancer Database, which covers approximately 70% of all cancer diagnoses in the United States, using robust statistical analyses. Limitations of the study include a retrospective study design using administrative data and some pertinent data that were not available. Conclusions: Despite increases over time, &lt;10% of HCCs are detected at T1 stage. The strongest correlates of survival among patients with T1 HCC are receiving care at an academic institution and surgical treatment.
Abstract 1386: 5-FU-induces PD-L1 in the absence of p53 via ATM dependent activation of STAT3
Authors: Tamas Sessler, Fiammetta Falcone, Peter Gallagher, Timothy Wright, Kienan Savage, Daniel B. Longley, Simon S. McDade
Journal: Cancer Research (2020)

Abstract Background: 5-Fluorouracil (5-FU) is an antimetabolite DNA damaging chemotherapeutics that forms the backbone for treatment of colorectal cancer (CRC) and currently it is the most commonly used anti-cancer drug. Despite the central role played by p53 in regulating DNA-damage response, its role in regulating response to 5-FU remains unclear. Methods: To better understand how p53 status differentially affects response to 5-FU, we conducted a detailed phenotypic analysis of the effects of 5FU alone or in combination with Oxaliplatin on cell cycle, DNA damage, cell death, DNA repair and consequent signaling across a panel of p53 isogenic, null and mutant CRC cell lines. Results: This revealed that while 5-FU induce both p53 dependent and independent cell death, the effects on cell cycle are profoundly different, with p53 deficient cells accumulating in S-phase with prolongated double strand breaks. This is not observed in p53 proficient cells, which are protected from these effects by induction of the p53 target gene p21/CDKN1A limiting cell cycle and enforcing suppression of cell cycle genes. Notably in both p53 or p21 deficient cells 5-FU results in sustained DNA damage-signaling through ATR and ATM in p53 deficient cells which preferentially arrest in S-phase. Importantly, these cells exhibit significant induction of cell surface expression of programmed death ligand-1 (PD-L1), which is enhanced by ATR inhibition concomitant with increased ATM activation. Further analysis indicates that transcriptional induction of PD-L1 is mediated through STAT3 in an interferon independent manner. Conclusion: This work adds significantly to our understanding of how p53 status impacts 5FU induced cell cycle arrest and response in CRC patients and have important implications for understanding 5-FU response, particularly in future combinations with immune checkpoint inhibitors. Citation Format: Tamas Sessler, Fiammetta Falcone, Peter Gallagher, Timothy Wright, Kienan Savage, Daniel B. Longley, Simon S. McDade. 5-FU-induces PD-L1 in the absence of p53 via ATM dependent activation of STAT3 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1386.
Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases
Authors: Jie Zheng, Valeriia Haberland, Denis Baird, Venexia Walker, Philip C. Haycock, Mark R. Hurle, Alex Gutteridge, Pau Erola, Yi Liu, Shan Luo, Jamie Robinson, Tom G. Richardson, James R. Staley, Benjamin Elsworth, Stephen Burgess, Benjamin B. Sun, John Danesh, Heiko Runz, Joseph C. Maranville, Hannah M. Martin, James Yarmolinsky, Charles Laurin, Michael V. Holmes, Jimmy Z. Liu, Karol Estrada, Rita Santos, Linda McCarthy, Dawn Waterworth, Matthew R. Nelson, George Davey Smith, Adam S. Butterworth, Gibran Hemani, Robert A. Scott, Tom R. Gaunt
Journal: Nature Genetics (2020)
Abstract 5706: Identifying regulators of cancer heterogeneity with phenotypic sorting and single cell sequencing
Authors: Kevin Chen, Stephanie Irene Fraley
Journal: Cancer Research (2020)

Abstract Intratumoral heterogeneity is a major challenge to the effective treatment of cancer. The genomic, transcriptomic, and epigenetic differences among tumor cells give rise to diverse phenotypes, some of which can persist in dysregulated environmental conditions and survive therapeutic attempts. Single cell sequencing (scSeq) technologies have improved our understanding of the transcriptional variation among tumor cells. However, it remains unclear how cell behavior is related to these alterations. Here, we link genotype to phenotype by employing a method of fluorescently labeling and isolating tumor cell subpopulations based on user-defined phenotypic characteristics from within a biologically relevant three-dimensional (3D) environment for subsequent scSeq and molecular analyses (Pheno-scSeq). We compare this Pheno-scSeq technique to traditional agnostic clustering of scSeq data and find significant differences. We then use Pheno-scSeq to guide our dissection of the mechanistic basis of heterogeneity in the invasive capacity of triple negative breast cancer cells. After seeding cells in 3D collagen and photoconverting based on invasion phenotype, we find that cells undergoing collective invasion are defined by a transcriptional program of migration, anabolism, and proliferation, suggesting a “go and grow” state contrasting with the “go or grow” hypothesis. Cells that do not invade form acini and are defined by a transcriptional program enriched for catabolism, senescence, and immune regulation. Functional assessment of the gene sets validates the relevance of the transcriptional program and reveals differential Human Leukocyte Antigen localization associated with differential migration phenotypes. Treatment with doxorubicin and paclitaxel reveals that acini cells are resistant to drug-induced death, while collectively invasive cells are more susceptible. Modulation of cell-matrix adhesion is explored to determine the potential for reprogramming between the two phenotypes and to identify couplings between migration, immune, and metabolic phenotypes. This study lends deeper insight into the mechanisms underlying phenotypic heterogeneity and may inform the success of precision oncology initiatives. Citation Format: Kevin Chen, Stephanie Irene Fraley. Identifying regulators of cancer heterogeneity with phenotypic sorting and single cell sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5706.
Abstract 6251: Blood brain barrier opening by TTFields: a future CNS drug delivery strategy
Authors: Ellaine Salvador, Almuth F. Kessler, Julia Hörmann, Malgorzata Burek, Catherine T. Brami, Tali V. Sela, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann
Journal: Cancer Research (2020)

Abstract Introduction: Although a number of effective drugs are available to treat central nervous system (CNS) disorders, their ability to breach the tight regulation of the blood brain barrier (BBB) still remains a major challenge. Recently, the use of tumor treating fields (TTFields) has become an effective treatment approach for glioblastoma. Furthermore, its combination with chemotherapy significantly improved overall patient survival. Nonetheless, how TTFields could affect the BBB has not yet been studied. Our recent findings exhibit the potential of TTFields administration to open up the BBB in vitro with an optimal frequency of 100 kHz. Consequently, in this study, we therefore aimed to validate our data in vivo. Experimental procedures: Subsequent to 100 kHz TTFields or heat treatment for 72 h, rats were i.v. injected with Evan´s Blue (EB). Next, they were sacrificed to extract and quantify EB from the brain. In the same manner, rats were injected with TRITC-dextran (TD), after which permeation was visualized in sectioned brains. Cryosections of rat brains were also prepared post-TTFields treatment. These were stained for intercellular junction proteins claudin-5, occludin and PECAM-1 as well as immunoglobulin G (IgG) to assess vessel structure. Finally, serial dynamic contrast-enhanced (DCE) MRI with gadolinium (Gd) contrast agent was performed before and after TTFields administration. Results: Permeation of both EB and TD was observed in the brain after TTFields application. Moreover, brain cryosections displayed claudin-5 and occludin delocalization but not PECAM-1. Accumulation of IgG in the brain parenchyma was also noted. Confirming these observations, increased Gd in the brain was shown by DCE-MRI post TTFields treatment. A reversion to normal conditions was, however, detected 96 h after end of treatment demonstrated by no difference in contrast enhancement between control and TTFields-treated rats. Conclusions: Administration of 100 kHz TTFields in rats led to alterations in BBB integrity and permeability, which signal its opening. The subsequent recovery of the BBB at the end of treatment demonstrates transient effects, hence presenting TTFields as a possible novel clinical strategy to open the BBB for enhanced and more effective drug delivery strategy for CNS disorders. Citation Format: Ellaine Salvador, Almuth F. Kessler, Julia Hörmann, Malgorzata Burek, Catherine T. Brami, Tali V. Sela, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann. Blood brain barrier opening by TTFields: a future CNS drug delivery strategy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6251.