tbuckley/cabot-search huggingface dataset:
Abstract NG14: Proteome instability is an immunogenic therapeutic vulnerability in mismatch repair deficient cancer
Authors: Nidhi Sahni, Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J. H. Shih, Guang Peng, David Menter, Melinda S. Yates, Scott Kopetz, Karen Lu, Russell Broaddus, Gordon B. Mills, Shiaw Y. Lin
Journal: Cancer Research (2020)

Abstract Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype, leaving a genomic scar known as microsatellite instability (MSI). MSI is observed in approximately 30% of endometrial cancers, 20% of gastric cancers, 15% of colorectal cancers, and in a smaller fraction of other tumor types. This hypermutator phenotype is thought to produce large numbers of immunogenic neoantigens, leading to the approval of MSI status as a clinical biomarker for immunotherapy. However, more than 60% of patients with MSI tumors fail to respond to immune checkpoint therapy. To uncover alternative therapeutic vulnerabilities for these patients, we used transcriptome signature-guided approaches to identify MLN4924 (pevonedistat), a Nedd8-activating enzyme inhibitor, as a potential therapy for dMMR/MSI cancers. We discover that destabilizing mutations from the dMMR mutation process lead to rampant proteome instability in MSI tumors, resulting in an abundance of misfolded protein aggregates. To compensate, MSI cancer cells activate a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins, which is blocked by treatment with MLN4924. The accumulation of misfolded proteins in MSI cancer cells following MLN4924 treatment activated the unfolded protein response, promoted immune cell migration, and induced immunogenic cell death. Antitumor vaccination with MLN4924-treated cells stimulated the generation of endogenous tumor antibodies and prevented tumor incidence upon re-challenge. Based on this immunostimulation, we combined MLN4924 with PD1 blockade, finding that the combination increased recruitment of CD8+ lymphocytes and improved therapeutic efficacy beyond either treatment alone. Taken together, our results indicate that targeting proteome instability is a novel therapeutic avenue for MSI patients and may potentiate immune checkpoint blockade, potentially increasing the depth and duration of response, as well as the fraction of dMMR/MSI patients who can benefit. Citation Format: Nidhi Sahni, Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J. H. Shih, Guang Peng, David Menter, Melinda S. Yates, Scott Kopetz, Karen Lu, Russell Broaddus, Gordon B. Mills, Shiaw Y. Lin. Proteome instability is an immunogenic therapeutic vulnerability in mismatch repair deficient cancer [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 NG14.
Abstract 945: Advancing cancer immunotherapeutics: A focus on characterization of anti-CTLA-4 mAbs for better anti-tumor immunity and less toxicity
Authors: Xuexiang Du, Mingyue Liu, Yan Zhang, Fei Tang, Chunxia Ai, Peng Zhang, Pan Zheng, Yang Liu
Journal: Cancer Research (2020)

Abstract Anti-CTLA-4 monoclonal antibodies confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAEs). How to uncouple the undesired irAEs from the beneficial CITE seen in cancer patients treated with anti-CTLA-4 and/or other checkpoints inhibitors has proven to be a daunting challenge, partially due to the lack of the understanding of the real MOA(mechanism of Action) of CITE and irAEs. Meanwhile, an animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. We not only discovered that the immunotherapy of current anti-CTLA-4 mAbs were dependent on Fc/Fc receptor mediated intra-tumor Treg depletion rather than the widely held mechanism of checkpoint blockade, which raised the reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy, we also establish one realistic irAEs model and find one mechanism of irAEs. In this model, the clinically used drug Ipilimumab (or TremeIgG1) induced severe irAEs especially when combined with an anti-PD-1 antibody; whereas another mAb L3D10 induced comparable CITE with very mild irAE under the same conditions. Humanization (HL12/HL32) of L3D10, which led to the loss of blocking activity, further increased safety without affecting the therapeutic effect. Furthermore, we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies. Citation Format: Xuexiang Du, Mingyue Liu, Yan Zhang, Fei Tang, Chunxia Ai, Peng Zhang, Pan Zheng, Yang Liu. Advancing cancer immunotherapeutics: A focus on characterization of anti-CTLA-4 mAbs for better anti-tumor immunity and less toxicity [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 945.
Abstract 5444: Clinical significance of tetraspanin CD63 in human ESCC
Authors: Yasunori Matsumoto, Masayuki Kano, Kentaro Murakami, Satoshi Endo, Takeshi Toyozumi, Tadashi Shiraishi, Toshiki Kamata, Takahiro Ryuzaki, Kazuya Kinoshita, Soichiro Hirasawa, Hisahiro Matsubara
Journal: Cancer Research (2020)

Abstract Background: ESCC(Esophageal Squamous Cell Carcinoma) is highly aggressive due to its tendency to metastasize to the lymph nodes and organs. Our laboratory previously reported that the exosome amount in the peripheral blood could predict the prognosis of ESCC patients. CD63 is a tetraspanin family protein and is often used as a marker of exosome.CD63 highly express in early stage melanoma and thought to be a suppressive factor against EMT (epithelial-to-mesenchymal transition) in melanoma. On the other hand, some report confirmed CD63 as a prometastatic factor via regulating E cadherin expression. The function of CD63 are still controversial. We herein assessed CD63 expression and clinicopathological findings in ESCCpatient, and assessed molecular roles of CD63 in ESCC cell lines. Materials and methods: The relationship between the CD63 expression in the resected ESCC specimen (from 1997 to 2006, n=86) and clinicathological features were assessed using immunohistochemical staining. Human ESCC cell lines (TE2,TE15) were used as high CD63 expression cell lines for in vitro analysis. CD63 was knockdown using siRNA, and CD63 down regulate was confirmed by western blot and PCR. The influence on the cell behavior and gene expressions were assessed by cell proliferation assay, mRNA microarray, and GSEA(Gene Set Enrichment Analysis). Results: There were no statistically significant correlation between the CD63 expression and age, sex, tumor depth (T), lymph node metastasis (N), distant organ metastasis (M), differentiation of tumor, lymphatic vessel invasion (ly), venous invasion (v), the type of progression. As for the prognosis, the high CD63 expression patients have significantly poorer prognosis than the low expression of CD63 patients. (P=0.047, log rank test). In vitro study, cell proliferation assay showed down expression of CD63 reduce cell proliferation. Knock down of CD63 downregulates HER2 expression and influence on other ERBB signaling pathways. Conclusions: High CD63 expression predicts poor prognosis in human ESCC. The molecular function of CD63 could have relationship to ERBB signaling pathways in human ESCC cells. Citation Format: Yasunori Matsumoto, Masayuki Kano, Kentaro Murakami, Satoshi Endo, Takeshi Toyozumi, Tadashi Shiraishi, Toshiki Kamata, Takahiro Ryuzaki, Kazuya Kinoshita, Soichiro Hirasawa, Hisahiro Matsubara. Clinical significance of tetraspanin CD63 in human ESCC [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 5444.
Abstract 880: Allogeneic CAR-T cell products containing 10 gene edits using CRISPR/Cas9 can retain full functionality <i>in vivo</i> and <i>in vitro</i>
Authors: Brigid McEwan, Meghna Kuppuraju, Zinkal Padalia, Jonathan Terrett, Demetrios Kalaitzidis
Journal: Cancer Research (2020)

Abstract Hematologic malignancies have proven most responsive to CAR-T therapies. However, there is significant variability in the depth and duration of response to autologous CAR-T cells. Furthermore, CAR-T responses in solid malignancies have been minimal. T cells from cancer patients can be compromised by the disease and prior treatments, and the use of allogeneic CAR-T products could potentially provide a more robust therapy. However, even CAR-T cells from healthy donors may benefit from additional gene edits that could enhance effector function, increase durability, evade immune mechanisms and/or combat the tumor microenvironment. These types of additional CAR-T features are readily enabled by CRISPR/Cas9 technology. While recent clinical data has demonstrated the persistence of therapeutic T cells that had been edited with CRISPR, the extent of gene editing that therapeutic T cells can tolerate has not been fully described. Herein, we have generated CAR-T cells with 10 gene edits. Loss of function alleles were produced in 9 genes and a CAR cassette was knocked into the TRAC locus via homology-directed repair. CD19-directed CAR-T cells with these 10 gene edits were fully functional in vitro, as shown by their ability to expand and kill target cells and secrete cytokines while remaining non-transformed. These cells were also highly efficacious in an in vivo model of CD19+ malignancy. Importantly, these edits, which produced insertions and deletions in target genes, could be detected in the blood of mice several months post injection. These data demonstrate that CRISPR/Cas9 can be used to create highly edited allogeneic CAR-T cells, unlocking the potential to enhance many functions relevant to CAR-T health and anti-tumor activity. Citation Format: Brigid McEwan, Meghna Kuppuraju, Zinkal Padalia, Jonathan Terrett, Demetrios Kalaitzidis. Allogeneic CAR-T cell products containing 10 gene edits using CRISPR/Cas9 can retain full functionality in vivo and in vitro [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 880.
Abstract 3300: Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors
Authors: Dan Zhao, Isa Mambetsariev, Haiqing Li, Chen Chen, Jeremy Fricke, Patricia Fann, Prakash Kulkarni, Yan Xing, Peter Lee, Andrea Bild, Erminia Massarelli, Marianna Koczywas, Karen Reckamp, Ravi Salgia
Journal: Cancer Research (2020)

Abstract Objectives: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients. Materials and methods: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis. Results: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06-0.59; P&amp;lt;0.01), EGFR (HR 7.38; 95% CI, 1.15-47.42; P&amp;lt;0.05), and TET2 (HR 0.15; 95% CI, 0.03-0.90; P&amp;lt;0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P&amp;lt;0.05). Conclusions: We described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC. Keywords: Lung cancer, molecular, next-generation sequencing (NGS), immune checkpoint inhibitors, TET2, FANCA, PD-L1, TMB, immunotherapy Citation Format: Dan Zhao, Isa Mambetsariev, Haiqing Li, Chen Chen, Jeremy Fricke, Patricia Fann, Prakash Kulkarni, Yan Xing, Peter Lee, Andrea Bild, Erminia Massarelli, Marianna Koczywas, Karen Reckamp, Ravi Salgia. Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors [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 3300.
Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities
Authors: Peter M George, Paolo Spagnolo, Michael Kreuter, Goksel Altinisik, Martina Bonifazi, Fernando J Martinez, Philip L Molyneaux, Elisabetta A Renzoni, Luca Richeldi, Sara Tomassetti, Claudia Valenzuela, Carlo Vancheri, Francesco Varone, Vincent Cottin, Ulrich Costabel
Journal: The Lancet Respiratory Medicine (2020)
SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials
Authors: Faiez Zannad, João Pedro Ferreira, Stuart J Pocock, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Martina Brueckmann, Anne Pernille Ofstad, Egon Pfarr, Waheed Jamal, Milton Packer
Journal: The Lancet (2020)
Abstract 23: Precision medicine approaches to Fanconi anemia oral cancer personalized prevention and treatment
Authors: Daniel K. Swenson, Beverly R. Wuertz, Mustafa M. Ali, Gretchen M. Unger, Frank G. Ondrey
Journal: Cancer Research (2020)

Abstract There is an increased risk of oral cavity and other head and neck cancers as Fanconi patients live longer post transplantation. DNA repair defects in Fanconi patients contribute to “field effect” in this population, which causes frequent recurrences and often fatal, second primary oral malignancies. These developments show a need for translation of new basic science concepts for this patient population. We are examining the effects of both Metformin and Pioglitazone, and Polo kinase and Wee Kinase inhibitors in Fanconi anemia oral cancer cell lines, and leukoplakia control cells. We employed 3 FA oral cancer cell lines for the current study. We performed clonogenic and cell proliferation (MTT) experiments in replicates and repeated those experiments to establish initial dose responses of the inhibitors at biologically relevant concentrations. We used ANOVA analysis with a P&amp;lt;0.05 as our level of significance. Concurrently, we are examining pioglitazone-metformin signaling pathways in biopsies from precancerous oral lesion (non-FA) patients treated with pioglitazone in our multiple chemoprevention clinical trials via confocal fluorescence microscopy. We found both the Wee Kinase inhibitor and POLO kinase inhibitor resulted in dose dependent decreases in proliferation and clonogenic potential in several experiments in all cell lines. We observed decreased proliferation at 72 hours at clinically achievable serum levels of 75%. However, we also observed cytotoxic effects as well, as judged by MTT reading at 72 hours being lower than the original Day 0 MTT readings. Pioglitazone treatment also resulted in dose dependent decreases in cell proliferation and clonogenic potential at clinically achievable serum levels. Similar effects can be achieved with metformin, however, at higher doses. Additionally, we have identified surrogate endpoints as suitable pharmacodynamic readouts by IHC analysis of the cell lines. There are precision medicine treatments for FA-associated oral carcinoma and these are feasible, based on earlier promising results we present here. We are attempting to discover new treatment methodologies for these patients, as conventional agents and radiation therapy are often unacceptable, due to the DNA fragility of the patient population. In combination, these efforts support our future goals of chemoprevention in this underserved prevention population. Citation Format: Daniel K. Swenson, Beverly R. Wuertz, Mustafa M. Ali, Gretchen M. Unger, Frank G. Ondrey. Precision medicine approaches to Fanconi anemia oral cancer personalized prevention and treatment [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 23.
Abstract 466: Epigenetic drug profiling in diffuse intrinsic pontine glioma
Authors: Hannah Tolson
Journal: Cancer Research (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and universally fatal form of childhood brain cancer. As prognosis has improved little over the last 40 years, exploring alternate drug therapies remains paramount. Roughly 80% of DIPG patients harbor mutations that result in the substitution of a lysine for a methionine at position 27 of histone variants 3.1 and 3.3 (H3.1K27M and H3.3K27M). This hallmark mutation causes global epigenetic changes in DIPG patients by dysregulating methylation and acetylation of histones, thus making the epigenome a potential therapeutic target. We explored vulnerabilities in 10 DIPG models (8 of which were H3.3K27M and 2 of which were H3.1K27M) to HDAC inhibitors (TSA and Panobinostat) and an LSD1 inhibitor (SP2577) both alone and in combination using drug dose response assays. As expected, Panobinostat showed high potency in each DIPG cell line, with 7 of the 9 lines having IC50 values less than 10 nM. In contrast, all 10 lines had no response to SP2577 apart from cytotoxic reactions in higher concentration ranges. SP2577 will thus be interesting to test in combination with Panobinostat with the intention of increasing its sensitivity. We also evaluated the efficacy of epigenetic drugs when used in combination with drugs targeting transcriptional pathways including TGN1076, a novel reversible CDK7 inhibitor. We found that TGN1076 shows marginal synergy with TSA, an HDAC inhibitor, and good synergy with JQ1, a BET inhibitor in the cell line DIPG6. Though equilibrating the epigenome remains a necessary objective in DIPG research, elucidating the mechanisms underlying extreme epigenetic shifts could provide important insight into disease pathogenesis. For this reason, we also focused on the histone methyltransferase protein PRC2 which is commonly implicated in epigenetic dysregulation in DIPG. Because the catalytic subunit of PRC2, EZH1/2, is allosterically regulated by another subunit, EED, in a “write and read mechanism,” we are testing the efficacy of the drug EED226 which binds to EED and modulates the function of PRC2. Analyzing the effects of this drug alone and in combination will provide a novel approach to managing PRC2 dysregulation and will potentially reveal future therapeutic strategies. Through screening novel drugs and testing their efficacies in combination with drugs that are commercially available, we intend to provide future therapeutic options for DIPG patients. Citation Format: Hannah Tolson. Epigenetic drug profiling in diffuse intrinsic pontine glioma [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 466.
Abstract IA17: Cellular interactions and regulatory mechanisms in head and neck cancer
Authors: Dario A.A. Vignali
Journal: Clinical Cancer Research (2020)

Abstract Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environment carcinogens or malignant transformation by human papilloma virus (HPV). Two studies will be discussed. First, we have performed transcriptional profiling of single cells from peripheral and intratumoral immune populations in HPV- and HPV+ HNSCC and healthy donors. We found a spectrum of transcriptional relationships from very similar to highly divergent between the tumor microenvironments (TME) in HPV- and HPV+ HNSCC. Our comprehensive survey of the TME in in HPV- and HPV+ HNSCC highlights the diversity of immune states and complexity of crosstalk between immune populations, and is a benchmark for analysis of the TME in human cancer. Second, many cancer patients do not develop a durable response to current standard of care immunotherapies despite substantial advances in targeting immune inhibitory receptors. A potentially important and unappreciated compounding issue, which may serve as a dominant resistance mechanism, is the inherent systemic immune dysfunction that is often associated with advanced cancer. Although this has been described for decades, primary mechanisms and drivers remain unknown. Lack of response to inhibitory receptor blockade therapy and increased disease burden has been associated with circulating, peripheral CD8+ T-cell exhaustion, which is defined by poor T-cell function linked to increased inhibitory receptor expression (PD1 or LAG3). Our recent studies have assessed if LAG3 and PD1 impact systemic T-cell function. Citation Format: Dario A.A. Vignali. Cellular interactions and regulatory mechanisms in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA17.