tbuckley/cabot-search huggingface dataset:
Abstract 4468: Cross-species analysis and immunophenotyping using of a focused panel of immune-responsive genes
Authors: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Hideki Nakagaki, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2020)

Abstract Immunotherapy has transformed the landscape of cancer therapy, unfortunately, not all patients can reap the benefits and identifying those patients that may benefit remains challenging. It is the consensus that patients with inflamed tumors are more likely to benefit from immunotherapies targeting immune checkpoints, and therapies aiming to stimulate or boost T cell anti-tumor immunity and modulate tumor inflammation are being investigated. Determining which type of immune therapy to administer depends largely on the patients immunophenotype. Various methods aimed at determining a tumor's immune profile are emerging or are available, of these, immune profiling by gene expression analysis is common. Several platforms are available, however, methods to analyze results vary. We previously used a transgenic mouse model of prostate cancer to identify target genes and developed a focused panel of immune-related genes. In addition, we designed a scoring system to profile the tumor's immune phenotype and assess tumor immune responses. Our aim is to extend the applicability of this analysis model to any platform capable of measuring these gene targets. As proof of concept for our analytical approach, we extended our assessment to human cancer by defining cancer specific immune profiles and assessing their clinical relevance. Our focused panel consisted of 115 genes (six reference/normalization genes and 109 immune-related genes) and our scoring system was based on an enrichment algorithm using various immune cell-specific signatures and immune related processes. We evaluated the robustness of this immunophenotyping approach using mRNA data from a cohort consisting of 8477 patients spanning 28 cancer types from The Cancer Genome Atlas (TCGA) Research Network. Our computational pipeline utilized unsupervised and machine learning approaches to identify and evaluate phenotype clusters from gene expression or immune signatures. In this study, Louvain clustering outperformed traditional hierarchical clustering. Using Louvain clustering, we identified distinct clusters from which immunophenotypes could be defined and compared these to various molecular and clinical features. Here, we summarize our findings and show that a minimal gene set effectively identified cancer immunophenotypes. This cross-species analysis corroborates our previous observation and paves the way for further development of our analysis model. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Hideki Nakagaki, Kazuto Nishio, Hirotsugu Uemura. Cross-species analysis and immunophenotyping using of a focused panel of immune-responsive genes [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 4468.
Abstract 1104: Folate intake and colorectal cancer risk during 36 years of follow-up in US women: A prospective cohort study
Authors: Fenglei Wang, Kana Wu, Yanping Li, Stephanie Smith-Warner, Edward Giovannucci, Walter Willett
Journal: Cancer Research (2020)

Abstract Background: Folate intake has been reported to be associated with a lower colorectal cancer (CRC) risk in several epidemiological studies. However, there are concerns about the potential for cancer promotion with an overly-abundant folate intake, especially after the mandatory folate fortification in the United States in 1998. Method: We investigated the association between folate intake and CRC risk among 83,165 women in the Nurses' Health Study, including 18 years of post-fortification follow-up; 2268 incident CRC cases were ascertained from 1980 to 2016. Folate intake from foods and supplements was assessed at baseline and updated every 4 years using a validated food-frequency questionnaire. Multivariate hazards ratios (HR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards regression. Results: Over the entire follow-up period (1980-2016), higher total folate intake was associated with a decreased risk of CRC (HRQ5vsQ1=0.80; 95% CI: 0.64-0.99). This association was stronger when total folate was assessed 12-24 years before CRC diagnosis. Multivitamin use for &amp;gt;15 years, but not a shorter duration of use, was associated with lower CRC risk. In the post-fortification period (1998-2016, n= 1169 CRC cases), high total folate intake (HRQ5vsQ1=0.80; 95% CI: 0.64-1.00) and current multivitamin uses, regardless of duration, were each associated with lower CRC risk. Conclusions: There was no evidence that high folate intake in the post-fortification period was related to increased CRC risk. Rather, high total folate intake was inversely associated with risk of CRC. Citation Format: Fenglei Wang, Kana Wu, Yanping Li, Stephanie Smith-Warner, Edward Giovannucci, Walter Willett. Folate intake and colorectal cancer risk during 36 years of follow-up in US women: A prospective cohort study [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 1104.
Abstract 521: CD45 targeted engineered toxin bodies deplete hematopoietic and malignant cells
Authors: Aimee Iberg, Garrett L. Robinson, Sara LeMar, Joseph D. Dekker, Jay Zhao, Hilario J. Ramos, Melissa M. Singh, Erin K. Willert
Journal: Cancer Research (2020)

Abstract CD45 is highly expressed on the cell surface of all nucleated hematopoietic cells, including malignant cells of B, T and myeloid lineage. CD45, a receptor tyrosine phosphatase that has important roles in antigen receptor signaling, has multiple isoforms that are differentially expressed on immune cell subsets. Targeting of CD45 with antibody-based therapies, tested in conjunction with reduced dose chemotherapy and radiation regimens, has shown promise in preclinical models and clinical trials as a conditioning therapy for bone marrow transplant (BMT), although these approaches are associated with safety limitations. A single agent, targeted conditioning method could increase patient safety and eliminate genotoxic effects associated with the conditioning regimens. Conditioning therapy by depletion of CD45 positive cells specifically has potential applications in oncology as well as non-oncologic, hematopoietic disease settings where engraftment of donor or modified stem cells could provide benefit. Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Targeted ETBs are being developed to specifically target and destroy CD45 expressing cells. ETBs targeting CD45 specifically bind to, internalize into and then trigger cell death of the target cells in vitro. ETBs have been designed using antibody fragments that recognize all isoforms of CD45. The CD45 targeted ETB has shown high potency in immortalized blood cancer cell lines of T cell, B-cell and eosinophil origin, including leukemia and lymphoma cell lines. Additionally, the ability of the CD45 targeted ETBs to deplete primary cells from healthy donors has been demonstrated. The direct cell kill activity of the CD45 targeted ETBs have the potential to deplete immune cells in the periphery and the bone marrow, as well as to deplete malignant hematological cells expressing CD45. In vivo depletion of human immune cells in murine models by CD45 targeted ETBs will be evaluated. Citation Format: Aimee Iberg, Garrett L. Robinson, Sara LeMar, Joseph D. Dekker, Jay Zhao, Hilario J. Ramos, Melissa M. Singh, Erin K. Willert. CD45 targeted engineered toxin bodies deplete hematopoietic and malignant cells [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 521.
Abstract 4271: Standardized approach for monitoring plasma cell disorders
Authors: Ulrika Johansson, Na Li, Suraj Saksena, Natalie Golts, Brent Gaylord
Journal: Cancer Research (2020)

Abstract Multi-color flow cytometry using consensus surface markers (CD138, CD38, CD19, CD45, CD27, CD56, CD81, and CD117), intracellular kappa and lambda, as well as other auxiliary markers is routinely being used for the identification and characterization of plasma cells. Here, we describe the development of a modular 10-color plasma cell panel for immunophenotyping of the plasma cell compartment. The panel was developed as an 8-color dried backbone, which can be supplemented with 2 liquid (drop in) reagents. Lyophilized or dried reagent cocktails in a unit test format are known to drive workflow efficiency in clinical settings by eliminating the need for manual cocktailing (of reagents), and frequent batch to batch verification procedures. Longer shelf life and room temperature storage are additional appealing features for lyophilized and dried products. We have developed a dried-down 8-color plasma cell panel, which is manufactured in a single test-per-tube, ready to use format, and can be supplemented with liquid (drop in) reagents. The flexibility of being able to add 2 liquid reagents to the dried backbone provides the option of using intracellular kappa and lambda to examine clonality or using CD38-multi-epitope and/or anti-p63 (VS38c) reagent(s). The single test-per-tube format is ideally suited for MRD applications, where sample size is limited and there is a need for acquiring a large number of events for data analysis. Also, the dried reagent panel is comprised of multiple high performing polymer dyes, which are brighter than conventional dyes, and afford high resolution of the relevant cell populations. Furthermore, the dried reagent tubes have a long shelf life (12 months) and significantly enhance the workflow efficiency. Comparison of the liquid and dried versions of the 10-color plasma cell panel using peripheral blood from healthy donors (as well as control cell lines) showed similar staining patterns, comparable population statistics, and fluorochrome brightness. The dried plasma cell tube(s) were also tested on bone marrow samples from healthy and diseased subjects in conjugation with intracellular staining for kappa and lambda. Our results demonstrate that the 10-color plasma cell panel can be used for identification of the plasma cell compartment (based on CD38 &amp; CD138 expression), assessment of aberrant marker expression (CD19, CD27, CD81, CD117, CD45, CD56) for the identification of normal and abnormal plasma cells, and examining clonality in multiple patient samples. Citation Format: Ulrika Johansson, Na Li, Suraj Saksena, Natalie Golts, Brent Gaylord. Standardized approach for monitoring plasma cell disorders [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 4271.
Abstract 3429: Targeting gain-of-function of mutant p53 C-terminal and oligomerization domains to disrupt activated DNA replication in breast cancer
Authors: Devon Lundine, George Annor, Viola Ellison, Gu Xiao, Carol Prives, Jill Bargonetti
Journal: Cancer Research (2020)

Abstract We recently documented that gain-of-function (GOF) mutant p53 (mtp53) R273H in triple negative breast cancer (TNBC) cells interacts with replicating DNA and PARP1 (Xiao et. al., Cancer Research 2019). The missense R273H GOF mtp53, without a functional central DNA binding domain, has the capacity to interact tightly with chromatin but it is unclear what regions of mtp53 are responsible for the chromatin-based DNA replication activities. GOF mtp53 proteins possess an intact C-terminal domain (CTD) and oligomerization domain (OD). In wild-type p53 the CTD and OD domain regulate non-specific DNA binding, post-translational modification, and protein tetramerization. We are targeting the CTD and OD regions of mtp53 to test if their disruption limits oncogenic GOF activity. We generated CRISPR/Cas9 edited R273H CTD and OD in the TNBC cell line MDA-MB-468, and also exogenously expressed such dual mutant proteins in p53 null cancers, to evaluate the roles played by oligomerization and non-specific DNA binding in mtp53 interactions with replicating DNA and PARP1. We determined the oligomerization state of R273H mtp53 using the glutaraldehyde crosslinking assay and observed that GOF mtp53 R273H mtp53 in breast cancer cells exists as a tetramer. Experiments are in progress to evaluate cell cycle progression, replication initiation, and mtp53 chromatin interactions in cells expressing missense mtp53 proteins with co-associated mutated CTDs or ODs. Our preliminary data suggests that disrupting the mtp53 CTD inhibits its interactions with chromatin and progression through the S-phase. Unpublished data on the roles played by the mtp53 CTD and OD in DNA replication will be presented at the 2020 AACR meeting. Acknowledgements: This work was funded by grants from the Breast Cancer Research Foundation BCRF-18-011 and BCRF-19-011 to Jill Bargonetti. Devon Lundine and Gu Xiao also received project support from TUFCCC/HC Regional Comprehensive Cancer Health Disparity Partnership, Award Number U54 CA221704(5) from the National Cancer Institute. Special thanks to Ella Freulich for help with CRISPR/Cas9 work and James J. Manfredi for mutant p53 plasmids to exogenously express protein. Citation Format: Devon Lundine, George Annor, Viola Ellison, Gu Xiao, Carol Prives, Jill Bargonetti. Targeting gain-of-function of mutant p53 C-terminal and oligomerization domains to disrupt activated DNA replication in breast 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 3429.
Abstract 3192: Quanticell, a novel histopathology technology for visualization and quantitation of membrane PSMA demonstrated in cell lines and clinical tissue
Authors: Hemi Dimant, Ankit Gandhi, Micheal Maker, Adam Markman, Jeanette Reinhardt, Stefan Collins, Jacob Hesterman, Joseph Krueger, Kenneth Bloom, Julie Bailis, Gloria Juan
Journal: Cancer Research (2020)

Abstract Prostate specific membrane antigen (PSMA), being both a biomarker and a therapeutic target, is important in prostate cancer (PC) diagnosis and treatment. Imaging and pathology are two of the most widely used approaches for PSMA detection in the diagnosis of PC. However, these techniques lack sensitivity for accurate assessment of low levels of PSMA expression and lack the capabilities to properly characterize heterogeneous PSMA expression. When using anti-PSMA imaging ligands, radiotherapies or immunotherapies, these drawbacks may ultimately prevent proper diagnosis and response prediction and could deny anti-PSMA treatment to qualified patients that have low PSMA expression. Better, more sensitive detection methods are needed for improved PSMA-based diagnosis and prediction of response. Quanticell is a novel histopathology technology utilizing fluorescent nanoparticles that are compatible with standard immunostaining practices. Combined with a dedicated software, Quanticell provides increased sensitivity and quantification and a wide dynamic range for improved detection and characterization of a broad range of target expression. A pilot study was conducted to demonstrate this technology on PSMA-expressing cell lines and clinical samples, and to evaluate its utility for discovery research and clinical studies. An anti-PSMA Quanticell protocol was developed and optimized on several PSMA-expressing cell lines, focusing on the lowest expressing sample. A dual-staining protocol for PSMA and a membrane marker was further developed to allow for detection and analysis of membrane-specific PSMA. Staining of negative and positive controls demonstrate high specificity to PSMA with high signal-to-noise that is not affected with increased primary concentration. When compared to DAB (diaminobenzidine) staining, we observed increased sensitivity in a low PSMA-expressing cell line, VCAP, indicated by increased detection of percent PSMA-positive cells. Additionally, using Quanticell, we demonstrate increased dynamic range in high expressing PSMA clinical samples compared to DAB staining, which is subject to saturation. Citation Format: Hemi Dimant, Ankit Gandhi, Micheal Maker, Adam Markman, Jeanette Reinhardt, Stefan Collins, Jacob Hesterman, Joseph Krueger, Kenneth Bloom, Julie Bailis, Gloria Juan. Quanticell, a novel histopathology technology for visualization and quantitation of membrane PSMA demonstrated in cell lines and clinical tissue [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 3192.
Abstract CT284: Phase 3 KEYNOTE-937: Adjuvant pembrolizumab versus placebo in patients with hepatocellular carcinoma and complete radiologic response after surgical resection or local ablation
Authors: Andrew Zhu, Masatoshi Kudo, Arndt Vogel, Thomas Yau, Jian Zhou, Eunhee Kim, Usha Malhotra, Abby B. Siegel, Ann-Lii Cheng
Journal: Cancer Research (2020)

Abstract Background: For patients with hepatocellular carcinoma (HCC) who are undergoing potentially curative surgical resection or local ablation, 5-year recurrence rates are up to 50%-80%; there is no standard of care for adjuvant treatment. The programmed death 1 inhibitor pembrolizumab is approved for the treatment of patients with HCC previously treated with sorafenib. There is no direct evidence of benefit with pembrolizumab in the HCC adjuvant setting, but a favorable benefit/risk profile is anticipated based on data from other indications. KEYNOTE-937 (NCT03867084) is a randomized, double-blind, phase 3 trial to examine the safety and efficacy of adjuvant pembrolizumab versus placebo in patients with complete radiologic response after surgical resection or local ablation of HCC. Methods: Eligible patients are aged ≥18 years and have confirmed HCC, complete radiologic response after complete resection or local ablation, Eastern Cooperative Oncology Group performance status of 0, and class A Child-Pugh score. Patients with past or ongoing HCV or controlled HBV are eligible if they meet certain criteria. Patients (N~950) will be randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks and stratified by geographic region, prior local therapy (resection vs ablation), recurrence risk, and alpha-fetoprotein level at diagnosis. Treatment will continue for up to 17 cycles (~1 year) or until documented disease recurrence, unacceptable toxicity, or investigator/patient decision to withdraw. Dual primary end points are recurrence free survival (RFS) and overall survival. Secondary end points are safety, tolerability, and quality of life. Exploratory end points include distant metastases-free survival (DMFS); time to recurrence (TTR); and genomic, metabolic, and/or proteomic biomarkers. RFS, DMFS, and TTR will be assessed radiographically by the investigator and/or by subsequent biopsy and confirmed by blinded independent central review. Adverse events (AEs), graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, will be recorded up to 30 days after last dose (90 days for serious AEs). Citation Format: Andrew Zhu, Masatoshi Kudo, Arndt Vogel, Thomas Yau, Jian Zhou, Eunhee Kim, Usha Malhotra, Abby B. Siegel, Ann-Lii Cheng. Phase 3 KEYNOTE-937: Adjuvant pembrolizumab versus placebo in patients with hepatocellular carcinoma and complete radiologic response after surgical resection or local ablation [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 CT284.
Abstract 153: Epigenetic loss of NSUN5 in glioma drives a global protein synthesis depletion along with the emergence of a stress adaptive translational program
Authors: Vanessa Ortiz Barahona, Maxime Janin, Manel Esteller
Journal: Cancer Research (2020)

Abstract One of the known hallmarks of cancer is an aberrant RNA transcriptome, and yet, it cannot always be fully due to genetic or epigenetic alterations at the transcriptional start sites of the genes. Indeed, recent evidences point out to new malignant alterations at the RNA level itself. RNA molecules have been found to show more than 100 differently chemically modified nucleotides, and such post-transcriptional modifications play a role in controlling RNA homeostasis, being all grouped under the term ‘epitranscriptome'. In our study, we reported that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate 5-methylcytosine RNA methyltransferase. As NSUN5 activity has not been formally described in human cells yet, we studied its potential targets in the human transcriptome, demonstrating its role in the methylation of the cytosine 3782 in the 28S ribosomal RNA (rRNA). Logically, we found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA, and this depletion drives an overall depletion of protein synthesis under stress conditions, analyzed by O-propargyl-puromycin (OP-Puro) and [3H] leucine incorporation into nascent proteins. However, together with the depletion of global protein synthesis, we observed the emergence of an adaptive translational program for survival under conditions of cellular stress, assessed by combining three NGS-experiments: RNA-seq, Ribo-seq and SILAC. Moreover, as one of the genes increasing its expression upon NSUN5 silencing is the stress-related enzyme NQO1, we found out that NSUN5-depleted gliomas are sensitive to bioactivatable substrates of the NQO1 enzyme. Most importantly, we observed that NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival, conferring it value as a predictor of better patient outcome for this otherwise devastating disease. Citation Format: Vanessa Ortiz Barahona, Maxime Janin, Manel Esteller. Epigenetic loss of NSUN5 in glioma drives a global protein synthesis depletion along with the emergence of a stress adaptive translational program [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 153.