bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1788: A novel costimulatory signaling domain for chimeric antigen receptor-engineering
Authors: Cho Hyun-Il , Kang Chung-Hyo , Lee Sang-Eun , Kim Mi-So , Lim Bo-Ra , Ha Jung-Min , Sohn Hyun-Jung , Kim Tai-Gyu 
Published: April 2023

Abstract
Chimeric antigen receptor (CAR)-engineered adoptive cell therapy has demonstrated a feasible, attractive “off-the-shelf” approach against various malignancies. Success of CAR-engineered cell therapy depends primarily on providing optimized costimulatory signals capable of achieving robust cell proliferation, persistence, and antitumor reactivity. We describe here the capability of a novel CD30-derived costimulatory signaling domain to generate effective CAR-redirected cells capable of eradicating hematological and solid cancers. After establishing CD19-redirecting second-generation CARs incorporating the CD30-derived intracellular signaling domain and third-generation CARs combining CD30 with either CD28 or 4-1BB, the effector functionality of CAR-transduced T cells was assessed in vitro and in vivo. Further, we evaluated the efficacy of epithelial cell adhesion molecule (EpCAM)-targeting third-generation CD30-encompassing CAR constructs for targeting solid tumors. The CD30-signaling CAR-T cells exhibited similar levels of cell proliferation, cytolytic efficacies, and cytokine secretion in vitro, and demonstrated improved tumor regression and prolonged survival in vivo with increased persistence of the CAR-T cells as those of other CARs with CD28 or 4-1BB costimulatory domain, which are currently in clinical use. Also, third-generation CARs including the CD30 costimulatory domain retained potent antitumor efficacies in vitro and in vivo independent of their position or type of partner costimulatory domain. More significantly, EpCAM-targeting CAR-T cells containing CD30-signaling domain revealed effective cytolytic activities correlating with EpCAM expression levels in the target cells. Our results demonstrate that the CD30-derived costimulatory domain could be an alternative for developing CAR-engineered therapeutics which may be applicable for various designs of CAR constructs, with an emphasis on effectiveness against solid tumors.
Citation Format: Hyun-Il Cho, Chung-Hyo Kang, Sang-Eun Lee, Mi-So Kim, Bo-Ra Lim, Jung-Min Ha, Hyun-Jung Sohn, Tai-Gyu Kim. A novel costimulatory signaling domain for chimeric antigen receptor-engineering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1788.
Abstract 1823: Overcoming siglec-9-mediated immunosuppression by using glycomimetics that block the binding of this receptor with its natural ligands
Authors: AlJohani Lojain I. , Patankar Manish , Tang Weiping , Stevens Christopher , Teng Peng 
Published: April 2023

Abstract
MUC16, a 3-5 million Da mucin overexpressed by ovarian cancer cells binds to Siglec-9, an inhibitory receptor on immune cells. Upon binding to Siglec-9, MUC16 triggers inhibitory signaling in the immune cells that allows ovarian cancer cells to evade cytolytic immune responses. Ovarian and other tumors express a plethora of cell surface as well as secreted glycoproteins with glycans that are terminated with the Siglec-9 ligand, α-2,3-linked sialic acid. Therefore, targeting the sialic acid-Siglec-9 axis has been of major interest to augment antitumor immunity. Here, we demonstrate that synthetic glycomimetic Siglec-9 ligands have the potential to enhance the immune recognition of ovarian cancer cells. We first demonstrate, using siglec-9 chimeras, that the glycomimetics developed by our group inhibit the binding of Siglec-9 to its natural ligands. Our data showed that 50-fold excess of the glycomimetics over Siglec-9 chimera prevented the Siglec-9 chimera from binding to the OVCAR-3 cell line (P.value, 0.039). Additionally, we demonstrate that glycomimetics (#153 and 157) developed by our group, enhance the recognition of ovarian cancer cell targets by human NK cells. In healthy donor 1, CD107a expression was increased (21, 17, 19 %) when 0.01, 0.025, 0.05 mM concentration of glycomimetic 153 was used, respectively. A statistically significant increase (5%) in CD107a expression was observed when the NK cells were treated with 0.05 mM concentration of glycomimetic 157. At higher concentrations of glycomimetic 153 and 157, inhibition of CD107a was repeatedly observed. These experiments, therefore, suggest that there is likely a certain concentration range of the glycomimetic that can be used to overcome NK cell suppression occurring via Siglec-9. To our knowledge, these data are among the first to demonstrate that specially designed glycomimetics can be used to overcome the suppression of NK cells against ovarian cancer cells. Future studies will employ murine and humanized models to demonstrate the therapeutic potential of the Siglec-9-targeting glycopeptides in enhancing immune responses against epithelial ovarian cancer.
Citation Format: Lojain I. AlJohani, Manish Patankar, Weiping Tang, Christopher Stevens, Peng Teng. Overcoming siglec-9-mediated immunosuppression by using glycomimetics that block the binding of this receptor with its natural ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1823.
Abstract 1946: Development and application of genetic ancestry reconstruction methods to study diversity of patient-derived models in the NCI PDXNet Consortium
Authors: Sanderson Brian J. , Lott Paul , Chiu Katherine , Quino Juanita Elizabeth , Vang April Pangia , Lloyd Michael W. , Consortium PDXNet , Srivastava Anuj , Chuang Jeffrey H. , Carvajal-Carmona Luis G. 
Published: April 2023

Abstract
Personalized medicine holds great promise for improving cancer outcomes, yet there is a large inequity in the demographics of patients from whom genomic data and models, including patient derived xenografts (PDX), are developed and for whom treatments are optimized. In this study we develop a genetic ancestry pipeline for the Cancer Genomics Cloud, which we use to assess the diversity of models currently available in the National Cancer Institute (NCI) supported PDX Development and Trial Centers Research Network (PDXNet). We show that there is an over-representation of models derived from patients of European ancestry, which is consistent with other cancer model resources. We discuss these findings in the context of disparities in cancer incidence and outcomes among demographic groups in the US. For example, for the top cancer health disparities affecting African Americans and Latinos, there is a significant lack of ethnic/race appropriate models needed to advance pre-clinical research and personalized clinical treatment. For stomach and liver tumors, which represent disparities in these two minority populations, there are only three available models derived from patients from such backgrounds. Fortunately, ongoing NCI-funded efforts in minority focused PDXNet centers are actively addressing these gaps. We further discuss these results in the context of power analyses to highlight the immediate need for the development of models from minority populations to address cancer health equity in personalized medicine.
Citation Format: Brian J. Sanderson, Paul Lott, Katherine Chiu, Juanita Elizabeth Quino, April Pangia Vang, Michael W. Lloyd, PDXNet Consortium, Anuj Srivastava, Jeffrey H. Chuang, Luis G. Carvajal-Carmona. Development and application of genetic ancestry reconstruction methods to study diversity of patient-derived models in the NCI PDXNet Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1946.
Abstract 2040: Molecular dynamic simulation of intermediates connecting KRAS and PRMT5 insight for targeting KRAS
Authors: Silverman Isaac V. , Stein Yitzchak F. , Gerber Michael Shawn , Maitra Radhashree , Goel Sanjay 
Published: April 2023

Abstract
Introduction: Therapeutic approaches to target mutant KRAS is in progress, and transcription regulator PRMT5 (Protein arginine methyltransferase) has been previously reported to be a viable, surrogate target. Mutation of oncogenic KRAS is prevalent in several cancer types often rendering aggressiveness to the disease. Herein we used extensive molecular dynamics simulations to understand the intermediate complexities of the cross-talk.
Methodology: GROMACS is a Molecular Dynamics Simulation software that renders a topology regulated by Newton’s Laws that can be employed to simulate interactions between proteins. Utilizing the STRING database, multiple pathways from KRAS linked to PRMT5 were extrapolated. Confidence values were determined. Protein complexes were downloaded from RCSB archives. Protein pairs were submitted to HDOCK for docking. Proteins were separated by chain identities, using PYMOL. Proteins were solvated and paired in GROMACS, and charges were neutralized. Each complex underwent energy minimization to configure the proteins in the most energetically favorable conformation. The complex was equilibrated and simulated. XmGrace was used to graph radius gyration between both proteins and their stabilities. The data produced were used to analyze the favorable interaction of the various pathways.
Results: Three pathways were analyzed, with high, intermediate, and low confidence values of interaction. The intermediate mediators were simulated in pairs and energy scoring was performed for each interaction. The radius of gyration (Rg) values was calculated for each protein in its respective pathway. A cutoff of 10 nanoseconds was used to confirm stability. A scale was constructed to predict the order of operations of each pathway. HRAS was determined to be actively involved in the crosstalk.
Conclusion: The crosstalk between PRMT5 and KRAS can be achieved through three different biochemical pathways with varying levels of confidence. Potentially, if one pathway is affected, an alternative route could be activated to achieve signaling toward PRMT5. These pathways introduce a more targeted approach toward discovering therapeutic advances against KRAS. More simulations are underway to compare the interactions of wildtype and mutant KRAS with their respective pathway intermediates.
Citation Format: Isaac V. Silverman, Yitzchak F. Stein, Michael Shawn Gerber, Radhashree Maitra, Sanjay Goel. Molecular dynamic simulation of intermediates connecting KRAS and PRMT5 insight for targeting KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2040.
Abstract 2204: Predicting survival outcomes in patients with acute myeloid leukemia: medium-sized versus large next-generation sequencing panels
Authors: Li Yonghong , Solis-Ruiz Jose , Racke Frederick K. , Press Richard D. 
Published: April 2023

Abstract
Background: Next-generation sequencing (NGS) multigene panels allow the identification of genetic variants in patients with acute myeloid leukemia (AML). This study assessed the effect of the NGS panel size on positivity rate and clinic utility in helping predict survival outcomes.
Design: This is a retrospective study of AML patients (n=76) who underwent both diagnostic and post-treatment testing with a large 220-gene NGS assay. Mutation profiles and measurable residual disease (MRD) status were assessed with the large panel or a subset of the genes on the panel (i.e., a medium-sized panel with 42 genes); MRD assessment excluded DTA mutations (i.e., mutations in preleukemic genes DNMT3A, TET2 and ASXL1). Kaplan-Meier method was used to compare overall survival between MRD positive and negative patients.
Results: The 76 patients evaluated were diagnosed with de novo AML (n=69) or secondary AML (n=7). The median age at diagnosis was 57 (interquartile range [IQR], 49-66) years; 37 (49%) were women; and the median follow-up was 273 (IQR, 174-473) days. At diagnosis, the medium-sized panel detected 276 somatic variants in 35 genes (average 3.6 variants per patient) whereas the large panel detected 351 somatic variants in 74 genes (average 4.6 variants per patient). These variants were frequently detected in methylation and epigenetic genes (25%), signaling genes (20%) and transcription factors (12%). After treatment, MRD-negativity was indicated in 27 patients by the medium-sized panel versus 23 patients by the large panel; MRD-positivity was indicated in 49 patients by the medium-sized panel versus 53 patients by the large panel. Shorter overall survival was associated with MRD-positivity as determined by both panels: medium-sized panel (hazard ratio [HR], 3.00; 95% CI, 1.01-8.93; P&lt;.05), large panel (HR, 3.41; 95% CI, 1.00-11.57; P&lt;.05).
Conclusion: A medium-sized NGS panel detected fewer somatic mutations than large NGS panel but both panels, when used as MRD markers, are similarly predictive of overall survival in AML patients.
Citation Format: Yonghong Li, Jose Solis-Ruiz, Frederick K. Racke, Richard D. Press. Predicting survival outcomes in patients with acute myeloid leukemia: medium-sized versus large next-generation sequencing panels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2204.
Abstract 2235: A treatment for glioblastoma with a novel epigenetic inhibitor and identification of its target
Authors: Kota Tokunaga 
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) is one of the deadliest human cancers. Despite extensive efforts to develop a new treatment, the prognoses of patients have not changed dramatically over the past several decades. LSD1 plays an essential role in the epigenetic regulation of gene expression in many cancer cells, including GBM, as it removes methyl groups from histone H3 lysine (K) 4me1/2 and H3K9me1/2. Since it was reported that suppression of LSD1 induced apoptosis of glioblastoma stem cells (GSCs), LSD1 has been expected as an effective therapeutic target for GBMs, particularly enriched with GSCs. We newly discovered an LSD inhibitor (S2172) that suppressed the LSD1 enzymatic activity effectively and sufficiently penetrated into brain. We found that S2172 showed a strong inhibitory effect on cell growth not only in GCS cells but also in differentiated GBM cells in vitro. In GBM cell line U251, IC50 of S2172 was lower than that of other LSD1 inhibitors (IC50 10.5 μM, 29.5 μM, 11.0 μM treated with S2172, Ory-1001, and CC-90011, respectively). We also found a robust suppression of transcription of oncogene Myc in differentiated GBM cells after S2172 treatment, which is highly expressed in most GBM cells and considered as a key element to maintain its stemness and proliferation. Consistent with the expression analysis, chromatin immunoprecipitation-sequencing (ChIP-seq) revealed that enrichment of H3K4m2 and H3K4m3 was efficiently altered by S2172 treatment along with the change of Myc expression. Finally, we treated U251 brain tumor mouse model with S2172. While S2172 had a strong effect in vitro, S2172 seemed unsuccessful in killing differentiated GBM cells in vivo. These data suggests that treatment of S2172 is less effective to differentiated GBM cells and this is consistent with previous report that LSD1 as a candidate therapeutic target in stem-like tumor propagating cells in GBM.
Citation Format: Tokunaga Kota. A treatment for glioblastoma with a novel epigenetic inhibitor and identification of its target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2235.
Abstract 2263: Complete remission of a patient with Merkel cell carcinoma treated with durvalumab
Authors: Sabbagh Saad , Dominguez Barbara , Sater Houssein Abdul 
Published: April 2023

Abstract
Merkel cell carcinoma (MCC) is a rare, cutaneous, neuroendocrine tumor that is highly aggressive. It is the second leading cause of death from skin cancer, after melanoma, despite accounting for less than 1% of malignant skin tumors. Due to the characteristic histopathological neuroendocrine features of the neoplasm, cases of MCC are often misdiagnosed as undifferentiated skin cancers or other tumors with small blue cell types. Clinical examination fails to establish the diagnosis in 99% of cases and pathological assessment by biopsy with immunohistochemistry is essential to confirm MCC diagnosis. Historically, cytotoxic chemotherapy combinations with platinum-based agents (Carboplatin or Cisplatin) plus Etoposide or Cyclophosphamide, Epirubicin, and Vincristine (CAV) agents were the primary systemic treatment for advanced cases. Despite available evidence sensitivity of MCC to chemotherapy, responses are not durable, and the literature is not supportive of combination chemotherapy (NCCN guidelines). The introduction of immunotherapy such as checkpoint inhibitors (ICI) particularly PD-1/PD-L1 blockers increased overall survival and achieved durable tumor regression in clinical trials leading to FDA approval in locally advanced and metastatic disease. Permbrluzimab and Avelumab are the only two FDA-approved ICIs as first-line standard-of-care treatments for MCC patients. What we are missing is data or trials examining the efficacy of other ICI such as Durvalumab, (anti-PD-L1) in MCC. We hereby report an unprecedented case of an 84-year-old female MCC patient with extensive axillary nodal involvement achieving complete remission after treatment with Durvalumab combined with Carboplatin and Etoposide.
Citation Format: Saad Sabbagh, Barbara Dominguez, Houssein Abdul Sater. Complete remission of a patient with Merkel cell carcinoma treated with durvalumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2263.
Abstract 2316: Automating ctDNA liquid biopsy workflow for mutation testing: From sample extraction to dPCR analysis utilizing the Maxprep™ Liquid Handler, Maxwell® extraction system, and high-plex detection assays
Authors: Granitsiotis Michael , Gutierrez Kimberly , Horejsh Doug , Yue Monica 
Published: April 2023

Abstract
Liquid biopsies are a minimally-invasive sampling approach to overcome the heterogeneity of tumors and represent a valuable source of circulating tumor DNA (ctDNA) for oncological biomarker analysis. The use of ctDNA as a surrogate for tissue DNA is increasingly popular, and advances in the detection and characterization of ctDNA has enabled liquid biopsy assay integration into clinical utilization. However, an innate challenge with measurement of ctDNA is the requirement for highly sensitive quantitation to reliably detect rare genetic aberrations. Digital PCR has emerged as a powerful technology addressing the needs for next-generation analysis of liquid biopsies samples. Having reliable assays for analysis of key oncology targets help drive adoption of this technology into real-world applications. The exquisite sensitivity of digital PCR requires sample preparation methods that reduce variation, making automation of any manual steps highly desirable. Automation also provides flexibility to scale up as testing volumes increase while simultaneously decreasing overall complexity for the operator. Here we present an automated workflow for ctDNA extraction and analysis using the Maxprep™ Liquid Handler, Maxwell® extraction system (Promega Corporation), and a new, high-throughput digital PCR consumable, the Ruby Chip (Stilla Technologies). This ultra-sensitive detection for liquid biopsy samples was performed using a high-plex dPCR assay.
Citation Format: Michael Granitsiotis, Kimberly Gutierrez, Doug Horejsh, Monica Yue. Automating ctDNA liquid biopsy workflow for mutation testing: From sample extraction to dPCR analysis utilizing the Maxprep™ Liquid Handler, Maxwell® extraction system, and high-plex detection assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2316.
Abstract 2501: A glioblastoma and blood-brain barrier in vitro model to assess the tumor microenvironment and temozolomide resistance
Authors: Lam Maxine S. , Aw Joey , Tan Damien , Vijayakumar Ragavi , Gordon Khloe S. , Birnbaum Michael E. , Sobota Radoslaw M. , Adriani Giulia , Pavesi Andrea 
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a dismal prognosis. Currently, Temozolomide (TMZ) and Bevacizumab are the main approved agents for primary and recurrent GBM, respectively. However, TMZ resistance is frequent and Bevacizumab does not improve overall survival. The heterogeneity of GBM and the presence of a highly selectively permeable blood-brain barrier (BBB) preclude the use of chemotherapeutics approved for other malignancies. Meanwhile, new therapy development is limited in part because most pre-clinical models do not recapitulate the key features of GBM that are relevant to therapy resistance and drug delivery. This is particularly important when validating immunotherapies such as engineered T cell therapy, which has shown some promise in the clinics. We therefore developed an in vitro 3D model that recapitulates the major features of the GBM tumor microenvironment (TME) that are involved in therapy resistance, including the dense tumor core and infiltrating invasive front observed in clinical tumors, surrounded by a perfusable BBB with a physiological permeability. With this model, we investigate the angiogenic nature of GBM, and the role of tumor organization and the TME in TMZ resistance and immunosuppression. We find that TMZ sensitivity decreases as complexity of tumor cell 3D organization increases, and identify pathways potentially associated with TMZ resistance and immunosuppression using proteomics and genomics approaches. Additionally, we find that tumor-associated vasculature has a higher permeability due to VEGFA from GBM tumors, which leads to the downregulation of endothelial junction proteins. Using an IL13Ra2-targetting chimeric antigen receptor (CAR) T cell as a model for engineered T cell therapy, we find that tumor-associated vasculature acts as a physical barrier to CAR-T cell extravasation, significantly impeding CAR-T cell efficacy. We then use the model to screen a CAR library to identify novel CAR combinations that can improve CAR-T cell extravasation and cytotoxicity in GBM.
Citation Format: Maxine S. Lam, Joey Aw, Damien Tan, Ragavi Vijayakumar, Khloe S. Gordon, Michael E. Birnbaum, Radoslaw M. Sobota, Giulia Adriani, Andrea Pavesi. A glioblastoma and blood-brain barrier in vitro model to assess the tumor microenvironment and temozolomide resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2501.