bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4227: NL-201, a de novo agonist of IL-2 and IL-15 receptors, demonstrates antitumor activity in preclinical B cell lymphoma models
Authors: Huard Justin , Mortales Christie , Chen Alex , Swanson Ryan , Walkey Carl , Arthur Bill 
Published: June 2022

Abstract
NL-201 is a computationally-designed IL-2/IL-15 cytokine mimetic under investigation in a phase 1 clinical trial for patients with solid tumors. This de novo protein signals through the IL-2Rβ/ɣ complex in an IL-2Rα-independent fashion, supporting immune function of both T cells and natural killer (NK) cells. In syngeneic tumor models of solid tumors, NL-201 demonstrates marked antitumor activity through multiple mechanisms of action, including upregulation of granzyme B in cytotoxic CD8+ T cells and NK cells. Here, we further explored the therapeutic potential of NL-201 in preclinical models of B cell malignancies. In cell-based studies, NL-201 augmented antibody-dependent cellular cytotoxicity (ADCC) of Toledo DLBCL (diffuse large B cell lymphoma) cells incubated with human NK cells and CD20 antibodies. Importantly, direct activation by NL-201 was specific to NK cells and did not impact STAT5 phosphorylation nor proliferation of the tested malignant cells. The administration of NL-201 monotherapy in mice bearing A20 B cell lymphoma syngeneic tumors yielded robust inhibition of tumor growth. Tumor xenografts from implanted Pfeiffer cells have also been evaluated to understand the activity of NL-201 in a model closely resembling DLBCL physiology. In summary, NL-201 is active as a single agent and in combination with CD20-targeted therapies in vitro, as well as demonstrating monotherapy activity in in vivo preclinical models of B cell malignancies as well as in combination with checkpoint inhibitors. The NL-201 enhancement of cytotoxicity by CD8+ T cells and NK cells supports additional exploration aimed at optimizing combinatorial approaches. These findings will inform the design of planned clinical studies with NL-201 in patients with B-cell lymphomas and other hematological malignancies.
Citation Format: Justin Huard, Christie Mortales, Alex Chen, Ryan Swanson, Carl Walkey, Bill Arthur. NL-201, a de novo agonist of IL-2 and IL-15 receptors, demonstrates antitumor activity in preclinical B cell lymphoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4227.
Abstract 4239: Development of multi-targeting immunomodulatory SeekR RNA therapeutics to overcome resistance to PD-1 blockade
Authors: O'ketch Marvin , Love Victoria A. , Kiefer Jeffrey A. , Lee David W. , Castaño Lizette A. , Mousses Spyro , Azorsa David O. 
Published: June 2022

Abstract
T-cell exhaustion describes the dysfunctional state of effector T cells in the tumor microenvironment that results from chronic and prolonged exposure to antigen. It also represents an important mechanism of clinical resistance to immune checkpoint blockade. Recently, the transcription factor NR4A1 has been shown to be upregulated in tumor-specific T cells and plays a role in driving exhaustion during chronic antigen stimulation of T cells. Pro-oncogenic activities of NR4A1 have long been observed in various solid tumors including colorectal and breast cancers, and co-expression of NR4A1 with known immune checkpoint markers such as PD-L1 have also been observed in various cancer cell lines. These findings have identified NR4A1 as an important target for overcoming resistance to cancer immunotherapy. We hypothesize that multi-targeting to simultaneously block PD-1 signaling and silence NR4A1 gene expression can reverse T-cell exhaustion and expand the clinical benefit of PD-1 blockade in immune therapy resistant solid tumors. Using our SeekR™ RNA therapeutics platform, we combined aptamer binders to PD-1 with siRNA against NR4A1, andNR4A1 and evaluated their ability to reverse T-cell exhaustion and re-activate T-cell based anticancer immunity in solid tumors. Specifically, we created SeekR™ therapeutic RNA molecules with dual flanking RNA aptamers binders to PD-1 and other checkpoint inhibitors, connected by a double stranded bridge that encodes for siRNA silencers that target multiple immunomodulatory genes, such as NR4A1. The novel anti-PD-1 RNA aptamer component serve to: A) direct and deliver the SeekR™ RNA oligo therapeutics to exhausted T-cells that express PD-1 receptors; and B) internalize the siRNA component into the T-cells. The siRNA components of the SeekR™ serve to silence NR4A1 which lead to reversal of the cytotoxic T-cell exhausted phenotype following chronic in-vitro stimulation. These results demonstrate that dual targeting of PD-1 and NR4A1 has the potential to reverse T-cell exhaustion and the potential to overcome cancer immunotherapy resistance in the clinic.
Citation Format: Marvin O'ketch, Victoria A. Love, Jeffrey A. Kiefer, David W. Lee, Lizette A. Castaño, Spyro Mousses, David O. Azorsa. Development of multi-targeting immunomodulatory SeekR RNA therapeutics to overcome resistance to PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4239.
Abstract 424: Development of HJC0152-based proteolysis-targeting chimera degraders for breast cancer therapy
Authors: Xu Junhai , Xu Jimin , Ma Ruixia , Zhou Mingxiang , Fricke Doerte R. , Chen Haiying , Kim Hyejin , Liu Xi , Zhou Jia , Shen Qiang 
Published: June 2022

Abstract
Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, is constitutively activated in various human cancers, and has been recognized as an attractive therapeutic target in cancer. STAT3 protein dimerizes and translocates to the nucleus to eventually transactivate downstream target genes. Despite some progress has been made in the past two decades, to date there is still lack of FDA-approved STAT3 inhibitors available for clinical use. Recently, proteolysis-targeting chimera (PROTAC) technology has dramatically advanced the development of therapeutics by introducing targeted protein degradation. Previously, our team has developed HJC0152, a promising STAT3 inhibitor, via structure- and fragment-based drug design strategies and in silico molecular modeling and docking. HJC0152 has demonstrated an attractive cancer therapeutic and preventive efficacy by targeting the non- estrogen receptor (ER)-based STAT3 signaling pathway. To achieve better potency and inhibition of STAT3 signaling, we therefore developed a series of HJC0152-based PROTAC protein degraders. These potential anticancer agents have been initially evaluated and several showed favorable potency in inhibiting the proliferation in a panel of breast cancer cell lines. We found that compounds JMX1122, JMX1123, and JMX1124 significantly inhibited proliferation and colony formation of a highly aggressive triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and the ER-positive breast cancer cell lines. Different from the lead compound HJC0152, which showed an early inhibition on the phosphorylation of STAT3 at the Tyr705 and Ser727 residues, the newly developed HJC0152-PROTACs showed a significantly late differential inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues, and reduced the total STAT3 protein level at 72 hours of treatment. Our current results support the notion that HJC0152-based PROTAC degraders potently suppress breast cancer cell proliferation and induce apoptosis, via direct targeting of STAT3 and its protein degradation. These compounds are currently being investigated for breast cancer cell migration and invasion, and will be evaluated for the in vivo inhibition of tumor growth and metastasis in different mouse models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z.
Citation Format: Junhai Xu, Jimin Xu, Ruixia Ma, Mingxiang Zhou, Doerte R. Fricke, Haiying Chen, Hyejin Kim, Xi Liu, Jia Zhou, Qiang Shen. Development of HJC0152-based proteolysis-targeting chimera degraders for breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 424.
Abstract 436: Rapid flow cytometric whole blood assay for assessment of SARS-CoV-2-reactive T cell immunity
Authors: Fülle Lorenz , Gert Philipp David , Traska Verena , Chatzopoulou Sofia , Dose Christian , Richter Anne , Schuster Marc 
Published: June 2022

Abstract
As of November 2021, the viral pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has infected more than 250 million individuals worldwide and killed over 5 million people. In addition to known risk groups, also cancer patients are at increased risk for severe disease progression. Therefore, understanding the nature of the accompanying immune response is essential, especially the role of T cells for successful virus defense but also during immunopathology leading to severe disease outcomes. Furthermore, as neutralizing antibodies are reported to decay within months post infection or vaccination or are even absent due to cancer treatment, SARS-CoV-2-specific T cell persistence is discussed as an indicator of long-term protective immunity. Especially, in immunocompromised cancer patients, levels of SARS-CoV-2-specifc antibodies may not be efficiently detected. Therefore, we developed a rapid and easy flow cytometric assay for the analysis of SARS-CoV-2-reactive CD4+ and CD8+ T cells directly from whole blood.
Citation Format: Lorenz Fülle, Philipp David Gert, Verena Traska, Sofia Chatzopoulou, Christian Dose, Anne Richter, Marc Schuster. Rapid flow cytometric whole blood assay for assessment of SARS-CoV-2-reactive T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 436.
Abstract 5043: Predicting melanoma staging using targeted RNA sequencing data using machine learning
Authors: Ahmed Fahad Shabbir , Irfan Furqan Bin 
Published: June 2022

Abstract
Introduction: Cancer staging can take essential time and expenses away from patients, both of which should be patients’ management. In this current study, we aim to develop a machine learning-based early TNM staging model.
Methods: Normalized ribonucleic acid sequencing (RNA-seq) counts data for melanoma patients was extracted from The Cancer Genome Atlas (TCGA). Six different experiments were run to produce machine learning algorithms for nodal metastasis, distant metastasis, combine (nodal or distant) metastasis, and higher vs lower tumor stage (T4/T3 vs T2/T1/Tis). All datasets were split using 80/20 for training and test sets. Synthetic Minority Oversampling Technique (SMOTE) was used to address the imbalanced distribution of the outcome. The algorithm accuracies were determined by a percent of sensitivity, specificity, predictive values (positive and negative: PPV and NPV), and area under the receiver-operator curve (AUROC).
Results: The best model for nodal metastasis was a random forest classifier (RF) with targeted gene expression (TE) showed higher sensitivity (98), specificity (100), PPV (100), NPV (94), and AUROC (1.00, 95%CI 0.91-0.99). TE for distant metastasis with RF, showed sensitivity (0), specificity (100), PPV (0), NPV (100), and AUROC (1.00, 95%CI 0.91-1.00). While TE for combined metastasis (nodal or distant) staging algorithm; Nodal or Distant Metastasis (TE) RF, showed sensitivity (98), specificity (100), PPV (100), NPV (99), and AUROC (1.00, 95%CI 0.88-0.98). The tumor staging (DEG and predicting higher stage i.e stage 3 or higher) algorithm; Tumor Staging (TE) RF, showed sensitivity (100), specificity (100), PPV (100), NPV (100), and AUROC (1.00, 95%CI 0.69-0.89) (Table 1).
Conclusion: Our machine learning models can predict tumor staging including higher vs lower stage tumor, nodal metastasis, and combined metastasis with high accuracy. However, these results need to be further validated.
Table 1. Machine learning models Experiment Sensitivity Specificity PPV NPV AUROC 95%CI Test Set Accuracy N Nodal Metastasis (Pan-Expression) DNN 66.22 16.98 52.69 26.47 0.495 0.25-0.47 54.55 479 Nodal Metastasis (Targeted Expression) DNN 81.13 100.0 100.0 88.10 0.982 0.62-0.83 90.21 479 Nodal Metastasis (Targeted Expression) RF 97.89 100.00 100.00 94 1.00 0.91-0.99 96.74 458 Distant Metastasis (Targeted Expression) RF 0.00 100.00 0.00 100 1.00 0.91-1.00 94.44 450* Nodal or Distant Metastasis (Targeted Expression) RF 97.56 100.00 100.00 98.56 1.00 0.88-0.98 98.91 458 Tumor Staging (Targeted Expression) RF 100.00 100.00 100.00 100.00 1.00 0.69-0.89 100.00 395 *27 cases with distant metastasis
Citation Format: Fahad Shabbir Ahmed, Furqan Bin Irfan. Predicting melanoma staging using targeted RNA sequencing data using machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5043.
Abstract 5067: Identify the combination efficacy and immune regulation of Abraxane combines with human IL-15 albumin binding domain fusion protein on pancreatic ductal adenocarcinoma animal model
Authors: Yueh Po-Fu , Hsu Fei-Ting , Lan Keng-Li 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the hardest medical challenge in the world. Nab-paclitaxel is significantly more effective chemotherapy drugs than paclitaxel formulated as Cremophor EL. In this study, we reported the immune effect of Abraxane to combine with our new design recombinant human IL-15 fused with albumin binding domain (hIL-15-ABD) on subcutaneously Panc02 and orthotopically KPC PDAC animal models. In our results, the combination treatment greatly reduced the subcutaneous tumor growth in Panc02 and KPC bearing models, compared with vehicle group. Furthermore, the combinational therapy successfully buildup the anticancer immunity microenvironment (TME) through increasing the activation of effector cells, such as of NK cells (CD3-/CD49b+/NK1.1+) and CD8+ T (CD8+/IFN-γ+/IL-2+) cells. Moreover, combination therapy may also decrease the accumulation of immunosuppressvie cells such as MDSCs (CD11b+/Gr-1+) and Tregs (CD4+/CD25+/Foxp3+). The combination of Abraxane and hIL-15-ABD were also reduced the NF-κB-mediated immunosuppressive markers, including IDO, Foxp3 and VEGF. In conclusion, Abraxane combined with hIL-15-ABD enhanced immue effector cells involved in both innate and adaptive immunities, reduced the TME’s immunosuppressive cells, and displayed superior inhibitory effect on both subcutaneous and orthotopic syngeneic murine pancreatic ductal adenocarcinoma models than that of either monotherapy. These results suggest that combinational therapy of Abraxane and hIL-15-ABD could be a promising treatment stratedgy for PDAC.
Citation Format: Po-Fu Yueh, Fei-Ting Hsu, Keng-Li Lan. Identify the combination efficacy and immune regulation of Abraxane combines with human IL-15 albumin binding domain fusion protein on pancreatic ductal adenocarcinoma animal model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5067.
Abstract 5089: RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer
Authors: Yu Changjun , Kang Weibiao , Yuan Yu , Zhang Junling , Huang Mengli , Chen Yanan , Xia Xihua , Bai Yuezong 
Published: June 2022

Abstract
Background: RNF43, a single transmembrane circular E3 ubiquitin ligase, has been identified as a tumor suppressor for a variety of cancers, including ovarian cancer, gastric cancer, pancreatic cancer, endometrial cancer and colorectal cancer. It is even considered to be carcinogenic driver mutations in cholangiocarcinoma, ovarian cancer, gastric cancer, endometrial cancer and colorectal cancer (CRC). However, the correlation between RNF43 mutation and CRC immunotherapy has not been reported yet.
Methods: We evaluated the role of RNF43 in CRC using publicly available data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). An in-house Chinese CRC cohort (n=2290) was used for the analysis of immune-related markers. The relationship between clinical pathologic features and RNF43 were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method.
Results: In the MSKCC cohort, a total of 108 CRC patients receiving immunotherapy were enrolled, of which 38 (34.9%) were over 60-year-old and 61 (56.0%) were male. RNF43 mutation was significantly associated with high TMB and high MSI score (all p &lt;0.05). Besides these, RNF43 mutation was discovered to be enriched in MSI instable. Kaplan-Meier survival analysis showed that patients with RNF43 mutation obtained better OS compared to RNF43 wild-type (not reach vs. 13 months, HR, 0.12; 95% CI 0.03-0.49; p=0.0034). In the TCGA cohort, CRC patients of stage I-IV were 16.6%, 38.5%, 28.2% and 14.2%, respectively. All of these patients received radiation therapy. No association was observed between RNF43 and OS (HR, 1.83; 95% CI 0.66-5.07; p=0.2479). In the in-house Chinese CRC cohorts, 210 (9.2%) patients carried RNF 43 mutations, of which 123 patients (58.6%) were male. RNF43 mutations were significantly associated with higher TMB levels (p&lt;0.0001) and PD-L1 TPS&gt; 1% (p=0.0110) in the in-house Chinese RCC cohorts.
Citation Format: Changjun Yu, Weibiao Kang, Yu Yuan, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5089.
Abstract 5123: Establishing circulating tumor cell-derived xenografts following a period of in vitro culture
Authors: Xiao Jerry , Schlegel Richard , Agarwal Seema 
Published: June 2022

Abstract
Cancer metastasis—the spread of cancer cells from a primary node to a distant site—is responsible for as much as 90% of all cancer-associated deaths due to treatment resistance and increased tumor burden. Once established, metastatic nodules oftentimes exhibit distinct molecular phenotypes from their original primary tumor, undermining gold-standard methods for determining treatments for patients, which typically rely on molecular characterization of the primary tumor. Unfortunately, a lack of robust, scalable, and appropriate models for studying differences in patient-derived primary and metastatic tumors has hindered progress in identifying metastasis-specific therapies. Previously, we reported the ability to establish in vitro cultures of circulating tumor cells (CTCs), a unique precursor population of cells that exhibits an ability to escape the primary tumor but not yet fully complete metastasis. We have since expanded the application of this GU-CTC platform to culture CTCs from the blood of patients diagnosed with a variety of metastatic cancers, resulting in the successful culture of 31 unique patient-derived CTC cell lines. Furthermore, following an initial short-term culture period, we also performed subcutaneous injection of mixed CTC cultures into immunocompromised mice, resulting in not only primary tumor formation, but also systemic metastatic nodule formation in as short as 3 months. These resulting CTC-derived xenografts (CDXs) have been demonstrated using metastatic pancreatic, colorectal, and lung adenocarcinoma-derived CTCs. Encouragingly, all CDX models also exhibited replicable metastatic patterns upon reimplantation, reinforcing the important role of CTCs as precursors to metastasis. Bulk RNA-sequencing of patient-matched whole blood, cultured CTCs, and CDX-derived primary tumor and metastatic tissues further identified enrichment of an epithelial-mesenchymal transition as well as several cancer-specific gene signatures consistent with an invasive phenotype. This extended GU-CTC platform therefore enables not only the robust and rapid expansion of CTCs through both in vitro and in vivo methods, but also offers an avenue for personalized drug screens in the effort to target cancer metastasis.
Citation Format: Jerry Xiao, Richard Schlegel, Seema Agarwal. Establishing circulating tumor cell-derived xenografts following a period of in vitro culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5123.
Abstract 5149: Autoantibodies to PAX5, PTCH1 and GNA11 as serological biomarkers in the detection of hepatocellular carcinoma in Hispanic Americans
Authors: Qiu Cuipeng , Wang Xiao , Wang Bofei , Ma Yangcheng , Zhang Xiaojun , Zhang Jian-Ying 
Published: June 2022

Abstract
Liver cancer, especially hepatocellular carcinoma (HCC), is the third cause of cancer death worldwide. In the United States, it remains higher incidence rates and worse survival in the Hispanic population than the other populations. Studies have demonstrated that autoantibodies to tumor-associated antigens (TAAs) could be biomarkers with low-cost, efficient, and highly sensitive characteristics. In this study, enzyme-linked immunosorbent assay (ELISA) was conducted to measure three autoantibodies to PAX5, PTCH1, and GNA11 in sera from 25 Hispanic Americans with HCC, 28 patients with liver cirrhosis (LC), and 27 patients with chronic hepatitis (CH) as well as sera from 85 healthy individuals. At the 95% specificity for healthy controls, 56%, 48%, and 44% of HCC sera (or patients) showed elevated levels of autoantibodies to PAX5, PTCH1, and GNA11 respectively. Among the patients with LC, frequencies for autoantibodies to PAX5, PTCH1, and GNA11 were 44%, 36%, and 25% respectively. In patients with CH, the frequencies of autoantibodies to PAX5, PTCH1, and GNA11 were 22%, 22%, and 15%, which were significantly lower than those in HCC (p&lt;0.01). The area under the curves (AUCs) of autoantibodies to PAX5, PTCH1, and GNA11 for identifying HCC from healthy controls were 0.912, 0.915, and 0.915, respectively. The sensitivity could be improved to 68% when three of the autoantibodies were combined with the AUC of 0.932. Therefore, autoantibodies to PAX5, PTCH1, and GNA11 showed significantly higher levels in Hispanic HCC than those in the CH or healthy controls. Also, these three autoantibodies could enhance the detection of HCC if they were combined as the parallel test. In conclusion, autoantibodies to PAX5, PTCH1, and GNA11 could be potential biomarkers for the detection of HCC in Hispanic Americans. Large size of samples is needed to further determine their potential value in clinical application.
Citation Format: Cuipeng Qiu, Xiao Wang, Bofei Wang, Yangcheng Ma, Xiaojun Zhang, Jian-Ying Zhang. Autoantibodies to PAX5, PTCH1 and GNA11 as serological biomarkers in the detection of hepatocellular carcinoma in Hispanic Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5149.