bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5995: Tumor genomic landscape in patients (pts) with and without liver metastasis in metastatic urothelial carcinoma (mUC)
Authors: Tripathi Nishita , Jo Yeonjung , Sayegh Nicolas , Chigarira Beverly , Nordblad Blake , Thomas Vinay Mathew , Haaland Benjamin , Nussenzveig Roberto , Gupta Sumati , Agarwal Neeraj , Swami Umang , Maughan Benjamin L. 
Published: June 2022

Abstract
Background: Presence of liver metastasis is associated with a poor prognosis in mUC. According to the prognostic model by Sonpavde et. al, post platinum treated mUC pts with liver metastasis had a 50% higher risk of death on immunotherapy compared to pts without liver metastasis (PMID 32552295). Herein, we hypothesize that pts with liver metastasis harbor a distinct tumor genomic landscape compared to pts without liver metastasis.
Methods: In this IRB-approved retrospective study, mUC pts with and without liver metastasis at baseline and available tumor comprehensive genomic profiling (CGP) from a CLIA-certified laboratory were included. Variants of unknown significance and mutated genes present in ≤ 5% of pts were excluded. A Chi-square test was used to compare the frequency of mutated genes between both groups. The p-value was adjusted for false discovery, significance was preset at 0.25.
Results: 114 pts were included. 16/114 pts had a liver metastasis. Median age was 69 and 67 years, male/female 12/4 and 72/26, smokers/non-smokers 6/10 and 46/52, for pts with and without liver metastasis respectively. The most frequent genomic alterations (GAs) were seen in TP53, CDKN2B and FGFR3. Pts with liver metastasis had significantly higher GAs in MYC (unadjusted p=0.009, adjusted p=0.24) compared to pts without liver metastasis. The median number of GAs per patient and the tumor mutation burden were not significantly different between groups.
Conclusion: Our results indicate GAs in MYC are significantly enriched in pts with liver metastasis compared to those without liver metastasis. These hypothesis generating data require external validation.
Genes Liver Metastasis: N=16 Non-Liver Metastasis: N=98 Adjusted P-value MYC 3(18.8%) 3(3.1%) 0.24 ERBB3 3(18.8%) 5(5.1%) 0.62 FGFR3 5(31.2%) 16(16.3%) 0.73 RICTOR 2(12.5%) 4(4.1%) 0.73 TP53 7(43.8%) 58(59.2%) 0.73 ERBB2 3(18.8%) 9(9.2%) 0.73 CDKN2B 7(43.8%) 31(31.6%) 0.73 ARID1A 3(18.8%) 21(21.4%) 0.90 RB1 3(18.8%) 24(24.5%) 0.90 KDM6A 2(12.5%) 19(19.4%) 0.90
Citation Format: Nishita Tripathi, Yeonjung Jo, Nicolas Sayegh, Beverly Chigarira, Blake Nordblad, Vinay Mathew Thomas, Benjamin Haaland, Roberto Nussenzveig, Sumati Gupta, Neeraj Agarwal, Umang Swami, Benjamin L. Maughan. Tumor genomic landscape in patients (pts) with and without liver metastasis in metastatic urothelial carcinoma (mUC) [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 5995.
Abstract 6012: Antitumor effect of natural killer cells on breast cancer cells in murine model
Authors: Yim Chaok , Lee Jun Woo , Kim Jin-Hee 
Published: June 2022

Abstract
Natural killer (NK) cells are play pivotal functions in the tumor microenvironment of cancer immune surveillance. The killing ability of NK cells is expected to contribute to death of cancer cell. To prove NK cells as a cell therapy, we frist manufactured NK cells from the peripheral blood of healthy donor who received informed consent in a GMP facility. And we verifed the killing ability of the NK cells by decreasing the size of the tumor in NOG mice inoculated with SKBR3, HER2-positive breast-cancer cell, into mammary fat pad (orthotopic models). In this study, sudden death of mice was not found even when 20 millions NK cells were injected into a NOG female with intravenous injection. Moreover, it was confirmed that the size of the tumor was significantly reduced after NK cell injection. It is necessary to study co-administration with a targeted therapy such as rastuzumab and pertuzumab, and NK cells as a cell therapy will help reduce the size of the tumor. In the future, additional research is needed on the combined administration of targeted therapeutics and NK cells.
Citation Format: Chaok Yim, Jun Woo Lee, Jin-Hee Kim. Antitumor effect of natural killer cells on breast cancer cells in murine 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 6012.
Abstract 602: 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity
Authors: Fenaux Jill , Huang Yao-ming , Melero Cristina , Chung Wei-Jen , Lee Suk , Ayupova Dina , Poggio Mauro , Glatt Dylan , Yi Zuoan , Lay Cecilia , Schmidt Maike , Majeed Sophia R. , Fuh Germaine , Chen Alice , Kumar Sushil 
Published: June 2022

Abstract
In the 23andMe genetic database, associations were observed for CD200R1 variants and autoimmune and cancer traits with opposing directionality. These data suggest that CD200R1 may be a pivotal checkpoint in immunosurveillance of cancer and a promising therapeutic target. CD200R1 is expressed widely on human T cells and myeloid cells; and binds to its cognate ligand CD200 to suppress the activity of immune cells. Elevated expression of CD200R1 was observed on tumor-infiltrating lymphocytes relative to peripheral blood mononuclear cells (PBMCs) from cancer patients. While the expression of CD200R1 and its ligand CD200 are well characterized, the downstream immunosuppressive role for CD200R1 in human tumors or the potentiation of anti-tumor T cell function by targeting of CD200R1 is not well understood. To test the therapeutic potential of inhibiting the CD200R1 pathway we developed 23ME-00610, a fully humanized monoclonal antibody that binds to all functionally relevant isoforms and haplotypes of CD200R1 with high affinity (KD values &lt; 0.1 nM), to target tumors that are reliant on the CD200R1 immunosuppressive pathway. 23ME-00610 completely displaced the ligand CD200 from CD200R1 in cell-based flow cytometry assays with blocking IC50 values that ranged from 0.32 to 1.04 nM depending on the concentration of CD200 ligand present, and inhibited downstream signaling through the adaptor protein DOK2 in a reporter-based assay. Functionally, 23ME-00610 reversed CD200-mediated suppression of chronically stimulated primary T cells. In addition, 23ME-00610 enhanced PBMC-mediated tumor killing with a mean EC50 of 2.09 nM using methods of real-time measurement of cytotoxicity of human CD200-expressing tumor cells when compared to control antibodies. Moreover, 23ME-00610 promoted IFNγ production, a key functional anti-tumor T cell cytokine, in cancer patients’-derived PBMCs. Taken together, these results demonstrate that 23ME-00610 has the potential to reverse CD200-mediated immunosuppression in the TME to enhance anti-tumor T-cell functions in cancer patients.
Citation Format: Jill Fenaux, Yao-ming Huang, Cristina Melero, Wei-Jen Chung, Suk Lee, Dina Ayupova, Mauro Poggio, Dylan Glatt, Zuoan Yi, Cecilia Lay, Maike Schmidt, Sophia R. Majeed, Germaine Fuh, Alice Chen, Sushil Kumar. 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity [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 602.
Abstract 6024: Developing a panel of orthotopic syngeneic tumor models for IO drug discovery
Authors: Liu Gaoxiang , Sun Quanhong , Shi Wenting , Gu Qingyang , Ji Qunsheng 
Published: June 2022

Abstract
Immuno-oncology (IO) therapy is the focus of drug discovery in recent years. Unlike chemotherapy or targeted agents, the pharmacological efficacy of immune-oncology therapies needs to be evaluated in animal models with functional immune system. Syngeneic tumor models are established by inoculating mouse cancer cell lines to immunocompetent mice with the same genetic background. The host mice have complete immune activity and show histocompatibility with homograft tumor tissues, which can maximize the simulation of the real tumor microenvironment. Subcutaneous syngeneic models are easily established and have been widely used; however, the subcutaneous tumors lack organ-specific stromal-tumor interactions that are critical for disease progression in patients. Orthotopic tumor models are established in organ-specific sites, facilitating metastatic spread, supporting immune and stromal component interactions, and providing a more disease-relevant tumor microenvironment for IO therapy assessment. In order to facilitate the development of IO drug, we have established a panel of orthotopic syngeneic tumor models. We generated a series of luciferase-labeled bioluminescent mouse tumor cell lines, which were then engrafted into the organ of interest to establish orthotopic models. Bioluminescent imaging (BLI) enabled non-invasive in vivo imaging of orthotopic tumor burden, the real time tumor growth, and the response to therapies, monitored by quantitative bioluminescent signals. Overall, these established orthotopic syngeneic tumor models recapitulate the clinically relevant tumor microenvironment and serve as a useful tool in the pre-clinical evaluation of immunotherapies.
Citation Format: Gaoxiang Liu, Quanhong Sun, Wenting Shi, Qingyang Gu, Qunsheng Ji. Developing a panel of orthotopic syngeneic tumor models for IO drug discovery [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 6024.
Abstract 6033: Understanding the role of Cep55 in initiation and progression of cancers
Authors: Rashidieh Behnam , Tria Simon M. , Khanna Kum Kum 
Published: June 2022

Abstract
CEP55 is a cancer-testis antigen, highly expressed in a wide range of solid tumors as well as chromosomally unstable cancers. CEP55 is normally silent in most adult somatic tissues except germ cells; however, its expression is induced early during cell transformation. Numerous studies using cell line xenografts have shown that CEP55 is required for the viability and survival of a diverse range of cancers in vitro and in vivo. To decipher the mechanisms by which Cep55 promotes chromosomal instability and tumorigenesis in vivo, we developed a novel knock-in transgenic mouse model that ubiquitously overexpresses Cep55 (Cep55Tg/Tg) and a conditional knockout (cKO) mouse model of Cep55 (Cep55-/-). While overexpression of Cep55 was sufficient to cause spontaneous tumorigenesis in vivo, Cep55 loss hindered tumorigenesis. When we bred adult Cep55 cKO mice with other tumor-prone models: oncogenic Kras expression (Kras G12D) and Pten tumor-suppressor loss, Cep55 loss significantly delayed tumorigenesis and prolonged survival validating it as a promising therapeutic target for diverse cancers. This reduction of tumorigenesis is concomitant with the downregulation of AKT and ERK signaling pathways, attenuation of epithelial to mesenchymal transition, and increased cytotoxic CD4/CD8 T-cell tumor infiltration. This indicates that Cep55 can impair the establishment of the adaptive immune response through modification in the tumor microenvironment and regulation of cell signaling. Mass spectrophotometry of mouse embryo fibroblasts and derived exosomes from wild-type and KO mice revealed the pathways altered by Cep55 such as extracellular matrix remodeling pathways, integrin-related signaling and cellular trafficking mediators indicating the contributions of Cep55 to cancer are beyond what have been reported so far. Overall, CEP55 is a promising target to prevent tumorigenesis and the progression of cancer through various mechanisms.
Citation Format: Behnam Rashidieh, Simon M. Tria, Kum Kum Khanna. Understanding the role of Cep55 in initiation and progression of cancers [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 6033.
Abstract 6039: Application of triple negative breast cancer patient-derived organoid and xenograft model for drug screening
Authors: Ryu Seungyeon , Kim Hoe Suk , KIM Jung Eun , Yoon So-Hyun , Lee Sangeun , Baek Moonjou , Lee Han-Byoel , Lee Dong Woo , Ku Bosung , Han Wonshik 
Published: June 2022

Abstract
Background: Breast cancer Patient Derived Organoids (PDOs) and patient-derived xenografts (PDXs) which recapitulate the tumor heterogeneity and molecular signatures of original tumor tissue, are useful tools to enable greater precision of both approved and experimental medicines through personalized therapeutic approaches. We focus on use of ex vivo PDOs, PDX-derived organoids (PDXOs), and vivo PDXs models for drug testing and personalized therapy. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in breast cancer.
Methods: Fresh surgical specimens of primary TNBC breast tumor (N=3) were used for PDOs. PDOs and PDX-derived organoids (PDXOs) were cultured in previously reported media compositions based on ECM hydrogel. PODs and PDXOs were subjected to drug screening for 22 anticancer drugs including chemoreagents and targeted drugs in the 3D HTS system. Drug sensitivity was tested in triplicate in different concentration ranges for 7 days. The IC50 for each drug was calculated by a sigmoidal dose-response curve, using the GraphPad Prism 9 program. For drug screening in PDXs models, PDOs were injected into the fourth mammary fat pads of NOD.Cg-Prkdcscid Il2rgtm1wjl/SzJ mice. WEE1 inhibitor (AZD1775) was administered by oral gavage (AZD1775, 30 mg/kg) for 3 weeks. Immunostaining of ER, PR, Her2, CK5 and Ki67 was performed in PODs, PODXs and PDX tumor tissues.
Results: All PDOs, PDXs, and PDXOs were ER-, PR- and HER2- negative. PDOs and PDXOs (172T, 185T, 207T) showed differential response to 22 anticancer drugs. In PDOs and PDXOs models, 172T and 207T PDOs and PDXOs are highly sensitive to AZD1775, but 185T PDOs and PDXOs less sensitive or never respond to treatment with AZD1775 (10 µM). In PDX models, treatment with AZ1775 decreased tumor growth (P&lt;0.0079) as well as distance metastasis in 207T-PDX mice, whereas in 172T- and 185T-PDX mice, the tumor growth and metastasis were not reduced compared with the vehicle group.
Conclusion: Consequently, PDOs, PDXOs and PDXs recapitulated immunohistological signatures of original tumor tissues. The results of WEE1 inhibitor response between PDOs, PDXOs and PDXs were consistent. This study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified drugs.
Citation Format: Seungyeon Ryu, Hoe Suk Kim, Jung Eun KIM, So-Hyun Yoon, Sangeun Lee, Moonjou Baek, Han-Byoel Lee, Dong Woo Lee, Bosung Ku, Wonshik Han. Application of triple negative breast cancer patient-derived organoid and xenograft model for drug screening [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 6039.
Abstract 6046: Targeting TBL1 inhibits nuclear β-catenin activity and enhances immune checkpoint inhibition efficacy in osteosarcoma
Authors: Nakahata Kengo , Nirala Bikesh K. , Shuck Ryan L. , Kurenbekova Lyazat , Yustein Jason T. 
Published: June 2022

Abstract
Background: Osteosarcoma (OS) is the most common bone malignancy in childhood and adolescence. Though the prognosis of OS patients has been improved by multimodal therapies, patients with metastatic disease still have a very poor prognosis. We previously reported a novel TBL1/β-catenin inhibitor, Tegavivint, suppresses OS primary tumor and lung metastasis using patient-derived cell lines. Wnt/β-catenin signaling is reported to influence intratumoral T cell infiltration and using murine syngeneic OS models we investigated the effects of Tegavivint on improving immune checkpoint inhibition and the OS tumor immune microenvironment.
Methods: We used murine OS cell lines F331 and F420 for in vitro and in vivo studies. We performed cytotoxicity studies using the CCK-8 assay and western blots to investigate downstream β-catenin signaling perturbations secondary to Tegavivint. Intratibial injections were performed into C57BL/6 mice using both murine cell lines. Tegavivint and anti-PD-1 antibody was administered as monotherapy or in combination. After treatment, we compared the tumor volume in the control, monotherapy (Tegavivint or PD-1 only) and combination therapy groups (Tegavivint and PD-1). We assessed T cell tumor infiltration using immunohistochemistry and flow cytometry.
Results: In vitro, Tegavivint suppresses the growth of F331 and F420 cell lines with IC50s of 9.52nM and 49.4nM, respectively after 72hours of treatment. In vivo, anti-PD1 monotherapy did not show any significant anti-tumor activity, but Tegavivint monotherapy significantly suppressed the growth of murine tumors (p&lt;0.05) and the combination therapy further improved overall anti-tumor activity. IHC staining showed an increase in CD8-positive T cells in Tegavivint monotherapy and combination therapy treated tumors compared with the control tumors. Furthermore, flow cytometry validated the increase in CD8-positive T cell infiltration and also showed an increase in intratumoral NK cells in Tegavivint treated tumors.
Conclusions: These results indicate that TBL1 inhibition, via Tegavivint, inhibits nuclear β-catenin activity and alters the tumor immune microenvironment and enhances immune checkpoint blockade in OS. Future directions include more comprehensive profiling and molecular analysis of the tumor and immune microenvironment, and evaluation of additional immune modulatory approaches for the treatment of OS.
Citation Format: Kengo Nakahata, Bikesh K. Nirala, Ryan L. Shuck, Lyazat Kurenbekova, Jason T. Yustein. Targeting TBL1 inhibits nuclear β-catenin activity and enhances immune checkpoint inhibition efficacy in osteosarcoma [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 6046.
Abstract 6053: Characterizing plasticity of chemotherapy-tolerant persister cells in rhabdomyosarcoma
Authors: Tang Weiliang , Fritzke Madeline , Stinson Spencer , Chen Eleanor 
Published: June 2022

Abstract
Rhabdomyosarcoma (RMS) is a rare pediatric soft tissue sarcoma (250-300 cases a year in the US). The prognosis for patients with relapsed and metastatic disease remains poor with less than 30% overall survival rate. Current treatment regimens are ineffective against relapsed disease of RMS. There remains the urgent to need to identify more effective therapy options. While some studies have demonstrated up-regulation of multi-drug resistance genes and abnormal activity of selected signaling pathways in chemotherapy-resistant RMS tumors, the cellular and molecular mechanisms underlying adaptive cell changes leading to persistent survival of treatment-resistant RMS cells remain poorly understood. The stem cell-like tumor propagating cells (TPCs) have the capacity for self-renewal and are thought to be responsible for initiating treatment-resistant relapse and metastasis of some cancer types. The drug-tolerant persister (DTP) cell population with stem-cell like features has been shown in some cancer types to exhibit plasticity in cell state and dynamic changes in chromatin and transcriptional activity. A better understanding of how the cellular plasticity of the DTPs is regulated is critical for developing therapies to overcome treatment resistance in RMS. We have shown that initial treatment of RMS cells with standard-of-care cytotoxic agent, vincristine, selects for a DTP that is enriched with CD133+ stem-like cells. By gene expression studies, MYC and YBX1 driven-gene networks are upregulated in CD133+ cells. Targeted disruption of MYC and YBX1 by CRISPR/Cas9 reduces self-renewal capacity of RMS cells, and overexpression of MYC and YBX1 confers tolerance on RMS cells to vincristine. RMS cells treated in long-term culture with incremental increase in vincristine dose gives rise to late DTP with a distinct transcriptional profile including up-regulation of many genes regulated by the myogenic regulatory factor, MYOD1. MYC binds to the promoters of YBX1 and MYOD1. The findings suggest dynamic transcriptional changes and cell state plasticity of the DTPs in RMS. Our ongoing work includes characterizing the mechanisms by which MYC and MYOD1 regulate cell state plasticity and transcriptional adaptation of the DTP, assess inter- and intra-tumoral transcriptional heterogeneity of treatment-refractory RMS tumors and determine prognostic significance of functional network modules of MYC, MYOD and their downstream genes. Our ultimate goal is to translate our findings into more effective therapies for treatment-refractory RMS patients.
Citation Format: Weiliang Tang, Madeline Fritzke, Spencer Stinson, Eleanor Chen. Characterizing plasticity of chemotherapy-tolerant persister cells in rhabdomyosarcoma [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 6053.
Abstract 6061: Novel β-Apopicropodophyllin derivative, JNC-1043, exerts anti-cancer and radiosensitizing effects
Authors: Park Jong Kuk , Kang A-Ram , Kwon Jin-Hee , Choi Jong-Ryoo , Song Jie-Young , Hwang Sang-Gu 
Published: June 2022

Abstract
In this study, we reported novel anti-cancer drug candidate, JNC-1043{(5S)-5-(4-Benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo[3',4':6,7] naphtho[2,3-d][1,3]dioxol-6-one}, synthesized from β-Apopicropodophyllin. Firstly, we analyzed anti-cancer effect of JNC-1043. We performed MTT assay to detect IC50 values on several cancer cells - breast, lung, pancreatic, blood, gastric, colorectal cancers. In these experiments, 0.1~1 μM IC50 values of JNC-1043 were calculated, and JNC-1043 treatments induced activation of caspase-3 and -8. Additionally, effective values of pharmacokinetic parameters in male rats and 2 weeks Dose Rate Finding (DRF) of JNC-1043 also detected. This result showed JNC-1043 is a promising anti-cancer candidate. Next, we tested whether radiosensitizing effect of JNC-1043. Each IC50 values of DLD-1 and HCT116 cell lines were calculated as 0.157, 0.1145, respectively. Cell counting assays were performed and then showed combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. JNC-1043 only- or IR only-treatment induced cell death by 50~60%, respectively, while combination of JNC-1043 and IR increased more 20~30% cell death than those of JNC-1043 only- or IR only-treatment in both cell lines. Clonogenic assay also performed, and then dose enhancement ratios (DER) of DLD-1 and HCT116 were calculated as 1.40, 1.53, respectively. Apoptosis also was detected with Annexin V-Propidium iodide assay. Combination of JNC-1043 and IR increased apoptosis more 30~40% than those of JNC-1043 only- or IR only-treatment. DCFDA-based assay also were performed to indicate ROS production was enhanced in combination of JNC-1043 and IR. In vivo xenograft experiment, combination of JNC-1043 and IR reduced tumor sizes less 50% and increased apoptosis more 30~40% than those of JNC-1043 only- or IR only-treatment. These results implied anti-cancer and radiosensitizing effect of JNC-1043 resulted from promotion of apoptosis via enhancement of ROS production.
Citation Format: Jong Kuk Park, A-Ram Kang, Jin-Hee Kwon, Jong-Ryoo Choi, Jie-Young Song, Sang-Gu Hwang. Novel β-Apopicropodophyllin derivative, JNC-1043, exerts anti-cancer and radiosensitizing effects [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 6061.