bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4153: PET/CT imaging of pancreatic ductal adenocarcinoma with a claudin-4 binding peptide in preclinical mouse model
Authors: Seo Jai Woong , Wang James , Kare Aris J. , Tumbale Spencer K. , Wu Bo , Raie Marina N. , Pandrala Mallesh , Ferrara Katherine W. 
Published: March 2024

Abstract
There is a critical need to develop new imaging and therapeutic strategies for pancreatic cancer. Current positron emission tomography (PET) imaging assessments of pancreatic ductal adenocarcinoma (PDAC) rely on 18F-FDG as a radiopharmaceutical. To increase the sensitivity of PDAC detection, we identified Claudin-4 (CLDN4), a tight junction transmembrane protein, as a PDAC biomarker through spatial transcriptomic and proteomic analyses. CLDN4 expression has previously been reported to be enhanced in 99% of primary and 100% of metastatic pancreatic cancer tissue samples and in 10 of 11 precancerous pancreatic intraepithelial neoplasia (PanIN) specimens. A small fragment of naturally occurring Clostridium perfringens enterotoxin (CPE) was previously reported to bind to the extracellular loop domain of CLDN4 protein (PDB:7kp4) with nanomolar (nM) affinity (Kd). A CLDN4 binding peptide (C4BP) was developed as a radioligand by modifying the n-terminus of C4BP which does not impact receptor binding. Here, we designed and synthesized a DOTA-PEG1-C4BP ligand on a rink amide resin using a microwave-assisted peptide synthesizer. Radiolabeling of DOTA-PEG1-C4BP (2 nmol) with 64CuCl2 (70 MBq) conferred 64Cu-C4BP (28 MBq/nmol) with 80% non-decay corrected yield and &gt;99% radiochemical purity. PET/CT imaging of 64Cu-C4BP (~0.1 μg/mouse) performed in an inducible PDAC (KrasLSL-G12D/+;Rosa26LSL-tdTomato/LSL-tdTomato(KT);Ptf1aCreER;Trp53fl/fl) model at 84 day after tamoxifen injection resulted in ~25% injected activity per cubic centimeter (IA/cc) accumulation in metastases and at ~18% IA/cc retention in pancreatic tumors within 30 minutes of tail vein injection with minimal background accumulation. Ex vivo PET imaging confirmed the localized accumulation of 64Cu-C4BP in transgenic mice within the colon, pancreas, and liver. Blocking of 64Cu-C4BP accumulation with the cold compound in a xenograft model (NOD/SCID) bearing Capan-1 PDAC tumors demonstrated the specificity of 64Cu-C4BP binding. Here we report that CLDN4 is a promising target and 64Cu-C4BP is a promising ligand for the detection of pancreatic cancer.
Citation Format: Jai Woong Seo, James Wang, Aris J. Kare, Spencer K. Tumbale, Bo Wu, Marina N. Raie, Mallesh Pandrala, Katherine W. Ferrara. PET/CT imaging of pancreatic ductal adenocarcinoma with a claudin-4 binding peptide in preclinical mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4153.
Abstract 4161: Identification of pancreatic adenocarcinoma using urokinase plasminogen activator probe detected using optoacoustic imaging
Authors: Kim Vung , Chuong Phillip , Bynum Ryan , Grizzle William , McNally Lacey R. 
Published: March 2024

Abstract
Purpose: Diagnosing and treating pancreatic cancer remains a challenge. The hypovascularized nature of pancreatic cancer renders modern chemotherapeutics and cancer detection contrast agents ineffective. A promising approach to the challenges is the adoption of a novel imaging technique known as Multispectral Tomography (MSOT). We hypothesize that a urokinase plasminogen activator (UPA) probe will enhance the detection of orthotopic pancreatic cancer xenografts.
Methods: Pancreatic tumor cell lines (Panc1, MiaPaca-2, S2VP10, and S2C9) were assessed for UPA-receptor expression using western blot analysis. UPA peptide was synthesized and to the HiLyte-750 NIR dye. Flow cytometry and immunofluorescence were utilized to examine the specificity and activity of this UPA-750. The UPA-750 binding efficiency was assessed through a competitive inhibition assay with a UPAR-blocking antibody using fluorescence microscopy. Then SCID mice (5 mice/group) received orthotopic implantation of S2C9 (1.5 x 105) or MiaPaCa2 (2.0 × 106) pancreatic tumor cells. UPA-750 or 750 dye alone was IV injected into mice after the tumors reached 3mm. Biodistribution and accumulation of UPA-750 were observed through MSOT images taken at 2-hour intervals over 8 hours and at 24 hours. UPA-750 in the tumor, liver, and kidney was confirmed through ex vivo fluorescent imaging.
Results: UPAR expression was observed in every pancreatic cancer cell line, with the greatest relative abundance in S2P9 cells (3.0X), followed by S2VP10 (2.5X), Panc1 (1.77X), and MiaPaca-2 (1.3X). Application of the UPAR blocking antibody on S2CP9, S2VP10, MiaPaCa2, and SKOV3p1 (positive control) cell lines resulted in the inhibition of cellular binding of the UPA-750, as evidenced by fluorescence microscopy. UPA-probe was successfully observed in pancreas tumor slices with peak intensity at 4-hrs of imaging by MSOT. Ex vivo NIR fluorescence imaging confirmed UPA-750 signal in pancreatic tumors but not in liver or kidney.
Conclusion: UPA-probe exhibits potential as a marker for pancreatic cancer.
Citation Format: Vung Kim, Phillip Chuong, Ryan Bynum, William Grizzle, Lacey R. McNally. Identification of pancreatic adenocarcinoma using urokinase plasminogen activator probe detected using optoacoustic imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4161.
Abstract 4164: Hybrid photoacoustic imaging and fast ultrasound localization microscopy to probe the tumor microenvironment
Authors: Zhao Shensheng , Basu Sayantani , Campbell Roy H. , Zhao Yang , Chen Yun-Sheng 
Published: March 2024

Abstract
Photoacoustic (PA) imaging can map the physiological conditions of tissues and track the biodistribution of contrast agents. Ultrasound localization microscopy (ULM) with microbubbles provides deep-tissue super-resolution blood vessel images and blood velocity maps. The integration of these techniques offers a potential tool for oncological applications, such as visualizing tumor hypoxia and vasculature. Additionally, because PA imaging and ULM can share the same ultrasound detector and data-acquisition system, PA images can seamlessly fuse with ULM images without requiring post co-registration processing. However, the acquisition time of ULM is considerably longer (several minutes per frame) compared to PA imaging (10 milliseconds to 100 milliseconds per frame), limiting the simultaneous acquisition of the two imaging modalities. To address this issue, we developed a deep learning model based on U-Net to accelerate the frame rate of ULM using information from sparse microbubble locations and power Doppler images. By enabling fast ULM acquisition, we developed an interleaved PA/fast ULM imaging technique to simultaneously capture photoacoustic and ULM images. Our experiments demonstrated up to a 16 times improvement in acquisition speed with U-Net, utilizing in vivo mouse brain and skin tumor data. The hybrid imaging sequence achieved super-resolution vascular and tissue oxygenation imaging with less than 2 seconds of acquisition time per frame in vivo. The implementation of this rapid dual imaging scheme enables the longitudinal monitoring of 3D tumor microvasculature and hypoxia conditions using a common linear ultrasound transducer. We monitored tumor growth of epidermoid carcinoma (A431) in a mouse model from Day 7 to Day 17 of tumor implantation, and the results reveal a significant decrease in tumor vasculature density and oxygen saturation as the tumor grew larger over time. The results indicate a positive relationship between oxygen saturation and vessel density. Our findings showcase the potential of this innovative technique for advancing deep tissue, high-resolution, multi-biological parameters imaging in oncological research.
Citation Format: Shensheng Zhao, Sayantani Basu, Roy H. Campbell, Yang Zhao, Yun-Sheng Chen. Hybrid photoacoustic imaging and fast ultrasound localization microscopy to probe the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4164.
Abstract 4186: Development of an orthotopic A549 lung carcinoma model in CD34+ humanized NCG mice and response to treatment with paclitaxel and pembrolizumab
Authors: Avrutskaya Anya , Rainbolt Elizabeth , John Bincy , Clouse Cara , Stackhouse Murray , Currie Christopher , Scatigno Sydney , Bronson Steven , Rowe Jenny , Hall Chassidy , Harris David P. 
Published: March 2024

Abstract
Translational in vivo models are needed to expedite the discovery of new treatments for lung cancer. One such approach is the use of humanized mouse models that enable immunotherapies targeting human immune cells to be evaluated for efficacy and tolerability. We developed an orthotopic lung carcinoma model in humanized mice (HuCD34 NCG), utilizing serial bioluminescence imaging to evaluate the activity of paclitaxel and pembrolizumab as single and combination agents. Paclitaxel, which disrupts microtuble function, and pembrolizumab, a PD-1-targeting immunotherapy, are both approved for the treatment of certain types of lung cancer. Paclitaxel kills cancer cells directly, and may also promote anti-tumor responses through enhanced presentation of tumor antigens and activation of T cells. Immunodeficient NCG mice were humanized with cord blood-derived hCD34+ stem cells from 3 donors. High levels of human cell engraftment, with expected frequencies of hCD45+ cells and other immune subsets, was observed by 14 weeks post-injection. Luciferase expressing A549 cells were implanted orthotopically into the pulmonary space of the left lobe of the lung, and animals were subsequently flux sorted into treatment groups. Tumor burden, measured by luciferase expression, increased progressively in untreated animals, and moribundity was often associated with clinical indications of respiratory distress. Treatment with paclitaxel significantly decreased the tumor burden and extended survival. In contrast, pembrolizumab did not control tumor growth or extend survival. There was no synergistic effect with the combination therapy, in fact, the addition of pembrolizumab was associated with a modest increase in tumor burden and disease progression. Comparative analysis of immune cell composition, function and persistence in lung and other tissues provided insights into the distinct pharmacodynamic responses associated with the different treatment regimens. This model establishes a robust in vivo platform to identify novel therapies for the treatment of lung cancer.
Citation Format: Anya Avrutskaya, Elizabeth Rainbolt, Bincy John, Cara Clouse, Murray Stackhouse, Christopher Currie, Sydney Scatigno, Steven Bronson, Jenny Rowe, Chassidy Hall, David P. Harris. Development of an orthotopic A549 lung carcinoma model in CD34+ humanized NCG mice and response to treatment with paclitaxel and pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4186.
Abstract 4187: Transcriptome profiling and characterization of peritoneal metastasis ovarian cancer xenografts in humanized mice
Authors: Kang Sung Wan , Lee Ji-young , Kang Ok-Ju , Kim Yong-Man , Choi Eun Kyung , Lee Shin-Wha 
Published: March 2024

Abstract
Background: Although immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human cancer and immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs, including immune checkpoint inhibitors (ICIs), which have demonstrated limited effectiveness in OC patients.
Methods: We established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+ Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). We assessed the efficacy of PD-1 blockade with pembrolizumab in the SKOV-3 Luc Hu-mouse model. The immune profiles of the tumors were characterized using colorimetric immunostaining and flow cytometry. Additionally, we analyzed RNA-seq data to investigate the gene expression signature of pembrolizumab refractory tumors.
Results: We confirmed tumor development in both OC cell lines within CD34+ Hu-mice. In these models, human lymphocyte and myeloid cell subsets were present in the tumors, draining lymph nodes, blood, and spleens. The SKOV-3 Luc tumor-bearing Hu-mice did not respond to pembrolizumab monotherapy. These tumors exhibited a high presence of tumor-infiltrating macrophages. Tumors in Hu-mice unresponsive to pembrolizumab showed a lower abundance of CD8+ T-cells, memory B cells, plasma cells, and a higher proportion of naïve M0 macrophages and mast cells compared to the PBS control. Furthermore, we identified 43 significantly enriched gene sets in these tumors. The differentially expressed genes (DEGs) were predominantly enriched in HDAC class I, RB1, KLF1/3, TCF21, MYD88, SMARCE1 target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts.
Conclusion: Our xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer potential avenues to explore mechanisms of resistance to PD-1/PD-L1 blockade in OC.
Citation Format: Sung Wan Kang, Ji-young Lee, Ok-Ju Kang, Yong-Man Kim, Eun Kyung Choi, Shin-Wha Lee. Transcriptome profiling and characterization of peritoneal metastasis ovarian cancer xenografts in humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4187.
Abstract 4193: Digital PCR as a novel way to assess chimerism of humanized immune system mice
Authors: Smith Nicholas , Hansen Sarah , Livingston Robert S. , Smith Steve , Roesch Paula , MacBride Megan M. 
Published: March 2024

Abstract
Humanized immune system (HIS) mice contain human and murine immune cells. Analysis of chimerism in HIS mice is typically accomplished via flow cytometry, but this requires collecting a 75 μl blood sample and access to a flow cytometer. Repeated bleeding can negatively affect the health of HIS mice, limiting serial analysis. Digital PCR offers a novel method for chimerism analysis, which uses much smaller blood volumes and can be performed on clotted or frozen samples, sample types unsuitable for flow cytometry. A digital PCR assay directly comparing the presence of three human genes and one murine gene was developed. This assay was validated in the huNOG-EXL HIS mouse engrafted with CD34+ hematopoetic stem cells from 3 unique donors via blind comparison with chimerism data from flow cytometry. At 10 weeks post engraftment, the digital PCR assay showed excellent correlation for all three human genes against chimerism as measured by flow cytometry of the peripheral blood. This assay represents a new, user-friendly, rapid tool for the analysis of HIS mice and may permit serial chimerism measurement using 10 μL whole blood. This assay may be useful to investigate other mouse-human chimera models, including mice harboring functional human hepatocytes, tumors, and other cells.
Citation Format: Nicholas Smith, Sarah Hansen, Robert S. Livingston, Steve Smith, Paula Roesch, Megan M. MacBride. Digital PCR as a novel way to assess chimerism of humanized immune system mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4193.
Abstract 4273: Genetically engineered mesenchymal stromal cells degrade hyaluronic acid to disrupt the ECM and enhance cancer therapy outcomes
Authors: Browne Alice T. , Clements Miranda , Ju Wei , Kaplan Rosandra 
Published: March 2024

Abstract
The extracellular matrix (ECM) is a vital component of cancer pathophysiology. However, little is known about how to modulate the ECM for therapeutic benefit effectively. Hyaluronic acid (HA) is a polysaccharide component of the ECM with increased deposition during tissue injury or inflammation. HA in the tumor microenvironment (TME) has been linked to aggressive cancer progression. We have found enhanced ECM remodeling behavior linked to pre-metastatic niche formation and metastatic progression. To remodel this ECM-enriched microenvironment, we developed HA-targeting genetically engineered mesenchymal stromal cells (GEMesys) expressing hyaluronidase (Hyal), the enzyme responsible for HA degradation. We examined the impact of Hyal-GEMesys in osteosarcoma (F42010), rhabdomyosarcoma (M-3-9M), and pancreatic cancer (Panc02) syngeneic murine models. Hyal-GEMesys delivered to tumor-bearing mice homed to primary tumor sites and successfully degraded HA in the TME. The degradation of HA also resulted in a significant remodeling of collagen. T cells in Hyal-GEMesy treated tumors display an activated CD4+CD44+ phenotype with a reduction of LAG3+PD1+ exhaustion markers. Additionally, Hyal-GEMesy treatment results in a significant decrease in hypoxic regions within tumors and reorganization of the tumor vasculature to a more normalized phenotype, marked by diminished CD31 expression. Hyal-GEMesy treatment reduces tumor volumes in osteosarcoma, rhabdomyosarcoma, and pancreatic cancer models and enhances chemotherapeutic efficacy. These findings suggest that reorganizing the tumor ECM with Hyal-GEMesys holds the potential to dismantle the protective stroma of the tumor, which often shields malignant cells from therapeutic reach, and combining anti-cancer and anti-stroma agents can enhance anti-tumor efficacy and patient outcomes.
Citation Format: Alice T. Browne, Miranda Clements, Wei Ju, Rosandra Kaplan. Genetically engineered mesenchymal stromal cells degrade hyaluronic acid to disrupt the ECM and enhance cancer therapy outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4273.
Abstract 429: A novel regulatory role of FLT3/ITD mutation in lipid metabolism of leukemia cells: The mechanism and therapeutic implications
Authors: Hu Yumin , Yin Feng , Zhao Mingyue , Lu Wenhua , Yu Tiantian 
Published: March 2024

Abstract
Internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3/ITD), is a common type of activating mutation and frequently detected in AML. FLT3/ITD is associated with poor prognosis of AML. In this study, we investigated the regulation of FLT3/ITD mutation on sterol regulatory element-binding protein (SREBP) and the therapeutic vulnerabilities of lipid metabolism in FLT3/ITD leukemia. With the transcriptomics analysis we found that FLT3/ITD controlled lipid metabolism via the transcription factor SREBP. The analysis of TCGA_LAML dataset revealed that a gene signature involved in fatty acid and cholesterol metabolism, which is regulated by SREBP, was upregulated in FLT3/ITD patients compared with FLT3/wild-type patients. The upregulation of SREBP protein expression in FLT3/ITD leukemia was confirmed using a genetically engineered mouse model. We further demonstrated that FLT3/ITD regulates the protein degradation of SREBP through the PI3K/AKT-GSK3β axis. The metabolomics analysis further showed that FLT3/ITD primarily regulates glycerophospholipid synthesis, which contribute to the key structure lipid in the membrane, specifically, the cardiolipin. Moreover, pharmacologic inhibition of SREBP activation and its downstream enzyme fatty acid synthase (FASN) sensitized FLT3-ITD AMLs to the treatment of FLT3 inhibitor quizartinib. Collectively, our findings reveal a novel regulation of FLT3-ITD in metabolic reprogramming and indicate a targetable vulnerability in a subset of refractory leukemia.
Citation Format: Yumin Hu, Feng Yin, Mingyue Zhao, Wenhua Lu, Tiantian Yu. A novel regulatory role of FLT3/ITD mutation in lipid metabolism of leukemia cells: The mechanism and therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 429.
Abstract 4292: Unraveling the interplay of aging, smoking, and mutation-driven clonal expansions in lung cancer evolution: A multifaceted approach
Authors: Briggs Amy N. , DeGregori James 
Published: March 2024

Abstract
Despite the well-established link between tobacco use and lung cancer, military personnel face additional risks due to heightened smoking rates and exposure to various environmental contaminants. Aging further amplifies susceptibility to lung cancer, contributing to elevated incidence rates among Veterans compared to non-Veterans. Our studies aim to elucidate the intricate relationship between aging, smoking, and mutation-driven clonal expansions in lung tissue, examining their impact on lung function and cancer evolution. Using cell culture and mouse models, we introduce mutations identified in human lung tissue into airway epithelial cells. Using CRISPR, base editing, and genetically engineered mouse models, we assess the effects on barrier function, cell differentiation, and gene expression. Ultimately, we are investigating the interaction between induced mutations, aging, and smoking, exploring how mutation-driven clonal expansions contribute to lung dysfunction and pre-malignant phenotypes, potentially forming a feedforward loop. This research addresses critical gaps in understanding the complex interplay of aging, smoking, and mutation-driven clonal expansions in lung cancer evolution. Findings have the potential to unveil novel insights into the development of lung dysfunction and malignancy, paving the way for safe and accessible interventions to reduce cancer risk and enhance lung health.
Citation Format: Amy N. Briggs, James DeGregori. Unraveling the interplay of aging, smoking, and mutation-driven clonal expansions in lung cancer evolution: A multifaceted approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4292.