bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3137: Development of AT2604, a highly efficacious  ADC targeting alkaline phosphatases ALPP  and ALPPL2​
Authors: Yeung Bryan K. , Koh Xiao Hui , Ling Wei Li , Tan Weiqi , Wu You Xue , Zhang Xi Yun , Tan Hong Yee , Liu Shao Jun , Zhong Chen , Zou Bin 
Published: March 2024

Abstract
Placental alkaline phosphatases, ALPP and ALPPL2, are highly homologous, membrane-bound proteins involved in fetal development. Despite having limited expression in normal tissues, they are highly differentiated in tumor cells making them ideal targets for antibody drug conjugate (ADC) development.
AT2604 is an ADC that consists of a humanized IgG1 anti-ALPP/ALPPL2 antibody that displays specificity over other human alkaline phosphatases and is cross reactive to NHP ALPPL2 but not to murine ALPPL2. The anti-ALPP/ALPPL2 antibody shows high target binding affinity and internalization into ALPP and ALPPL2 positive cells.​ AT2604 utilizes AxcynCYSTM technology for site-specific conjugation to achieve a highly homogeneous (&gt;97%) DAR4 ADC product. The payload is the clinically validated microtubule disrupting agent monomethyl auristatin E (MMAE) conjugated to the antibody via a protease-cleavable peptide linker approved for ADC use.
When evaluated in mouse xenograft models of gastric (NCI-N87) and pancreatic (HPAC) cancer, AT2604 displayed strong tumor growth inhibition (&gt;90%) at 1 mg/kg (QW3 × 2 dosing) in both models. Furthermore, a pre-tox study in non-human primates concluded AT2604 has a HNSTD of 10 mg/kg (QW3 × 3 dosing) and did not exhibit any non-reversible adverse effects; implying that AT2604 possesses an improved safety profile over other vedotin-based ADCs. Taken together, the data supports the continued development of AT2604 towards evaluation in human trials.​
Citation Format: Bryan K. Yeung, Xiao Hui Koh, Wei Li Ling, Weiqi Tan, You Xue Wu, Xi Yun Zhang, Hong Yee Tan, Shao Jun Liu, Chen Zhong, Bin Zou. Development of AT2604, a highly efficacious  ADC targeting alkaline phosphatases ALPP  and ALPPL2​ [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 3137.
Abstract 3154: The role of nuclear kinases in pancreatic carcinogenesis
Authors: LaRue Kayla , Sigafoos Ashley , Flores Luis , Tader Brooke , Fernandez-Zapico Martin 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is a devastating disease predicted to be the second leading cause of cancer deaths in the next 15 years. Thus, there is an urgent need to develop new treatment approaches based on a better understanding of cellular and molecular mechanisms controlling this dismal progression. PDAC development is marked by nuclear morphological changes likely resulting in changes in chromatin organization and gene expression. Oncogenic KRAS, present in more than 90% of tumors, plays a key role in disease initiation and progression and is sufficient to induce these nuclear morphology changes. Work from our lab has identified the nuclear lamina protein Emerin as a mediator of KRAS-induced nuclear morphology changes. Further, a BioID experiment identified a KRAS-induced interaction of Emerin with a group of nuclear kinases belonging to the ribosomal S6 kinase (RSK) and mitogen- and stress- activated protein kinase (MSK) families. In silico analysis identified candidate MSK and RSK phosphorylation sites in Emerin. Thus, we hypothesize that the nuclear kinase families RSK and MSK can act as effectors of the KRAS-Emerin axis to regulate PDAC nuclear morphology. Further studies will be done to confirm if Emerin can be phosphorylated by RSK and MSK, and to validate that this relationship is dependent on oncogenic KRAS signaling and if its nuclear morphological changes are regulated by this GTPase. Overall, this work aims to define a novel signaling axis for RSK and MSK in controlling nuclear dynamics that play a role in disease progression of PDAC, which can lead to the identification of new therapeutic targets.
Citation Format: Kayla LaRue, Ashley Sigafoos, Luis Flores, Brooke Tader, Martin Fernandez-Zapico. The role of nuclear kinases in pancreatic carcinogenesis [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 3154.
Abstract 3166: Lipid nanoparticles as an efficient transfection method for the delivery of elephant TP53 and retrogene9 into osteosarcoma cells
Authors: Sanborn Madison , Rogers Aaron , Mitchell Gareth , Kennington Ryan , Sharp Miranda , Schiffman Joshua D. , Abegglen Lisa M. 
Published: March 2024

Abstract
Lipid nanoparticles (LNPs) continue to be at the forefront of nanotechnology research due to their versatile and effective ability to deliver DNA, RNA, and small molecules through the cell membrane. Since LNPs are formulated with lipids found naturally in cells, they generate a lower risk for immunogenic response and cause significantly less cell death than traditional transfection methods, such as electroporation. Our microfluidics assembled LNPs have shown transfection efficiencies over 80%, substantially higher than observed with other transfection techniques, and continues to increase over the first 72 hours. We previously reported that elephant TP53 (EP53) induces apoptosis in cancer cells at higher rates than human TP53 (huTP53), and elephant TP53 RETROGENE9 (EP53-R9) contributes to apoptosis through transcription independent mechanisms. To further characterize the effectiveness of these genes, osteosarcoma cell lines were transfected with huTP53, EP53, and EP53-R9 nanoplasmid and mRNA loaded LNPs. Cells treated with EP53 and huTP53 nanoplasmid-loaded LNPs had significantly increased caspase activity and cell death compared to those treated with the empty vector control (P&lt;.0001), with over 90% of all cells treated with either type of p53 dead after 72 hours. Immunocytochemistry was performed to image cells using confocal microscopy, which showed a 36-fold increase in TP53 signal in the nucleus of nanoplasmid LNP treated cells after 72 hours as compared to untreated osteosarcoma cells. In contrast, cells treated with the mRNA LNPs had a 7-fold increase in TP53 signal over 72 hours, though the transfection efficiency was equivalent to the nanoplasmid treated cells. Future studies will assess the efficacy of EP53 and EP53-R9 LNPs in vivo in osteosarcoma mouse models. These results demonstrate the potential of LNP mediated delivery of EP53 and EP53-R9 to be developed as a new treatment approach for cancer patients.
Citation Format: Madison Sanborn, Aaron Rogers, Gareth Mitchell, Ryan Kennington, Miranda Sharp, Joshua D. Schiffman, Lisa M. Abegglen. Lipid nanoparticles as an efficient transfection method for the delivery of elephant TP53 and retrogene9 into osteosarcoma cells [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 3166.
Abstract 3174: Crosstalk between protein translation and DNA replication during stress response and cancer therapy
Authors: Wang Fangfang 
Published: March 2024

Abstract
Tumor microenvironment, which includes both various types of cells (tumor cells, stromal cells, immune cells, etc.) and an interstitial fluid system, plays a key role in tumorigenesis, therapy response, and disease outcome. While the cell component has been heavily studied in cancer treatment, the interstitial fluid system has not. A key feature of the fluid system is constant oscillation of osmolytes such as salt, glucose, and proteins due to unstable blood supply and tumor metabolism, resulting in cycles of osmotic stress and recovery. Yet, how this osmotic stress - recovery cycle mediates tumorigenesis and cancer therapy remains poorly understood. Our unpublished results reveal sequential activation of molecular events during osmotic stress and recovery. In the stress stage, protein translation, transcription, and DNA replication are inhibited. Following recovery, protein translation resumes, gene transcription is greatly upregulated, but DNA replication is not immediately recovered. It turns out that a DNA replication checkpoint is activated during recovery; as a result, DNA replication is halted. Defects in activating protein translation inhibition during stress fail to activate the replication checkpoint during recovery, indicating a causative link from protein translation inhibition to DNA replication checkpoint activation. Many genes involved in this crosstalk are altered in a wide range of human tumors. Ovarian cancer cells that are resistant to standard of care (for instance, cisplatin) demonstrate defects in this crosstalk; however, they were also more sensitive to a combination of osmotic stress followed by the presence of replication checkpoint inhibitors during recovery than parental cancer cells. These findings highlight a unique role of the interstitial fluid system in tumor development and therapy response. They also suggest a new anticancer strategy by combining osmotic stress with checkpoint inhibitors. Key words: Tumor microenvironment; osmotic stress; protein translation control; DNA replication checkpoint; cancer therapy
Citation Format: Fangfang Wang. Crosstalk between protein translation and DNA replication during stress response and cancer therapy [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 3174.
Abstract 3193: Utilizing a pH sensitive peptide (pHLIP) for antigen-directed T cell therapy
Authors: Yurkevicz Annali M. , Liu Yanfeng , Glazer Peter M. 
Published: March 2024

Abstract
Many targeted therapies, such as antibody drug conjugates (ADCs) and chimeric antigen receptor (CAR) T cell therapies, rely on the identification of an optimal antigen as the cell marker for targeting cancer cells. However, there is a paucity of antigen candidates that are sufficiently specific to epithelial cancers. Therefore, technologies that can mark tumor cells for immune recognition could prove beneficial in the treatment of these solid cancers. pH low insertion peptides (pHLIPs) act as a unique delivery platform that can specifically target the acidic microenvironment of tumors, sparing healthy tissue in the process. We developed a pHLIP-peptide conjugate (pHLIP-SIINFEKL) to deliver the SIINFEKL peptide, an immunogenic fragment of ovalbumin, to investigate antigen delivery and recognition to tumors in vivo. When processed intracellularly, SIINFEKL is presented for immune recognition through the major histocompatibility complex (MHC) class I pathway. We observed selective delivery of pHLIP-SIINFEKL both in vitro and in vivo using fluorescently labeled constructs. In vitro, treatment of melanoma tumor cells with pHLIP-SIINFEKL resulted in recognition by SIINFEKL-specific T cells (OT1), leading to T cell activation and effector function. Mechanistically, we show that this recognition by OT1 cells was abrogated by siRNA knockdown of the β2 microglobulin (β2m) component of MHC class I in the target tumor cells, indicating that an intact antigen processing pathway in the cancer cells is necessary to mediate the effect of pHLIP-directed SIINFEKL delivery. In vivo, pHLIP-SIINFEKL treatment of tumor-bearing mice resulted in recruitment of OT1 T cells and suppression of tumor growth in two syngeneic tumor models in immunocompetent mice, with no effect when mutating either the pHLIP or SIINFEKL components of the conjugate. These results suggest that pHLIP-mediated peptide delivery can provide a novel approach to decorate solid tumors with engineered antigens for enhanced immune recognition and anti-tumor efficacy.
Citation Format: Annali M. Yurkevicz, Yanfeng Liu, Peter M. Glazer. Utilizing a pH sensitive peptide (pHLIP) for antigen-directed T cell therapy [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 3193.
Abstract 3237: KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer
Authors: Johnson Jessica D. , Chen Yihong , Jayamohan Sridharan , He Yi , Jamwal Diksha , Pandey Neetesh , Kost Edward , Vadlamudi Ratna K. , Sareddy Gangadhara R. 
Published: March 2024

Abstract
Background: Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase (KDM1A/LSD1) is highly overexpressed in OCa. However, whether KDM1A plays a role in chemoresistance and whether its inhibition enhances chemotherapy response in OCa is unknown. In this study, we explored the hypothesis that KDM1A inhibition will sensitize OCa cells to standard-of-care chemotherapy.
Methods: Transduction of KDM1A-specific shRNA was used to generate KDM1A knockdown (KD) cells. Cell viability, colony formation, and apoptosis assays were used to determine the impact of KDM1A KD on sensitization of SKOV3, OVCAR8, and OVCAR5 OCa cells to cisplatin, carboplatin, and paclitaxel. The combination effect of KDM1A inhibitors (NCD38 and SP2509) and chemotherapy drugs was further determined. Mechanistic studies were conducted using RNA-sequencing, RT-qPCR, and Western blotting. In vivo efficacy ofKDM1A knockdown with or without chemotherapy was determined using OCa orthotopic xenograft models.
Results: Analysis of TCGA datasets revealed that KDM1A expression is negatively correlated with OCa survival, and its expression is high in patients who do not respond to chemotherapy. Further, Western blotting results show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A-KD or KDM1A inhibition sensitized OCa cells to chemotherapy drugs in reducing cell viability, survival, and enhancing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistantA2780-CP70 cells to carboplatin treatment. RNA-seq studies revealed that KDM1A-KD and cisplatin-regulated genes showed negative correction with epithelial-mesenchymal transition (EMT) and positive correlation with apoptosis-related pathways. Importantly, KDM1A KD in combination with cisplatin significantly reduced the tumor growth in the orthotopic OCa xenograft model.
Conclusion: These results suggest that the combination of KDM1A inhibitors with chemotherapy is a viable therapeutic approach for the treatment of OCa
Citation Format: Jessica D. Johnson, Yihong Chen, Sridharan Jayamohan, Yi He, Diksha Jamwal, Neetesh Pandey, Edward Kost, Ratna K. Vadlamudi, Gangadhara R. Sareddy. KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer [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 3237.
Abstract 3238: Therapeutic targeting of the genome guardian sirtuins in metastatic prostate cancer
Authors: Giri Subhajit 
Published: March 2024

Abstract
Introduction: The effective treatment paradigm for the lethal form of metastatic prostate cancer (mPCa) remains challenging. Almost all mPCas eventually develops therapy resistance against androgen receptor (AR) inhibitors (e.g., Enzalutamide, Abiraterone) or to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors (Olaparib, Niraparib, Talazoparib) (HRRd) when used as monotherapy. Although the patients in the ARSi+PARPi combination produced significantly longer radiologic progression-free survival (rPFS), a substantial number had attained therapy resistance by the end of the study tenure. So, a newer therapy is urgently needed. In recent years, a new targetable therapeutics development domain has been unfolding with an expanding understanding of the role of SIRTuins in prostate cancer cell survival, invasion, and progression to an aggressive metastatic state. Here, we will investigate the therapeutic efficacy of SIRT1/7 inhibitor (SIRT1/7i) and determine synergy with DNA-damaging PARP inhibitor combinations through a battery of cell and molecular assays using various prostate cancer cellular models.
Methods: We have treated the mPCa cell lines 22Rv1, LAPC4, PC3 and LnCAP as well as prostate epithelial cell line RWPE1 with SIRT1 inhibitor SIRT1-IN-2 (MedChemExpress, HY-146689), SIRT7 inhibitor 97491 (MedChemExpress, HY-135899) and AR inhibitor Enzalutamide individually as well as in combination of PARP inhibitor Olaparib. The treatment of the SIRT1 and SIRT7 monotherapy arm was 72 hours long, and combination therapy continued for 7 days. The cell viability was assessed with CellTiter-Glo® 2.0 Cell Viability Assay (Promega). The cell cycle progression and proliferation analysis were done using flow cytometry through Propidium iodide staining and AnnexinV-FITC apoptosis detection chemistry. Cell survival was orthogonally assessed using colony counting assays. We adopt RAD51 foci counting assays and COMET assays for evaluating treatment-induced genome instability.
Results: The preliminary result suggested that the SIRT1i+Olaparib and SIRT7i+Olaparib combination significantly sensitized the mPCa cell lines 22Rv1, PC3, and LnCAP for cell death compared to the prostate epithelial cell RWPE1. Upon the combination treatment, the mPCa cell lines showed elevated apoptotic cell death, reconfirmed through colony counting assay.
Conclusion: Therapeutic combination treatment of SIRT1 and SIRT7 inhibition with Olaparib could be an effective treatment option for aggressive metastatic prostate cancer.
Citation Format: Subhajit Giri. Therapeutic targeting of the genome guardian sirtuins in metastatic prostate cancer [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 3238.
Abstract 3250: LNA gapmer to gastrin inhibits growth and metastases of human pancreatic cancer in mice
Authors: Chekuri Godhanjali , Chen Wenqiang , Shivapurkar Narayan , Cao Hong , Kularatne Ruvanthi N. , Stern Stephan , Smith Jill P. 
Published: March 2024

Abstract
Background: Pancreatic cancer has a poor prognosis and novel strategies are needed to improve the survival. Gastrin stimulates growth of pancreatic cancer by an autocrine mechanism and RNAi techniques that decrease gastrin expression have been shown to inhibit growth of this malignancy in vitro. Locked nucleic acid (LNA) Gapmers are antisense oligonucleotides (ASO) that have long half-life and stability in vivo, hence represent a potential method to deliver RNAi for cancer therapeutics. We developed an LNA Gapmer that selectively downregulates gastrin expression in pancreatic cancer cells in culture. The goal of this project was to test this anti-gastrin Gapmer in vivo as a novel therapy for pancreatic cancer.
Methods: The anti-gastrin LNA Gapmer was modified using thiol-click chemistry to conjugate a peptide to the 5’ end and render the Gapmer target-specific with the ability to bind selectively to the cholecystokinin-B receptor that is over-expressed in pancreatic cancer. Forty athymic nude mice with established AsPC-1 human pancreatic orthotopic tumors were divided into four groups of equal tumor size. Mice (N=10 per group) were treated with PBS (controls), an untargeted LNA-Gapmer, the CCK-BR targeted Gapmer (60nM), and the CCK-BR targeted Gapmer (120nM) intraperitoneally twice a week for 4 weeks. Growth was monitored by luciferase IVIS imaging. At necropsy, tumors were excised, and metastases counted.
Results: Mean tumor mass was 43% smaller in mice treated with the targeted Gapmer-120nM (P=0.0007). Untargeted and targeted Gapmer 60nM slightly decreased tumor mass but this difference was not significant. Compared to PBS control-treated mice, metastases were significantly less in mice treated with the untargeted Gapmer by -39% (p=0.01); in the targeted Gapmer-60nM by -44% (p=0.003), and with the targeted Gapmer-120nM by -72% (p&lt;0.0001). Gastrin mRNA analysis of the tumors by qRT-PCR confirmed downregulation of gastrin.
Conclusion: Novel LNA Gapmers that downregulate gastrin mRNA expression decrease growth and metastases of pancreatic cancer in a dose-related fashion.
Citation Format: Godhanjali Chekuri, Wenqiang Chen, Narayan Shivapurkar, Hong Cao, Ruvanthi N. Kularatne, Stephan Stern, Jill P. Smith. LNA gapmer to gastrin inhibits growth and metastases of human pancreatic cancer in 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 3250.
Abstract 3262: Elucidating the mechanism of resistance to tyrosine kinase inhibitors in ROS1-and ALK-fusion non-small cell lung cancer: The role of CD74
Authors: Ho Vivian , Izumi Motohiro , Lee Meghan , Shibahara Daisuke , Kobayashi Ikei S. , Kobayashi Susumu S. 
Published: March 2024

Abstract
The therapeutic landscape in treating advanced oncogene-mutated non-small cell lung cancer (NSCLC) was revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Despite the efficacious breakthrough and improved patient outcomes, disease progresses once more due to the seemingly inevitable development of drug resistance in tumor cells. This poses a considerable predicament in the clinical management of oncogene-mutated NSCLC and signifies the importance of elucidating the mechanism of resistance in tumor cells that harbor these genomic alterations which give rise to oncogenic drivers. Recent evidence suggests that drug-tolerant persister (DTP) cells, which are tolerant to initial exposure to TKIs give rise to acquired drug-resistant cells. Currently, the mechanism by which tumor cells undergo a drug-tolerant state is not well understood in NSCLCs driven by ALK or ROS1 fusion. Previously, we identified CD74 as a gene that may play a role in a drug-tolerant state in EGFR-mutated lung cancer via single-cell RNA-sequencing (scRNA-seq). Here, we sought to determine whether the CD74 signaling also leads to resistance to TKIs in NSCLCs with ALK or ROS1 fusion. We showed that CD74 expression increased at both the mRNA and protein levels after treatment with respective TKIs in ALK and ROS1 fusion cells lines. Notably, the ALK and ROS1 fusion cell lines also exhibited an increase in mRNA expression levels of upstream and downstream genes of CD74. Additionally, we generated CD74 knock-out and overexpression models in two cells lines, HCC78 (SLC34A2-ROS1 fusion) and H2228 (EML4–ALK fusion), to further examine the role of CD74 expression in DTP cells. We demonstrated that resistance to TKIs were dependent on CD74 expression. Furthermore, it was determined that anti-CD74 antibody-drug conjugates, in combination with TKIs, synergistically induced apoptosis in these cell lines. In conclusion, our data suggest that CD74 can be a therapeutic target in NSCLC with ALK or ROS1 fusion.
Citation Format: Vivian Ho, Motohiro Izumi, Meghan Lee, Daisuke Shibahara, Ikei S. Kobayashi, Susumu S. Kobayashi. Elucidating the mechanism of resistance to tyrosine kinase inhibitors in ROS1-and ALK-fusion non-small cell lung cancer: The role of CD74 [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 3262.