bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6652: Overcoming immune resistance in DNA mismatch repair deficient tumors
Authors: Mestrallet Guillaume 
Published: April 2023

Abstract
Patients with Lynch Syndrome, an inherited mismatch repair deficiency, have an increased risk for developing microsatellite unstable (MSI-H) cancers. Our team recently identified shared immunogenic frameshift peptides in patient tumors that can be targets of T cell surveillance and preventative MSI-H cancer vaccines. We hypothesize that in Lynch Syndrome some premalignant lesions are capable of evading immune surveillance from cytotoxic T lymphocytes due to immune checkpoint expression and immunosuppression from tumor, myeloid and stromal cell populations. Immune checkpoint blockade (ICB) showed promising results in the treatment of MSI-H tumors and are being evaluated in the adjuvant setting of patients with Lynch syndrome post surgical resection. However, a significant percentage of advanced MSI-H tumors resist ICB suggesting evolving mechanisms of immune resistance. We will use a MSI-H in vivo mouse model and additionally develop 3D spheroids cocultured with immune cells to characterize the underlying immune resistance mechanisms. The MSI-H mouse model will first be applied to identify shared frameshifts in MSI-H tumors by WES to develop vaccination approaches preventing tumor growth. Then, we will quantify MSI-H tumor growth and immune infiltration in the MSI-H mouse model, with or without ICB. We will analyze the presence of immunosuppressive pathways and myeloid subsets in high growth resisting tumors by immunohistochemistry, scRNAseq, spatial transcriptomics and flow cytometry. In addition, we will perform short-term in vitro spheroid-splenic cell co-cultures to better characterize the early immune resistance mechanisms. We will also perform these spheroid-immune cell co-cultures using the immune cells taken from mice after vaccination or ICB to identify the early myeloid immune resistance mechanisms. Overall, the identification of shared immune frameshifts in MSI-H tumors will allow developing peptide vaccination approaches to prevent tumor growth. Further, the identification of myeloid resistance pathways will guide therapeutic strategies against tumor resisting to ICB and/or vaccination.
Citation Format: Guillaume Mestrallet. Overcoming immune resistance in DNA mismatch repair deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6652.
Abstract 6692: Identification of circulating tumor cells based on machine learning
Authors: Lee Jae Hyuk , Park Sung Ho , Kang Jihoon , Lee Jihyun , Kim Soee , Kim Jungwon , Sohn Young Woong , Lee Jong Kil 
Published: April 2023

Abstract
Circulating tumor cells (CTC) are tumor cells that have shed into the bloodstream from primary tumor and circulate in the blood. CTC could provide better understanding of tumor metastasis and show the possibility as promising biomarker for early detection of cancer, cancer prognosis, noninvasive monitoring of treatment response, and personalized medicine. However, the isolation and characterization has been a major technological challenge due to their rareness among the massive blood cells. CytoGen’s Smart BiopsyTM CTC platform comprised of CTC isolator, IF (Immunofluorescence) Stainer, and Cell Image Analyzer is a unique and competitive technology platform for the isolation and analysis of CTC from blood. Intact live CTC could be isolated gravity-based filtration via high-density micro-porous (HDM) chip with minimized cellular damage and high retrieval rate. For the more accurate and quick analysis of CTC after isolation with Smart BiopsyTM CTC platform, we are developing the analysis method of CTC identification using machine learning technologies. Preliminary results of machine learning showed the accurate separation of CTC and PBMC (peripheral blood mononuclear cells) based on the specific markers of them. CTC identification based on machine learning technologies might be reliable analysis method and give secure information of CTC.
Citation Format: Jae Hyuk Lee, Sung Ho Park, Jihoon Kang, Jihyun Lee, Soee Kim, Jungwon Kim, Young Woong Sohn, Jong Kil Lee. Identification of circulating tumor cells based on machine learning. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6692.
Abstract 812: Treatment of metastatic cancers using immunotherapeutic cowpea mosaic virus nanoparticles
Authors: Chung Young Hun , Volckaert Britney A. , Steinmetz Nicole F. 
Published: April 2023

Abstract
This study investigates the use of an immunotherapeutic plant virus, namely the cowpea mosaic virus (CPMV), that when used prophylactically and therapeutically can protect against metastatic cancer in multiple tumor mouse models. Metastatic cancer continues to be the main cause of death of most cancer patients, and new treatment modalities must be engineered to protect patients from metastatic disease. For instance, peritoneal metastases (PMs) are oftentimes fatal, and patients survive for a median 6 months following diagnosis. PMs are common for colon, ovarian, gastric, appendiceal, and pancreatic cancers. Previously, it was demonstrated that CPMV is a potent in situ vaccine causing tumor shrinkage with abscopal effect and long-term protection observed in tumor mouse models and canine cancer patients. CPMV functions as a toll like receptor (TLR) agonist and acts on innate immune cells to induce tumor cell killing and antigen processing to eventually prime adaptative and tumor-specific immunity. However, metastatic cancers such as PMs are not easily and directly injectable and therefore, we have expanded the ability of CPMV to protect against PMs by engineering targeted CPMV nanoparticles. Data indicates that CPMV can improve survival and slow tumor growth in a murine colon PM model compared to controls and that long-term survivors are further protected from re-challenge indicating tumor specificity. Analysis from current and past studies indicate that CPMV injection into the intraperitoneal space leads to distinct upregulation of immunostimulatory cytokines and recruitment of innate immune cell populations. PMs lead to extreme declines in quality of life of patients, and current treatments can be ineffective in slowing down or reducing tumor development and death - in tackling this problem, the data clearly points to the strong potential for CPMV-mediated therapeutics in the treatment and prophylaxis of PMs.
Dr. Steinmetz is a co-founder of and has a financial interest in Mosaic ImmunoEngineering Inc. The other authors have no conflict of interest to declare.
Acknowledgments: This work is supported in part through NIH grants R01 CA274640, R01 CA224605, R01 CA253615, CDMRP W81XWH2010742, and the Shaughnessy Family Fund for Nano-ImmunoEngineering (nanoIE at UC San Diego).
Citation Format: Young Hun Chung, Britney A. Volckaert, Nicole F. Steinmetz. Treatment of metastatic cancers using immunotherapeutic cowpea mosaic virus nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 812.
Abstract 833: Exosomes isolation via lyophilization for Philadelphia-positive leukemia therapy
Authors: Rehman Fawad Ur , Qazi Rida e Maria , Sajid Zahra , Mian Afsar Ali 
Published: April 2023

Abstract
Background: Exosomes are extracellular vesicles having less than 200 nm size, secreted extracellularly by almost all types of cells. They regulate intercellular communication by delivering RNAi, proteins, viruses, and soluble factors as inherited payloads. In recent years, the application of exosomes to deliver small molecules have been widely investigated in tissue regeneration, therapeutics, as well as diagnostics. However, the isolation of exosomes has remained challenging mainly due to limitations of specialized instruments and the least cost-effective reagents. In this study, we developed a novel method to isolate exosomes from cultured cells.
Experimental: The supernatant from cultured cells was collected and subjected to lyophilization after low-speed centrifugation. The characterization and quantification of exosomes were performed using Bradford assay. Scanning Electron Microscopy (SEM) and Nanoparticles Tracking Analysis (NTA) were carried out for shape and size distribution. Western blot was performed for the evaluation of the exosome specific surface markers (CD63, CD9, CD81, calnexin, HSP70, and TSG101). The as-isolated exosomes were loaded with commercial dyes (Cy5, Eosin) for the evaluation of their drug delivery properties. Furthermore, their drug loading and release were confirmed by loading tyrosine kinase inhibitors (TKIs) as a payload. Finally, the anti-leukemic drugs (dasatinib and ponatinib) were loaded on the isolated exosomes for targeting leukemia cell line i.e., K562 and BCR-ABL expressing Ba/F3 cells in in vitro model, using MTT assay for cell proliferation and Annexin-V/PI for apoptosis detection.
Results: Here we found that the isolated exosomes have round shape with an average size of ~130 nm. They expressed known exosome markers including CD63, CD9, CD81, calnexin, HSP70, and TSG101. These exosomes could efficiently target and deliver dyes (Eosin and Cy5) and TKIs (dasatinib and ponatinib) to K562 and Ba/F3-cells expressing BCR-ABL. The TKIs-loaded exosomes inhibited the growth of leukemic cells and induced apoptosis in a dose dependent manner.
Conclusion: We claim the development of a new method for active exosome isolation from cell culture. These exosomes could qualify for all the essential characterization, drug loading, and release ability by harnessing proliferation and inducing apoptosis in Ph+ leukemia cells.
Citation Format: Fawad Ur Rehman, Rida e Maria Qazi, Zahra Sajid, Afsar Ali Mian. Exosomes isolation via lyophilization for Philadelphia-positive leukemia therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 833.
Abstract 837: Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases
Authors: Adams Gregory P. , Khor Tin , Chen Feng , Ma Kai , Scocca Marion , Venkatesan Aranapakam , Reddick Cathy , Hilgart Mary , Gardinier Thomas , Wu Fei , Turker Melik , Chen Peiming , Patel Vaibhav , Bayever Eliel 
Published: April 2023

Abstract
Antibody-drug conjugates (ADCs) exhibit limited efficacy against brain malignancies due to their inability to cross the blood-brain barrier (BBB) and penetrate into solid tumors. In clinical imaging studies C’Dots readily crossed tumor-disrupted BBB and penetrated across/localized in tumors in the brain avoiding healthy brain. CDCs are ultra-small (6-7 nm) nanoparticles with a silica core coated by short polyethylene glycol chains conjugated to up to 80 small payload and targeting moieties, creating highly potent and avid agents. CDCs’ small size mediates rapid renal clearance leading to limited exposure to healthy tissues.
ELU001 is a potent anti-FRα CDC with an average of 21 exatecan topoisomerase-1 inhibitor payload molecules and 13 folic acid targeting molecules on its surface. ELU001 is currently in a dose escalation trial in patients with systemic solid tumor indications that have the potential to overexpress FRα. Early signs of activity with a manageable safety profile have been seen across antigen expression levels.
ELU001 exhibits in vitro potency in the sub/low nanomolar range against cancer cell lines that express 3+, 2+ or 1+ levels of FRα. In studies performed in immunodeficient mice bearing intracranial NCI-H2228-luc bioluminescent non-small cell lung cancer tumors, ELU001 was observed to penetrate across disrupted BBB and localize in tumors. Microscopic analysis revealed that ELU001 distributed throughout the tumors but not into the healthy brain. Treatment with a single cycle of ELU001 Q3Dx3 in mice bearing either early (Day 7) or late (Day 14) brain tumors was well tolerated and resulted in significant reduction in tumor burden measured by bioluminescence as well as a prolonged survival benefit. Retreatment of these animals resulted in an additional decrease in tumor burden. These results suggest that ELU001 may have promise for the treatment of metastatic brain tumors that are difficult to treat with currently available agents.
Citation Format: Gregory P. Adams, Tin Khor, Feng Chen, Kai Ma, Marion Scocca, Aranapakam Venkatesan, Cathy Reddick, Mary Hilgart, Thomas Gardinier, Fei Wu, Melik Turker, Peiming Chen, Vaibhav Patel, Eliel Bayever. Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 837.
Abstract 860: The dynamics of LINE-1 retrotransposition in cellular populations
Authors: Martis Stephen , Solovyov Alexander , Lihm Jayon , Li Hao , Greenbaum Benjamin 
Published: April 2023

Abstract
Retrotransposons are genetic elements that have the ability to copy and paste themselves in the genome via the proteins they encode. Since the rapid growth of a retrotransposon can be highly deleterious at the organismal level, many of these genetic parasites are suppressed or have been inactivated over evolutionary time. However, the human genome still hosts the active retrotransposon LINE-1, whose aberrant expression is associated with various diseases, especially epithelial cancers. Despite these associations, a quantitative understanding of the dynamics and diversity of LINE-1 insertions in somatic tissue is lacking. In order to address this gap, we present a population dynamic model of LINE-1 retrotransposition in individual cells. Using the model, we show that at demographic equilibrium, the LINE-1 copy number distribution is broader than would be expected from classical population genetic models. We demonstrate how this broadening distorts the frequency spectrum of insertions. We compare the model's predictions to data from whole genome sequencing of individual tumor cells.
Citation Format: Stephen Martis, Alexander Solovyov, Jayon Lihm, Hao Li, Benjamin Greenbaum. The dynamics of LINE-1 retrotransposition in cellular populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 860.
Abstract 882: Functional enrichment analysis of somatic mutations identifies novel risk factors for pediatric neuroblastoma
Authors: Middleton Nolan D. , Shelden Eric 
Published: April 2023

Abstract
Pediatric neuroblastoma is among the most common solid tumors in children and accounts for approximately 15% of childhood cancer mortalities. Neuroblastomas are highly heterogeneous cancers, and few common genetic alterations are currently associated with neuroblastoma tumorigenesis. Additionally, few genetic variations have been established as predictive factors for clinical outcomes in neuroblastoma cases. Here, a biological systems-level approach utilizing publicly-accessible data from the Genomic Data Commons was taken to identify genetic variations associated with altered survival times in neuroblastoma cases. Two survival analyses of clinical neuroblastoma cases were conducted: one associated with genetic variations in individual somatic genes and the other associated with groups of mutations identified using functional enrichment analysis. Mutations in only two individual genes displayed significant associations with altered survival: ALK (ALK receptor tyrosine kinase), a known hallmark of neuroblastoma, and DNAH17 (dynein axonemal heavy chain 17). In contrast, patient cohorts established by functional enrichment analysis of mutated genes identified 148 biological systems where somatic gene variations were significantly associated with altered survival. Gene sets defined by the function of their products in ALK signaling, as well as alteration in cells treated with Crizotinib, an inhibitor of receptor tyrosine kinases including ALK, both displayed highly significant association with altered survival. Of the 148 systems identified, 128 others lacked any association with ALK. Of these, eight showed a more significant association with altered survival than the ALK signaling pathway itself. These results identify novel risk factors associated with reduced survival in pediatric neuroblastoma patients
and illustrate the potential of systems-level analysis to generate insight into the biology of heterogeneous cancers.
Citation Format: Nolan D. Middleton, Eric Shelden. Functional enrichment analysis of somatic mutations identifies novel risk factors for pediatric neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 882.
Abstract 91: Multi-omic single-cell approach reveals transcriptional and epigenetic plasticity in breast cancer
Authors: Mohammed Hisham 
Published: April 2023

Abstract
Breast cancer is known to be highly heterogenous at the transcriptional and genetic level. In order to study functional consequences of this heterogeneity, we applied single-cell RNA-seq and single-cell Multi-ome (RNA+ATAC) on hormone responsive cell line and organoid models after multiple timepoint hormone treatments. We also developed TITAN, an LDA based machine learning tool to identify ‘cell states’ in single-cell datasets. Our results suggest that response to hormone signalling is highly heterogenous at the single-cell level, resulting in multiple divergent epigenetic and transcriptional cell states. We identified driver transcription factors for these states and defined epigenetic mechanisms regulating state change. Subsequently, we also investigated epigenetic and transcriptional states in primary breast tumors. We analysed 20 breast tumor samples using the single-cell Multi-ome (ATAC+RNA) approach and compared them to matched adjacent normal tissues. Our results identified epigenetic reprogramming events in breast cancer and novel transcription factors in the process. Using bulk DNA-sequencing as a reference, we inferred sub-clonal populations from both the RNA and ATAC modalities, allowing us to define heterogenous chromatin accessibility events that align with genetic sub-clones as well as those that are independent of it. Our dataset provides a comprehensive view of epigenetic and transcriptional events in breast tumorigenesis.
Citation Format: Hisham Mohammed. Multi-omic single-cell approach reveals transcriptional and epigenetic plasticity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 91.
Abstract 946: A silver jubilee for synthetic lethality in cancer treatment: where do we stand
Authors: Lee Joo Sang , Chung Youngmin , Kammula Ashwin V. , Schaffer Alejandro A. , Ruppin Eytan 
Published: April 2023

Abstract
Background: Synthetic lethality (SL) denotes a genetic interaction between two genes whose co-inactivation is detrimental to cells. Since the seminal paper of Hartwell and colleagues has raised the possibility that SL can be used to devise highly selective cancer treatments, it has been one of the promising approaches for precision oncology and drug discovery. Many different avenues have so far been explored to bring this idea to the clinic. As 25 years have passed by now, we take stock and systematically and comprehensively chart the landscape of SL-based preclinical research and clinical trials.
Approach and Key Findings: We systematically mined both public and commercial databases to curate the preclinical and clinical landscape of the SL-based oncology studies. Our analysis shows that the number of SL oncology studies is rapidly growing since the first identification of the well-known BRCA-PARP synthetic lethality axis. Importantly, we find that the success rate of SL oncology trials is significantly higher than non-SL-based trials. While more than 70% of SL-oncology trials involve genes in the most-studied DNA damage response (DDR) pathways, the fraction of SL trials involving non-DDR pathways keeps growing since 2009. We further charted the landscape of SL triplets, which is a promising future higher-order extension of the conventional pairwise SL interactions. We find that only about 8% of preclinically validated SL triplets were clinically tested in trials, providing new opportunities for more refined clinical trial design. Our analysis suggests that emerging opportunities in SL oncology may arise from metabolic and paralogous interactions, disease-agnostic biomarkers, context-specific combinations against treatment resistance, artificial intelligence and data science approaches, and multi-omics patient stratification signatures.
Significance: Taken together, our findings testify that a considerable potential benefits of SL based approaches are yet untapped, reinforcing the belief that the synthetic lethality approach may serve as a key driver of precision oncology going forward.
Citation Format: Joo Sang Lee, Youngmin Chung, Ashwin V. Kammula, Alejandro A. Schaffer, Eytan Ruppin. A silver jubilee for synthetic lethality in cancer treatment: where do we stand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 946.