bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1327: Affinity tuning anti-CD123 chimeric antigen receptor natural killer cell therapy to treat acute myeloid leukemia
Authors: Kizerwetter Monika , Yang Huilin , Rahnama Ruyan , Bonifant Challice , Spangler Jamie 
Published: March 2024

Abstract
Acute myeloid leukemia (AML) is a highly prevalent blood and bone marrow cancer characterized by the uncontrolled growth of abnormal myeloblasts. Current treatments for AML often result in systemic toxicities for patients, many of whom will still experience relapse. There is thus an unmet need to develop safer and more effective therapies targeting AML. Chimeric antigen receptor (CAR) T cells, which are engineered to express a cancer-targeting extracellular antibody single-chain variable fragment (scFv) linked to an intracellular T cell-activating domain, have shown promise in treating B cell leukemias, but their success has been limited in myeloid leukemias. This is due in part to the lack of AML-specific target antigens. Moreover, impaired T cell function, a hallmark of AML, is also problematic when relying on autologous T cell activation upon reinfusion. We overcame the limitations of CAR T therapy in AML by developing CAR-expressing natural killer (NK) cells targeting CD123. While present on both healthy and AML cells, CD123 is expressed at &gt;10-fold higher levels on malignant cells. Furthermore, use of NK allows use of fully functional allogeneic cells from healthy donors, since NK cells do not induce graft-versus-host-disease. To optimize the tumor cell selectivity of CAR NK cells, we employed the yeast display directed evolution platform to isolate anti-CD123 scFvs with varying affinities and are identifying and characterizing clones that maximize the interaction with CD123high AML cells over healthy CD123low cells, as determined by binding, cytotoxicity, cytokine secretion, and intracellular signaling studies. Collectively, our efforts introduce a new paradigm for engineered cell therapeutics with significant promise for AML treatment.
Citation Format: Monika Kizerwetter, Huilin Yang, Ruyan Rahnama, Challice Bonifant, Jamie Spangler. Affinity tuning anti-CD123 chimeric antigen receptor natural killer cell therapy to treat acute myeloid leukemia [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 1327.
Abstract 1398: The role of ST8SIA2 & ST8SIA4 in melanoma progression and metastasis
Authors: Amirfallah Amirali , Gallant Kayla , Cavallo Maria , Huang Zongguan , Hartsough Edward 
Published: March 2024

Abstract
Melanoma is the deadliest form of skin cancer; while early detection affords patients a 5-year survival rate greater than 90 percent, survival for metastatic patients is poor. Metastatic dissemination is reliant on melanoma’s ability to escape immune surveillance and migrate to distant organs. These processes are heavily influenced by cell surface proteins, which themselves can be regulated by post-translational modifications (PTM) like protein glycosylation. An understudied glycosylation that may affect immune evasion and cancer progression is polysialylation (polySia). Here, a long-chained polymer of sialic acid moieties is formed by the polysialyltransferases ST8SIA2 and ST8SIA4. In silico analysis suggests that compared to normal skin, primary cutaneous melanoma has elevated expression of both ST8SIA2 and ST8SIA4. Interestingly, although ST8SIA4 is upregulated in metastatic samples, its expression is associated with increased survival. Further analysis revealed a positive correlation between CD8+ T cell infiltrates and ST8SIA4 expression. Furthermore, analysis of ST8SIA2 expression shows an inverse correlation with survival and T Cell CD8+ cells infiltration, suggesting ST8SIA2 and -4 differentially regulate the tumor immune microenvironment. One potential polySia modified cell surface protein, mediating these effects is Cell Adhesion Molecule 1 (CADM1). CADM1 is a target of ST8SIA2 and may also be modified by ST8SIA4. Loss of CADM1 increases the invasive properties of melanoma cells and our recent point mutational analysis reveals that the adhesive function of CADM1 might be regulated by polySia at Asp 113. In addition to its role in cancer migration and invasiveness, CADM1 expression may also affect the tumor immune environment. Further investigations are needed to untangle the complex relationship between PolySia modification and melanoma immune evasion and metastasis.
Citation Format: Amirali Amirfallah, Kayla Gallant, Maria Cavallo, Zongguan Huang, Edward Hartsough. The role of ST8SIA2 & ST8SIA4 in melanoma progression and metastasis [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 1398.
Abstract 1421: The HDAC6-specific inhibitor AVS100 (SS208) blocks M2 polarization of tumor associated macrophages and potentiates immunotherapy in preclinical tumor models
Authors: Kovalovsky Damian , Noonepalle Satish , Suresh Manasa , Kumar Dileep , Berrigan Michael , Horvath Anelia , Kim Allen , Quiceno-Torres David , Musunuri Karthik , Villagra Alejandro 
Published: March 2024

Abstract
Inhibition of HDAC6 was associated with an increased proinflammatory tumor microenvironment and an antitumoral response. Here, we show that a highly specific HDAC6 inhibitor AVS100 (SS208), blocks M2 polarization in murine and human macrophages while partially affecting M1 polarization. AVS100 effects were observed as blocked upregulation of M2-related gene signature under M2 polarizing conditions and blocked generation of CD206+ and Arg1+ macrophages. Oral administration of AVS100 had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti-PD1 treatment, leading to complete remission in melanoma and increased response in colon cancer. Flow cytometry and scRNAseq analysis of tumor-infiltrating immune cells revealed an increase of proinflammatory/anti-inflammatory ratio in tumor-associated macrophages as well as an increase of intratumoral CD8 effector T-cells after AVS100 treatment. Interestingly, cured mice didn’t relapse and became resistant to a subsequent tumor challenge, suggesting acquired antitumoral T-cell immunity. T-cell repertoire analysis of effector/memory T-cells in cured mice revealed a higher number of immunodominant T-cell clones after AVS100 treatment, indicating increased T-cell expansion. Finally, AVS100 has demonstrated no mutagenicity and a strong safety profile in rats and dogs, leading to its recent U.S. FDA clearance of an Investigational New Drug (IND) application and planned initiation of Phase Ia/b clinical trials targeting locally advanced or metastatic solid tumors in the first half of 2024. Altogether, we have performed the preclinical characterization of a novel small molecule inhibitor targeting HDAC6 for solid cancers. AVS100 had an antitumoral effect as single agent and improved the efficacy of immune checkpoint inhibition by blocking the immunoregulatory tumor microenvironment and increasing T-cell immunity.
Citation Format: Damian Kovalovsky, Satish Noonepalle, Manasa Suresh, Dileep Kumar, Michael Berrigan, Anelia Horvath, Allen Kim, David Quiceno-Torres, Karthik Musunuri, Alejandro Villagra. The HDAC6-specific inhibitor AVS100 (SS208) blocks M2 polarization of tumor associated macrophages and potentiates immunotherapy in preclinical tumor models [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 1421.
Abstract 1422: A novel gut microbiota therapeutic approach for enhancing immune checkpoint inhibitor therapy
Authors: Valle Priscilla Del , Nguyen Gabriella , Choi Yongbin , Sabaeifard Parastoo , li Wenng , Lichterman Jake , Coughlin Laura , Poulides Nicole , Sanjuan Angelica , Koh Andrew Y. 
Published: March 2024

Abstract
Immune checkpoint inhibitor therapy (ICT) has revolutionized cancer care, but up to 50% of patients do not respond to ICT. A host factor implicated in variable ICT response is the gut microbiome: a) germfree/antibiotic-treated mice do not respond to ICT; b) human ICT responders have distinct gut microbiome signatures compared to non-responders; and c) fecal microbiota transplants are safe and potentially effective in cancer patients previously unresponsive to ICT. We have previously established that ICT induces translocation of gut microbiota into secondary lymphoid tissues (particularly the mesenteric lymph nodes) and tumor which is required to enhance extraintestinal anti-tumor immunity (PMID: 36867675). Here, we have developed a novel gut microbiota therapy (GMT) which circumvents the challenges and limitations of conventional microbiome therapies that use live microbes. GMT utilizes specific components derived from commensal gut microbiota identified in our published clinical study (PMID:28923537) that can be administered parenterally (subcutaneous/intravenous) to safely and reproducibly enhance ICT efficacy in multiple preclinical cancer models (B16-F10 with anti-PD-1 and/or CTLA-4, MC38 with or without anti-PD-1, humanized mouse with human melanoma and human anti-PD-1). GMT acts by agonizing the pattern recognition receptors hTLR1/2/6, hNOD2 and hSTING. GMT induces anti-tumor cytokines (IL-12) but does not significantly increase sepsis associated cytokines (IL-6, TNFa) in both human immune cells and in non-human primates. Mechanistically, GMT acts via dendritic cells, and potentially through increased expression of delta-like ligand protein 4 (DLL4), a Notch signaling ligand that activates Notch 1/4 in T cells and promotes Th1 and Th17 differentiation. Current efforts to identify the active components of GMT are underway in which we have used serial liquid-liquid extractions (ethyl acetate followed by water:methanol:chloroform) and subsequent reverse phase chromatography to identify the most active fractions and identification of the bacterial components/constituents within these fractions. Together, these results demonstrate that GMT has the potential to serve as an innate immune adjuvant (akin to vaccine adjuvants) that enhances the effect of immunotherapy for possibly many cancer types.
Citation Format: Priscilla Del Valle, Gabriella Nguyen, Yongbin Choi, Parastoo Sabaeifard, Wenng li, Jake Lichterman, Laura Coughlin, Nicole Poulides, Angelica Sanjuan, Andrew Y. Koh. A novel gut microbiota therapeutic approach for enhancing immune checkpoint inhibitor 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 1422.
Abstract 1430: Development of transparent transgenic zebrafish model to study anti-cancer drug induced in vivo cardiotoxicity
Authors: Rajpurohit Surendra K. , Gossman Taitum , Nasanally Sai , Bhatt Keshu , Van Derhei Aiden , Hotwani Simran , Manhiani Devan-Anmol , Pasi Rohan , Mi Jiaqi , Arora Vishal , Lokeshwar Balakrishna 
Published: March 2024

Abstract
Cardiotoxicity is the second leading cause of death among cancer survivors and can manifest as arrhythmia, acute coronary syndrome, acute heart failure, or pericarditis/myocarditis. Chronic myocyte damage and apoptosis can transition from an asymptomatic phase to adaptive myocardial hypertrophy, followed by decreased left ventricular ejection fraction, and eventual heart failure. Cardio-oncology is an emerging field that studies cancer therapy-associated cardiotoxicities. The development of reliable and effective preclinical models for cardiotoxicity prediction and prevention is essential to improving the long-term cardiac health of cancer patients. Zebrafish are a promising animal model for the field of cardio-oncology and have emerged as an invaluable tool for investigating genetic and molecular aspects of cardiovascular research. Zebrafish heart cells are like human heart cells at the molecular level, making them an ideal system for studying the genetic underpinning of cardiac function. Zebrafish myl7 gene, a myosin light chain-7 gene, is a regulatory gene of heart orthologs to human MYL7. In-vivo imaging is limited due to the opacification of skin and subdermal structures. To conduct in-vivo whole organism imaging studies, skin transparency is a primary requirement, necessitating the blocking of pigmentation. The Zebrafish Casper mutant maintains skin transparency throughout its life, offering the ideal combination of sensitivity and resolution for in-vivo analyses and imaging. In this study, we have developed a novel transparent transgenic zebrafish model and established time-lapse in-vivo confocal microscopy to study cellular phenotype/pathologies of cardiomyocytes. The newly developed homozygous transparent transgenic Casper/myl7:RFP; annexin-5:YFP/NF-kB: GFP/mpeg1:mcherryFP, allows us to study cell death process (Annexin5) and inflammatory activity (NF-kB) in microglia and cardiomyocytes. We have successfully established in vivo fluorescence and confocal microscopy in this newly developed strain, enabling the study of cellular morphology and function changes under various conditions. This will allow us to elucidate cell death patterns, and cardio-inflammatory and cardiotoxicity pathways.
Citation Format: Surendra K. Rajpurohit, Taitum Gossman, Sai Nasanally, Keshu Bhatt, Aiden Van Derhei, Simran Hotwani, Devan-Anmol Manhiani, Rohan Pasi, Jiaqi Mi, Vishal Arora, Balakrishna Lokeshwar. Development of transparent transgenic zebrafish model to study anti-cancer drug induced in vivo cardiotoxicity [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 1430.
Abstract 1434: Modeling the 3q26 OncCassette using genetically engineered mice
Authors: Meneses Kayleah M. , Liu Yi , Weems Capella R. , Jamieson Lee , Nguyen Duy T. , Justilien Verline , Murray Nicole R. , Fields Alan P. 
Published: March 2024

Abstract
Lung squamous cell carcinoma (LUSC) is a devastating disease, accounting for ~30% of all lung cancer diagnoses and ~40,000 deaths annually in the United States alone. LUSC patients suffer from high prevalence of relapse and a dismal 5-year survival of only ~24%. The lack of animal models that reflect the salient features of human disease to assess the safety and efficacy of drugs, and to explore the underlying molecular mechanisms of LUSC tumor biology, is a major impediment for LUSC patients. We have identified concomitant 3q26 copy number gain (CNG) and TP53 loss as a defining genetic alteration present in ~90% of LUSC tumors. Furthermore, we have identified and characterized three 3q26 oncogenes (PRKCI, ECT2 and SOX2) that genetically and biochemically collaborate to drive LUSC tumor formation. Using syngeneic mouse modeling, we have demonstrated that coordinate overexpression of Prkci, Ect2 and Sox2, and loss of Trp53 in ex vivo cultures of lung basal stem cells (LBSCs; a cell of origin for LUSC) drives transformation of these cells into tumors of exclusively LUSC histopathology. These findings lead to the hypothesis that PRKCI, ECT2 and SOX2 represent a multigenic driver of 3q26 CNG-driven LUSC, which we term the 3q26 OncCassette. Based in these findings, we have developed and begun characterizing the first autochthonous genetically engineered mouse model (GEMM) to study 3q26 OncCassette-driven tumorigenesis. Our novel immune competent GEMM will provide critical insight into tumor initiation and progression of preneoplastic lesions to malignant LUSC and allow characterization of the immune landscape in these tumors.
Citation Format: Kayleah M. Meneses, Yi Liu, Capella R. Weems, Lee Jamieson, Duy T. Nguyen, Verline Justilien, Nicole R. Murray, Alan P. Fields. Modeling the 3q26 OncCassette using genetically engineered 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 1434.
Abstract 1440: Retinoblastoma binding protein 9 regulates intestinal inflammation and inflammation-associated carcinogenesis
Authors: Nakanishi Yuki , Hamada Kensuke , Omatsu Mayuki , Iwane Kosuke , Kitamoto Hiroki , Okabe Maokoto , Muta Yu , Yamamoto Shuji , Fukuda Akihisa , Kasashima Hiroaki , Seno Hiroshi 
Published: March 2024

Abstract
The intestinal epithelium constitutes the mucosal barrier, and its dysfunction promotes microbial invasion from the gut lumen, which further induces the intestinal inflammation. Chronic intestinal inflammation, as observed in poorly controlled inflammatory bowel diseases (IBD), leads to the development of inflammation-associated cancer. Thus, a deeper understanding of the regulatory system that controls intestinal homeostasis is essential. Retinoblastoma-binding protein 9 (RBBP9) is expressed in a range of human cancer cells. RBBP9 was initially reported to have the ability to regulate the cell cycle pathway. More recent studies have identified RBBP9 as a serine hydrolase (SH) that promotes cancer progression by subverting the anti-proliferative function of TGFβ in a pancreatic cancer model. However, little is known about the roles RBBP9 plays in the development of intestinal cancer. In this study, we investigated the role of RBBP9 in inflammation and inflammation-associated cancer in the intestine. Analyses of surgically resected human samples and publicly available datasets demonstrated that RBBP9 expression was reduced in patient samples of ulcerative colitis (UC) and colitis-associated cancer (CAC). Genetically knockout mice for Rbbp9 (Rbbp9−/−) were susceptible to experimental colitis induced by dextran sulfate sodium (DSS). Furthermore, Rbbp9−/− mice exhibited enhanced azoxymethane/DSS-induced tumorigenesis, a model for human CAC. Mechanistically, RNA sequencing of these tumors showed increased enrichment of inflammation-associated signatures, including interferon signaling pathways. Ex vivo organoid experiments revealed the suppressive function of RBBP9 in interferon signaling-mediated apoptosis of the intestinal epithelium. Simultaneous inhibition of RBBP9 and STAT1, a downstream transcription factor of interferon signaling, reverted the apoptotic phenotype of Rbbp9−/− organoids. Collectively, our data provide insight into the understanding of the crucial role of RBBP9 in protecting against intestinal inflammation and inflammation-related tumorigenesis via regulating the interferon signaling-mediated apoptotic pathway.
Citation Format: Yuki Nakanishi, Kensuke Hamada, Mayuki Omatsu, Kosuke Iwane, Hiroki Kitamoto, Maokoto Okabe, Yu Muta, Shuji Yamamoto, Akihisa Fukuda, Hiroaki Kasashima, Hiroshi Seno. Retinoblastoma binding protein 9 regulates intestinal inflammation and inflammation-associated 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 1440.
Abstract 1489: The role of EPAS1 and TEAD1 in gastric cancer liver metastasis
Authors: Lee DONG KI , Park Hyun Woo , Cheong Jae-Ho , Gee Heon Yung 
Published: March 2024

Abstract
Gastric cancer ranks fifth in incidence and fourth for cancer-related mortality worldwide. While the liver is widely recognized as the leading site of metastasis in gastric cancer, the intricate mechanisms underpinning its tropism toward the liver and the hematogenous metastasis process remain poorly understood and demand further investigation.
Hematogenous metastasis encompasses the generation of circulating tumor cells from the primary tumor site and their subsequent attachment to the metastatic niche. This process involves the transition between adherent and suspension states. In our investigation of anchorage dependency, we identified 20 transcription factors upregulated in suspension cells compared to adherent cells and 18 transcription factors upregulated in adherent cells relative to suspension cells, respectively.
To investigate factors involved in gastric cancer metastasis, RNA sequencing of paired primary and metastatic tissue samples obtained from 15 patients diagnosed with advanced gastric cancer was conducted, which disclosed the selective upregulation of EPAS1 and TEAD1 in metastatic liver tissue compared to the matched primary tumor tissue and the metastatic tissue originating from other sites.
Through in vitro analysis, we observed a portion of adherent cells transitioning into suspension cells when subjected to a hyperdense environment. We also observed cell reattachment upon harvesting and replating these suspension-state transited cells. Comparing EPAS1 and TEAD1 expression in these states unveiled increased expression of EPAS1 and TEAD1 in reattached cells relative to suspension-state cells.
We established a gastric cancer metastasis mouse model introducing gastric cancer cells into the mouse circulatory system via intracardiac injection to validate our findings. In vivo imaging was utilized to confirm systemic metastasis. After fluorescence-based cell sorting, EPAS1 and TEAD1 expression in cancer cells collected from the blood, liver, and ovary were assessed. We detected higher expression of EPAS1 and TEAD1 in liver metastasis compared to the circulating tumor cells. Furthermore, EPAS1 and TEAD1 were upregulated in liver metastatic cancer cells compared to ovarian metastatic cancer cells.
Our findings underscore EPAS1 and TEAD1 as pivotal factors governing gastric cancer liver tropism and metastasis, offering insights that may contribute to targeted interventions in the clinical landscape.
Citation Format: DONG KI Lee, Hyun Woo Park, Jae-Ho Cheong, Heon Yung Gee. The role of EPAS1 and TEAD1 in gastric cancer liver metastasis [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 1489.