tbuckley/cabot-search huggingface dataset:
Abstract 5268: Targeting DHX9 triggers interferon response and replication stress in small cell lung cancer
Authors: Takahiko Murayama, Jun Nakayama, Kathy Q. Cai, Kenichi Miyata, Andrey Efimov, Yinfei Tan, Yan Zhou, Kerry S. Campbell, Yibin Yang, Siddharth Balachandran, Israel Cañadas
Journal: Cancer Research (2024)

Abstract Small cell lung cancer (SCLC) is the most lethal type of lung cancer. The uniqueness of this tumor consists of an initial exquisite response to chemotherapy. However, at relapse, which occurs nearly in all patients, the tumor is resistant to all available therapies, causing a premature death of the patient. Despite the addition of immune checkpoint blockade (ICB) therapy to standard chemotherapy, response rates are modest and only a very small fraction of SCLC patients responds to these therapies because of immunologically “cold” microenvironment. Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry”, has emerged as an effective strategy to convert immunologically “cold” tumors into “hot”. Here, through a curated CRISPR-based screen of RNA Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in SCLC cells. Depletion of DHX9 induced accumulation of cytoplasmic dsRNA, which mainly derived from repetitive sequences of short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs), and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced the aberrant accumulation of R-loops (DNA/RNA hybrids), which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in tumor cells, selectively killing them. In vivo, DHX9 deletion in SCLC tumor cells promoted a decrease in tumor growth while inducing a more immunogenic tumor microenvironment (TME), invigorating responsiveness to immune checkpoint blockade (ICB). These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, and represents a promising and unexplored target for SCLC and other “cold” tumor types where replication stress and genomic instability contribute to pathology. Citation Format: Takahiko Murayama, Jun Nakayama, Kathy Q. Cai, Kenichi Miyata, Andrey Efimov, Yinfei Tan, Yan Zhou, Kerry S. Campbell, Yibin Yang, Siddharth Balachandran, Israel Cañadas. Targeting DHX9 triggers interferon response and replication stress in small cell lung 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 5268.
Abstract 4727: Large scale drug response comparison across different neuroblastoma cell model systems
Authors: Se Whee Park, Ernest Liu, Aironas Los, Brinton Seashore-Ludlow, Päivi Östling, Jan Molenaar, Olli Kallioniemi, Jakob Stenman, Kasper Karlsson
Journal: Cancer Research (2024)

Abstract Traditionally neuroblastoma research has predominantly used 2D cell lines, which, despite their simplicity, often fall short in mirroring the physiological complexity of actual tumors. Recently, 3D models like patient-derived tumor organoids (PDO) and patient-derived xenografts (PDX) have emerged as superior alternatives, offering more realistic predictions of patient treatment responses. This study aims to discern the differences in drug response between conventional 2D cell lines and the more advanced 3D neuroblastoma models - specifically, patient-derived organoids (nPDO) and patient-derived xenograft organoids (nPDXO). Employing high-throughput drug screening of 528 cancer drugs, we evaluated the drug responses across traditional 2D cell lines, nPDOs, and nPDXOs. Additionally, focused experiments with 29 selected drugs were conducted to determine the influence of culture topology on drug efficacy. The findings were compared to a study by Hansson et al.1 that used nPDXO. Our study discovered a pronounced difference in drug sensitivity between 2D cell lines and 3D models, with 3D models showing heightened sensitivity. Interestingly, 2D cell cultures had a more heterogenous drug response compared to 3D models. The drug response correlation between nPDOs and nPDXOs was relatively high (Spearman ~0.8), indicating consistent responses across these models. Our comparison underscores the impact of model system choice on drug response studies in neuroblastoma. The study highlights important differences in drug response between neuroblastoma 2D and 3D cell culture models. However, only subtle differences were found between PDO and PDX-derived organoid lines, despite differences in treatment centers and media compositions. This suggests that while the choice of cell culture topology greatly impacts drug response, PDO and PDX derived lines can largely be used interchangeably for drug screening experiments. References: 1. Hansson et al, ﻿Therapeutic targeting of KSP in preclinical models of ﻿high-risk neuroblastoma, Science Translational Medicine(2020) Citation Format: Se Whee Park, Ernest Liu, Aironas Los, Brinton Seashore-Ludlow, Päivi Östling, Jan Molenaar, Olli Kallioniemi, Jakob Stenman, Kasper Karlsson. Large scale drug response comparison across different neuroblastoma cell model systems [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 4727.
Abstract 1638: Regulation of spindle pole integrity by the MASTL-ENSA-aurora a pathway during mitosis
Authors: Seul Kim, Kyoungho Jun, Ye-Hyun Kim, Jae Sung Kim
Journal: Cancer Research (2024)

Abstract The preservation of spindle pole integrity is crucial for proper spindle assembly and chromosome segregation in mitosis, yet the precise mechanisms governing spindle pole integrity remain elusive. During mitosis, phosphorylated Ensa (p-ENSA) localizes to spindle poles, and the inhibition of ENSA leads to a range of mitotic defects, including misaligned chromosomes, multipolar spindles, asymmetric bipolar spindles, and centrosome aberrations, resulting in a delayed mitotic progression. Remarkably, the mitotic delay induced by ENSA inhibition is alleviated upon depletion of PP2A-B55α, but spindle pole defects persist. Significantly, we have observed an interaction between ENSA and Aurora A during mitosis, and the inhibition of ENSA diminishes Aurora A expression at the mitotic spindle poles. Intriguingly, the injection of MKI-2-sensitized tumors is associated with heightened chromosomal instability and downregulation of the MASTL-ENSA-Aurora A pathway in an orthotopic breast cancer mouse model. These findings offer new insights into the regulation of spindle pole integrity through the MASTL-ENSA-Aurora A pathway during mitosis, emphasizing the pivotal role of ENSA in recruiting Aurora A to the spindle pole, independently of PP2A-B55α. Citation Format: Seul Kim, Kyoungho Jun, Ye-Hyun Kim, Jae Sung Kim. Regulation of spindle pole integrity by the MASTL-ENSA-aurora a pathway during mitosis [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 1638.
Abstract 1645: Telomere-related genes associated with clinical-pathological in pancreatic ductal adenocarcinoma
Authors: Erika Curiel Gómez, Vilma Maldonado Lagunas, Jorge Meléndez Zajgla
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) ﻿stands as one of the leading causes of cancer deaths worldwide. Studies have suggested that telomeres shortening is linked to genetic instability, higher risk of developing pancreatic cancer and pancreatic tumorigenesis. However, previous research has predominantly focused on either telomere length or specific telomere-related genes in pancreatic cancer. Therefore, it is essential to elucidate the association between telomere-related genes and pancreatic cancer to identify novel ﻿therapeutic strategies and establish prognostic biomarkers. Telomere-relevant genes were downloaded from the TelNet database. Expression data from primary tumour of The Cancer Genome Atlas-PAAD (TCGA-PAAD) cohort, the Genome Sequence Archive CRA001160 dataset and the GTEx database were obtained for screen for differentially expressed genes (DEGs). Gene set enrichment analisis was performed using the Enrichr software. The gene essentiality queried from the gene dependency database of the Achilles-DepMap project was also assessed. Finally, data of The Cancer Genome Atlas-PanCancer CaPa cohort and healthy pancreas from the GTEx database, obtained from the UCSC Xena project, were used to correlate gene expression with stemness signatures and clinical-pathological variables. We identified 300 telomere-associated DEGs, Of these, 73 genes were common to studies and they were to be enriched in biological processes related to the cell cycle and telomere homeostasis. The differentially expresed of ASS1, S100P, IGF2BP2, MET, ABCC3 and RAC1 genes were significantly associated with overall survival and recurrence-free survival, conferring them prognostic value. Furthermore, the expression profiles of these genes are significantly associated with the histological grade of the disease, as well as with tumour T-N classification, the presence of residual tumour, the degree of response to treatment and stemness signatures. Among these, three genes of particular interest (KLF3, RAC1 and ABI1) were identified and shown to be highly essential in pancreatic cancer cell lines. In summary, we have identified a telomere gene-related signature for pancreatic cancer, highlighting the prognostic value of KLF3, RAC1, and ABI1 genes. This signature is significantly associated with clinical-pathological variables of the disease, potentially offering new insights for individualized therapy. Citation Format: Erika Curiel Gómez, Vilma Maldonado Lagunas, Jorge Meléndez Zajgla. Telomere-related genes associated with clinical-pathological in pancreatic ductal adenocarcinoma [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 1645.
Abstract 3185: Glatiramer acetate enhances tumor retention and mitigates systemic toxicity of toll-like receptor 9 agonists as intratumoral immunotherapy
Authors: Huan Gong, Daniel J. Griffin, Chad E. Groer, Xiaoqing Wu, Moustafa M. Abdelaziz, Sa Wu, Liang Xu, Laird M. Forrest, Cory J. Berkland
Journal: Cancer Research (2024)

Abstract Pathogen-associated molecular patterns (PAMP) are conserved molecular structures produced by microorganisms that are recognized as foreign by receptors of the innate immune system. Unmethylated cytosine-guanine oligodeoxynucleotides (CpG ODNs) are a storied drug class from the PAMP family that ligates Toll-like receptor 9 (TLR9). CpG ODNs have shown promising antitumor effects in preclinical studies by inducing potent pro-inflammatory immune responses. However, there are still practical challenges that have hindered clinical success, including inefficient in vivo delivery and severe immune-related toxicities caused by systemic exposure to CpG. We previously identified that glatiramer acetate (GA), an FDA-approved, lysine-rich polypeptide, could be applied as a cationic drug delivery vector for CpG delivery proximal to the injection site while mitigating systemic release of pro-inflammatory cytokines. To dive into the mechanism and evaluate pharmacological efficacy in more pathological models that simulate colorectal carcinoma, we validated the biodistribution of GA-CpG complexes (or R4B) and explored their safety and antitumor immunity in multiple mouse colorectal carcinoma models. In the CT26 single tumor model, intratumoral R4B treatment displayed comparable antitumoral efficacy as CpG treatment. Genome-wide transcriptome analysis showed that R4B treatment elicited much more prominent immune system response pathways in both lesions and spleens. The biodistribution study proved that R4B localized and gradually released CpG around the injection site while ‘naked’ CpG diffused away from the injection site quickly. In the CT26 dual tumor-bearing model, intratumoral administration of R4B generated systemic immune efficacy that led to an abscopal effect on distant untreated cancers, comparable to treatment with CpG alone. Notably, R4B treatment accomplished these effects with greatly mitigated systemic pro-inflammatory cytokines compared to CpG alone. These data help further elucidate the noncanonical role of glatiramer acetate to serve as a nucleic acid delivery scaffold that potentiates the safety of CpG adjuvant for cancer immunotherapy. Citation Format: Huan Gong, Daniel J. Griffin, Chad E. Groer, Xiaoqing Wu, Moustafa M. Abdelaziz, Sa Wu, Liang Xu, Laird M. Forrest, Cory J. Berkland. Glatiramer acetate enhances tumor retention and mitigates systemic toxicity of toll-like receptor 9 agonists as intratumoral immunotherapy [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 3185.
Abstract 1319: In vivo programming of natural killer cells and T cells using mRNA delivered cytotoxic chimeric antigen receptors
Authors: Neha Diwanji, Daniel Getts, Yuxiao Wang
Journal: Cancer Research (2024)

Abstract Introduction: Current generation of adoptive cell therapy relies on ex vivo engineering of immune cells with tumor-targeting chimeric antigen receptors. In addition to manufacturing challenges, ex vivo engineered cells such as CAR-NK and CAR-T show limited tumor infiltration and persistency within tumor microenvironment. A method leveraging mRNA-based delivery for in-vivo engineering of these cells could address these issues but has not been established. Conventional mRNA/LNP when infused systemically result in significant accumulation in liver tissue and the CAR has no immune cell specificity in their expression or function. Method: Many immune receptors are heterodimeric complexes composed of a ligand binding subunit (e.g. CD16 and TCR) and a signaling adaptor containing Immunoreceptor Tyrosine-based Activation Motif (ITAM) (e.g. FcRγ and CD3ζ). Notably, the cell surface expression of the ligand binding subunit often depends on the expression of the ITAM adaptor. Based on this we fused HER2-targeting scFv to multiple activating receptors whose expression is restricted to NK cells and T cells, and evaluated their expression and anti-tumor function. Results: We developed a series of Natural Cytotoxic Receptor (NCR)-based in vivo CAR constructs by fusing HER2-targeting scFv to the native extracellular and transmembrane sequences of the receptor NKp30, NKp44 and NKp46, These CARs engage signaling adaptor FcRγ or DAP12 expressed in NK cells, and exhibit potent tumoricidal activity against HER2+ ovarian cancer cells as well as mediate tumor-induced cytokine and chemokine response. Using Huh7 liver cell as a model for off-target expression in hepatocytes, we found that NKp44 and NKp46-based CAR requires their cognate signaling adaptors for stable cell surface expression. We also showed that similar strategy can be used to design receptors for selective expression on the surface of T cells utilizing CD3ε chain fused with tumor targeting scFv. Conclusion: These results demonstrated the feasibility of engineering primary NK cells with CARs based on the NCR family of receptors NKp44 and NKp46, whose expression requires the immune-restricted signaling adaptors. These CAR-NK receptors do not contain intracellular signaling motifs but can engage and activate their signaling natural adaptors to initiate tumor killing and cytokine response. An mRNA/LNP based delivery of NKp44-based CAR for cancer treatment is currently under clinical development. Citation Format: Neha Diwanji, Daniel Getts, Yuxiao Wang. In vivo programming of natural killer cells and T cells using mRNA delivered cytotoxic chimeric antigen receptors [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 1319.
Abstract 5963: VGLL1-derived peptides demonstrated anticancer effect by inhibiting VGLL1-TEAD4 interaction
Authors: Sangmi Ock, Changsub Lee, Wongi Jung, Ina Whang, Kyung-Soo Kim, Jongmin Han, Sujin Yim, Bo-Kyung Kim, Hong-Sub Lee, Kwan-Young Chang, Misun Won
Journal: Cancer Research (2024)

Abstract YAP/TAZ, cofactors of TEA domain-containing transcription factor TEADs (TEAD1-4), play a key role in the HIPPO pathway, which is involved in various function including embryonic development, organ size, cell proliferation, tissue regeneration, and the development and progression of several cancers. YAP/TAZ is therefore considered as master regulators of various cancers. However, we are interested in VGLL1, a cofactor of TEAD4, because it is mainly involved in the proliferation and metastasis of various cancers, including gastric, breast, pancreatic, and ovarian cancers. In gastric cancer, VGLL1 expression is regulated by the PI3K/AKT/β-catenin pathway. VGLL1 is then phosphorylated at S84 by TGF-β/ribosomal S6 kinase 2 (RSK2) and interacts with TEAD4 to express target genes such as MMP9, cyclin D1, IGFBP3, IGFBP5 and ITGαV. which are involved in cancer malignancy. We designed S84-containing VGLL1-derived peptides (VGLL1S84 peptides, SCVP), which consist of 7 to 15 amino acids linked to CPP, a cell-penetration peptide. We evaluated SCVP to inhibit the VGLL1-TEAD4 interaction and their therapeutic potential as anticancer agents. SCVP suppressed the growth of gastric and breast cancer cells expressing high levels of VGLL1, EGFR, and/or HER2. In the RNA-seq analysis of NUGC3 to elucidate the molecular mechanisms of SCVP induced cell death, SCVP-treated cells showed gene expression changes in metabolic pathway, RAS signaling, PI3K-AKT signaling, Wnt signaling, TNF signaling, and mTOR signaling. However, RNA-seq analysis of breast cancer cells treated with SCVP showed changes in the expression of genes involved in cell cycle, DNA replication, DNA repair, and apoptosis. Then, we performed CRISPR/Cas9 screening using SCVP and sgRNA library to explore companion biomarkers and genetic interactors of VGLL1 for targeted cancer therapy. As a result, we identified several candidate genes, including ZNF292 and PLK1, as synthetic lethal genes of VGLL1. As expected, HCC70 cells with ZNF292 mutation showed increased sensitivity to SCVP. We also found that SCVP in combination and the PLK inhibitor volasertib resulted in a synergistic effect on the growth inhibition of breast cancer cells. In conclusion, we demonstrated VGLL1 as a novel target for anticancer drug development, and elucidated the molecular mechanism and therapeutic potential of the SCVP in gastric and breast cancers. Citation Format: Sangmi Ock, Changsub Lee, Wongi Jung, Ina Whang, Kyung-Soo Kim, Jongmin Han, Sujin Yim, Bo-Kyung Kim, Hong-Sub Lee, Kwan-Young Chang, Misun Won. VGLL1-derived peptides demonstrated anticancer effect by inhibiting VGLL1-TEAD4 interaction [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 5963.
Abstract 374: Hypoxia-induced mitochondrial glutathione transporter expression causes drug resistance in colorectal cancer
Authors: Chin-Chun Lin
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the third most common type of cancer worldwide, with higher incidence and mortality rates. In order to adapt stress conditions during cancer progression, the cancer cells will be subject to metabolism reprogramming to increase energy production and remove hazardous substances. One of the important organelles, mitochondria is responsible for cellular ATP production, ion homeostasis, and several metabolic pathways. Therefore, mitochondria require a series of transporters called solute carrier family 25 (SLC25) to transport metabolites crossing the mitochondrial inner membrane, and dysregulation of those transporters causes abnormal cell morphology and diseases. In this study, members of the SLC25 family were analyzed in CRC via bioinformatics analysis, and a mitochondrial glutathione transporter was identified to overexpress in several public datasets of CRC and our own clinical specimens. In addition, its role has not been reported in any disease, including cancer. To systemically analyze the underlying mechanism causing overexpression of glutathione transporter during CRC progression, several stress conditions had been applied to colon cancer cells. However, only hypoxia was identified to induce its protein expression but not mRNA expression. Since a previous study reported that glutathione deprivation induced its protein expression, hypoxia didn’t alter the abundance of glutathione level suggesting that another glutathione-independent regulatory mechanism might be involve it. Interestingly, our findings revealed that hypoxia-induced glutathione transporter protein expression was mediated through the activation of internal ribosome binding site-mediated translation under hypoxia. To identify the potential role of glutathione transporter during colon cancer progression, its mitochondrial metabolite profiles from knockout cells of previous studies were further analyzed and identified that the changes of metabolites were associated with the urea cycle which had been reported to be associated with the sensitivity of oxaliplatin and 5-fluorouracil (5-FU) in cancer treatment. Importantly, our results showed that hypoxia-attenuated those chemotherapeutic effects were abolished by loss of glutathione transporter in colon cancer cells, indicating its crucial role in hypoxia-induced drug resistance. In conclusion, our study shows that glutathione transporter increased by hypoxia might lead to drug resistance of cancer therapy in colon cancer. Citation Format: Chin-Chun Lin. Hypoxia-induced mitochondrial glutathione transporter expression causes drug resistance in colorectal 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 374.