bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5419: Claudin-7 mediates Rab25-induced suppression of colon cancer cell invasion
Authors: Cho Su Jin , Jeong Bo Young , Yoon Se-Hee , Park Chang Gyo , Lee Hoi Young 
Published: March 2024

Abstract
Ras-related protein 25 (Rab25) is a member of small GTPase, and growing evidence demonstrates the context-dependent roles of Rab25 in cancer progression. While Rab25 aggravates cancer cell invasion in ER-positive breast, ovarian, and gastric cancers, Rab25 is under-expressed and suppresses colon and triple-negative breast cancer progression. Claudins are major components of tight junctions, and disruption of claudins is implicated in tumorigenesis. Among 27 known members of the claudin family, claudin-7 is suggested to suppress colon cancer progression. Previously, we identified that Rab25 induces endothelial-mesenchymal transition (EMT) and invasiveness of several types of cancer cells through activating the β1 integrin/epidermal growth factor receptor (EGFR)/Snail signaling cascades. However, little is known about the underlying mechanism of Rab25-induced tumor suppression. In the present study, we identify the critical role of claudin-7 in Rab25-induced suppression of colon cancer invasion. 3D Matrigel and modified Boden chamber were used to assess the invasiveness of colon cancer cells. Wound-healing assay was used to analyze colon cancer cell migration. 3D Matrigel was used to analyze tumor growth. Immunoblotting was used to assess the protein expression. Rab25 induced claudin-7 expression in colon cancer cells through protein stabilization. In addition, the enforced expression of claudin-7 not only reduced the EGFR/Ras signaling activity and Snail expression but also attenuated colon cancer cell invasion. However, silencing of claudin-7 expression rescued the tumor suppressive role of Rab25, thereby increasing colon cancer cell invasiveness. Collectively, our data demonstrate for the first time that Rab25 reduces the EGFR/Ras/Snail signaling activity and inhibits colon cancer cell invasion by upregulating claudin-7 expression.
Citation Format: Su Jin Cho, Bo Young Jeong, Se-Hee Yoon, Chang Gyo Park, Hoi Young Lee. Claudin-7 mediates Rab25-induced suppression of colon cancer cell invasion [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 5419.
Abstract 5470: ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma
Authors: Tzaridis Theophilos , Liu Jingbo , Prabhu Varun , Wechsler-Reya Robert , MacDonald Tobey 
Published: March 2024

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor with a for certain molecular subgroups very low overall survival and therefore an urgent need for novel treatment approaches. Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 are inhibitors of the dopamine receptor 2 (DRD2) and more importantly induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). ONC201 has shown objective responses in patients with diffuse midline gliomas and is currently being evaluated in the Phase 3 ACTION study. ONC206 is currently in Phase I clinical trials for pediatric and adult patients with primary brain tumors. In this study, we evaluated the preclinical therapeutic effects of ONC206 in medulloblastoma in vitro and in vivo and investigated the molecular mode of action for this imipridone. We found evidence for high expression of ClpP at both the RNA and protein level in medulloblastoma tumours, compared to very low expression in normal brain and normal cerebellum. In addition, we saw a pronounced reduction in cell viability of human Group 3 and Group 4 and murine medulloblastoma cells treated with ONC206 with extremely low IC-50s (range: 14nM - 2μM).After treatment with ONC206, we observed a significant downregulation of mitochondrial electron transport chain complexes I and III and mitochondrial hyperpolarization, as well as an induction of the ATF4 pathway, thereby implying that ONC206 induces an integrated stress response and mitochondrial damage. In order to test the efficacy of ONC206 in vivo, we used murine models of SHH-driven and Group 3 medulloblastoma as well as Group 3 patient-derived xenografts (PDXs). ONC206 led to a significant prolongation of survival in both murine models, with the SHH mice demonstrating a remarkable survival benefit. Mice from both Group 3 PDXs also responded to ONC206, with 25% of ONC206 treated animals exhibiting long-term tumor-free survival. Our results highlight ONC206 as a novel attractive therapeutic option for patients with relapsed medulloblastoma and importantly pave the way for a clinical trial testing the efficacy of ONC206 in the treatment of these patients.
Citation Format: Theophilos Tzaridis, Jingbo Liu, Varun Prabhu, Robert Wechsler-Reya, Tobey MacDonald. ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma [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 5470.
Abstract 5533: The difference of immune microenvironment betweende novometastatic and non-metastatic microsatellite instability-high colorectal cancer
Authors: Chen Kuo-Hsing , Hs Chia-Lang u , Su Yu-Li , Yuan Chang-Tsu , Tsai Jia-Huei , Liang Yi-Hsin , Cheng Ann-Lii , Yeh Kun-Huei 
Published: March 2024

Abstract
Introduction: Microsatellite instability-high (MSI-H) colorectal cancer (CRC) consists of 15% of all CRC but only 2-4% of metastatic CRC. The favorable prognosis of non-metastatic (early-stage) MSI-H CRC may be related to vigorous immune reaction in tumor microenvironment. However, the mechanisms of immune evasion in metastatic (late stage) MSI-H CRC are largely unknown.
Materials and Methods: We retrospectively collected patients with MSI-H CRC from National Taiwan University Hospital and Kaohsiung Chang Gung Memorial Hospital. The archival tumor specimens were used for immune cells analysis by Nanostring PanCancer Immune Panel, and spatial immune characterization by multiplex immunofluorescence stains. Only surgical resected primary tumors and metastatic tumors were included. Gene expression and immune cells composition were compared between non-metastatic and de novo metastatic tumors.
Results: We enrolled 59 and 27 patients with early-stage and late-stage MSI-H CRC, respectively. Twelve metastatic site tumors were also collected. The clinicopathologic characteristics between patients who have early- and late-stage MSI-H CRC were not significantly different. There are heterogeneous immune cell compositions in these 98 MSI-H tumors. Compared to early-stage MSI-H tumors, there are significantly fewer cytotoxic (difference -0.497, p = 0.001) and dendritic cells (difference -0.528, p = 0.021) in late-stage MSI-H tumors. Gene set enrichment analysis disclosed significantly decrease in the expression of JAK-STAT-IFN-γ- and antigen processing-related pathways in late-stage MSI-H tumors. The top 5 genes with significantly differential expression between late-stage and early-stage tumors are C7, TNFRSF12A, MFGE8(up-regulated) and CXCL5, IFNL1, GZMH, HMGB1 and CXCR1 (down-regulated).
Conclusions: There are significantly fewer cytotoxic and dendritic cells in late-stage MSI-H CRC, compared to early-stage MSI-H CRC, which is associated with decrease expression in JAK-STAT-IFN-γ- and antigen processing-related pathways.
Citation Format: Kuo-Hsing Chen, Chia-Lang u Hs, Yu-Li Su, Chang-Tsu Yuan, Jia-Huei Tsai, Yi-Hsin Liang, Ann-Lii Cheng, Kun-Huei Yeh. The difference of immune microenvironment betweende novometastatic and non-metastatic microsatellite instability-high 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 5533.
Abstract 5546: CRISPR-based kinome screen identifies Ikbkb as a regulator of phagocytic evasion in hepatocellular carcinoma
Authors: Chan Sze Man , Lee Terence Kin Wah 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent malignancies worldwide and is associated with poor prognosis. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the oncology landscape by targeting genes critical for immune checkpoint pathways, leading to the immune evasion of cancer cells. Phagocytosis checkpoints have emerged as essential checkpoints for cancer immunotherapy by functioning as “don’t eat me” signal to suppress immune response. Given the druggable properties of protein kinases, together with recent reports showing the antitumor immunity of kinase inhibitors, we aimed to identify protein kinases critical for phagocytic evasion in HCC by transducing a lentiviral sgRNA expression plasmid containing 2,852 unique single-guide RNAs (sgRNAs) targeting the 713 mouse kinase gene in mouse HCC cells, RIL-175, and subsequently co-incubated with RAW 264.7 macrophages. Based on the deep sequencing analysis comparing the sgRNA distribution in RIL-175 with or without co-incubation, we identified the Ikbkb gene as top-sensitizing hit on this screen, with at least two-fold sgRNA reduction upon incubation with macrophages.
To verify the phagocytic evasive role of Ikbkb in HCC, we have employed CRISPR/Cas9 knockout approach to delete Ikbkb in mouse HCC cell line, RIL-175 cells. The results showed that upon co-incubation with RAW 264.7 cells, the Ikbkb knockout cells exhibited increased phagocytosis, as confirmed by both flow cytometry analysis and microscopy observation. The analysis of the TCGA-LIHC cohort revealed that the expression level of Ikbkb was elevated and associated with unfavorable clinical outcomes. Notably, Ikbkb expression was found to be significantly correlated with established anti-phagocytic markers, including CD24, CD47, and CD274, further supporting their roles in the anti-phagocytic activities of HCC cells.
In summary, we have uncovered IKBKB as a cancer-intrinsic regulator of phagocytosis, which has the potential to target IKBKB as a novel therapeutic strategy to enhance the efficacy of current ICI treatments for HCC patients.
Citation Format: Sze Man Chan, Terence Kin Wah Lee. CRISPR-based kinome screen identifies Ikbkb as a regulator of phagocytic evasion in hepatocellular carcinoma [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 5546.
Abstract 5551: Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment
Authors: Khoury Rami , Kleiner Ron , Yeini Eilam , Ajamil Daniel Rodriguez , Dangoor Sahar Israeli , Sanalla Tamer , Barshack Iris , Satchi-Fainaro Roni 
Published: March 2024

Abstract
Several mutations have been identified that are associated with an increased risk of triple-negative breast cancer (TNBC), including those that are deleterious in the BRCA gene. TNBC is associated with the worst prognosis and the highest incidence of brain metastasis (30%) among all subtypes of BC. Despite objective responses to poly (ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-mutated TNBC, benefits are transitory. Furthermore, our understanding of the effect of PARP inhibitors (PARPi) in treating breast cancer brain metastasis (BCBM) and modulating its tumor microenvironment (TME) is still lacking. To this end, we analyzed the brain TME of BRCA-mutated BCBM in the absence or presence of treatment with PARPi. Interestingly, we found that the immune TME of the brain hinder the antitumor activity of PARPi by upregulating multiple immunosuppressive molecules, including PD-L1. Furthermore, we found that BCBM overexpress P-selectin through its interaction with the tumor-associated microglia, bone marrow-derived macrophages and endothelial cells in the TME. Thus, we designed a novel nanoparticle (NP) targeting P-selectin to serve as a brain-penetrant delivery system for the treatment of BCBM. In order to target BRCA-mutated BCBM, we harnessed our novel P-selectin-targeted NPs to entrap PARPi and other immune modulators that we found to exert synergistic activity when combined. To evaluate the antitumor activity of our P-selectin-targeted NPs, we established 3-dimensional (3D) ex vivo and in vivo BRCA-mutated BCBM models. Importantly, we saw favorable effects of the P-selectin-targeted NPs in comparison to the combination of the free drugs, suggesting that out targeted-NPs overcome the TME-mediated resistance to PARPi through the modulation of the immunosuppressive microenvironment of the brain.
Citation Format: Rami Khoury, Ron Kleiner, Eilam Yeini, Daniel Rodriguez Ajamil, Sahar Israeli Dangoor, Tamer Sanalla, Iris Barshack, Roni Satchi-Fainaro. Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5551.
Abstract 5554: Breast cancer with different chemosensitivity has distinct influence on the immune microenvironment
Authors: Skourti Eleni , Seip Kotryna , Egeland Eivind V. , Jabeen Shakila , Mensali Nadia , Øynebråten Inger , Juell Siri , Inderberg Else M. , Engebråten Olav , Corthay Alexandre B. , Mælandsmo Gunhild M. , Prasmickaite Lina 
Published: March 2024

Abstract
Triple Negative Breast Cancer (TNBC) is a BC subgroup with the least favorable outcome and limited therapeutic options. Chemotherapy has long been the standard treatment, but resistance often develops. In recent years, various immunotherapy approaches have diversified, including combinations of chemo and immunotherapies. Increased understanding on how the difference in chemosensitivity affects the immune cells is of importance for further development of chemo-immunotherapies for TNBC. In this project we investigate how TNBC with distinct chemosensitivity modulate the immune microenvironment. Specifically, we explore the influence of the secretome, derived from the chemoresistant versus the sensitive BC cells, on macrophages (MØs) and T-cells. We have disclosed the chemosensitivity-dependent differences in the secretome, which were associated with diverse effects on MØ recruitment, polarization, and activation. Currently we investigate the secretome influence on interferon (IFN)-activated MØ. IFN stimuli is known to trigger tumoricidal activities in MØ, and we are setting up a co-culture assay, where such MØ functions could be explored in vitro. To study the secretome influence on T-cells, we employ T cell receptor (TCR)-engineered T cells that become activated in the presence of target cells. The preliminary results indicate that activation of the TCR T-cells was reduced in the presence of the “chemoresistant” secretome, suggesting its immunosuppressive influence. Work is in progress to validate this observation using other TCR T cells and functional markers of active T cells.
Citation Format: Eleni Skourti, Kotryna Seip, Eivind V. Egeland, Shakila Jabeen, Nadia Mensali, Inger Øynebråten, Siri Juell, Else M. Inderberg, Olav Engebråten, Alexandre B. Corthay, Gunhild M. Mælandsmo, Lina Prasmickaite. Breast cancer with different chemosensitivity has distinct influence on the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5554.
Abstract 56: Preclinical in vivo characterization underpinning LGR5-targeting CAR-T cells as a cancer immunotherapy
Authors: Foeng Jade , Tyllis Timona , Abbott Caitlin , McPeake Dylan , Thompson Emma , Bandara Veronika , Gundsambuu Batjargal , Napoli Silvana , Bonder Claudine , Comerford Iain , Sadlon Tim , Barry Simon , McColl Shaun 
Published: March 2024

Abstract
Incidences of early-onset colorectal cancer (CRC) have been accelerating worldwide. To begin to address the lack of therapeutic options for CRC, we have developed a CAR-T cell therapy specific for leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). LGR5 is known to potentiate Wnt/Β-catenin signaling and mark cells-of-origin in intestinal cancers. Extensive screening has demonstrated elevated expression of LGR5 in CRC, which is correlated with reduced patient survival. In CRC, LGR5 has been intimately linked with metastasis, cell survival and perturbation of chemotherapeutic interventions. We have developed a 9-day preclinical manufacturing method to generate LGR5-targeting CAR-T cells with a minimally differentiated T cell phenotype, which was concomitant with significant cytotoxic and activation marker expression. In human CRC xenograft mouse models, LGR5-targeting CAR-T cells eradicated tumors at doses as low as 800,000 CAR+ cells, and were capable of significantly inhibiting advanced tumor growth following delayed administration. Robust CAR-T cell-mediated immunological protection was observed in rechallenge experiments, in which secondary tumor growth was undetectable in mice which had tumors rejected following previous CAR-T cell administration. LGR5 protein and mRNA expression was also detected in a diverse range of cancer families, including ovarian, brain, liver and stomach, expanding upon the clinical indications with which LGR5-targeting CAR-T cells may be harnessed. These results contribute to a preclinical body of work that culminated in a Phase I/IIa clinical trial in metastatic colorectal cancer patients, which was approved for initiation by the FDA and commenced in 2023 (NCT05759728).
Citation Format: Jade Foeng, Timona Tyllis, Caitlin Abbott, Dylan McPeake, Emma Thompson, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Claudine Bonder, Iain Comerford, Tim Sadlon, Simon Barry, Shaun McColl. Preclinical in vivo characterization underpinning LGR5-targeting CAR-T cells as a cancer 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 56.
Abstract 5604: Modulating DNA repair through endo-exonuclease inhibition: a new therapeutic paradigm in oncology
Authors: Chow Terry , Duan Jianmin , Colin Patrick , Bier Colin 
Published: March 2024

Abstract
DNA damage repair (DDR) mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. Endo-exonuclease (EE)1 plays a key role in this process and increase EE expression has been observed in the cancer cells examined. In this context, we identified a dicationic diarylfuran, pentamidine, which is an antiparasitic drug that has been used clinically to treat opportunistic infections such as Pneumocystis carinii. Pentamidine is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay and is known to be active on cancer cells. In a proof of concept study2, tumor with increased EE expression (determined by IHC) showed the best response to this drug.
We have now identified novel mono- and di-amidine analogs of pentamidine that are more effective than the parent drug in both in vitro and in vivo studies. Furthermore, pre-clinical animal studies of our lead candidate, MTDX203, showed an increased anti-cancer activity with a higher safety index than pentamidine. Based on a predictive PK/PD model, a human iv infusion dose administered twice weekly at ~0.4 mpk (i.e. 28 mg/day, ~10% of pentamidine effective iv dose) is expected to be clinically effective. Our work establishes the EE as a therapeutic target for cancer and identifies a new First in Class of novel anti-cancer agents.
1Chow et al. (2004) MCT 3:911-9182 NCT01378143: Pentamidine (OCZ103-OS) in Patients With Unresectable and Locally Recurrent or Metastatic Colorectal Cancer Undergoing Standard Chemotherap
Citation Format: Terry Chow, Jianmin Duan, Patrick Colin, Colin Bier. Modulating DNA repair through endo-exonuclease inhibition: a new therapeutic paradigm in oncology [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 5604.
Abstract 5639: TIP60-independent mechanism of BRD8 is involved in colorectal tumorigenesis
Authors: Yamaguchi Kiyoshi , Nakagawa Saya , Yamaguchi Rui , Sheridan Paul , Takane Kiyoko , Ikenoue Tsuneo , Nagatoishi Satoru , Kozuka-Hata Hiroko , Oyama Masaaki , Aikou Susumu , Ahiko Yuka , Shida Dai , Tsumoto Kouhei , Miyano Satoru , Imoto Seiya , Furukawa Yoichi 
Published: March 2024

Abstract
Modifications of histone tails control chromatin structure, and the acetylation is generally associated with euchromatin and transcriptional activation. Acetylated lysine residues are recognized by bromodomains, which serve as acetyl-lysine binding modules and participate in transcriptional regulation. Bromodomain-containing protein 8 (BRD8) is a subunit of the NuA4/TIP60-histone acetyltransferase complex. Although BRD8 has been considered to act as a co-activator of the complex, its biological role remains to be unclear. In this study, we revealed that BRD8 accumulates in colorectal cancer cells through the inhibition of ubiquitin-dependent protein degradation by the interaction with MRG domain binding protein (MRGBP). RNA-seq analysis coupled with genome-wide mapping of BRD8-binding sites disclosed that BRD8 transactivates a set of genes independently of TIP60, a catalytic subunit of NuA4 complex, and that BRD8 regulates the expression of multiple subunits of the pre-replicative complex (pre-RC) in concert with the activator protein-1 (AP-1) transcription factor. Depletion of BRD8 induced cell-cycle arrest at the G1 phase and suppressed proliferation of colorectal cancer cells. We have also shown that the bromodomain of BRD8 is indispensable for not only the interaction with histone H4 or transcriptional regulation but also its own protein stability. These findings provide a new insight into the roles played by BRD8 in human colorectal carcinogenesis and will contribute to the development of new chemotherapeutic agents targeting the bromodomain of BRD8.
Citation Format: Kiyoshi Yamaguchi, Saya Nakagawa, Rui Yamaguchi, Paul Sheridan, Kiyoko Takane, Tsuneo Ikenoue, Satoru Nagatoishi, Hiroko Kozuka-Hata, Masaaki Oyama, Susumu Aikou, Yuka Ahiko, Dai Shida, Kouhei Tsumoto, Satoru Miyano, Seiya Imoto, Yoichi Furukawa. TIP60-independent mechanism of BRD8 is involved in colorectal tumorigenesis [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 5639.