tbuckley/cabot-search huggingface dataset:
Abstract 4060: The role of paraspeckles in EWS activated cancers
Authors: Renee A. Kinne, Peter C. Hollenhorst
Journal: Cancer Research (2025)

Abstract The ETS family of transcription factors become aberrantly activated in multiple cancers. This activation is dependent on the co-activator EWS in both prostate cancer and Ewing sarcoma, an adolescent bone cancer. In prostate cancer, EWS is a binding partner necessary for oncogenic ETS, primarily ERG, activation. In Ewing sarcoma, the intrinsically disorder region (IDR) of EWS is fused to ETS members, primarily FLI1, and promotes aberrant expression and activation. The IDR of EWS promotes liquid-liquid phase separation (LLPS) and acts as a transcriptional activation domain. Current studies link LLPS with oncogenesis, making the LLPS ability of EWS a potential mechanism for oncogenic co-activation. In cells, EWS is found in phase separated bodies such as paraspeckles. Paraspeckles are nuclear bodies that have a role in transcriptional regulation, but their role in cancers is not well understood. I have shown that ERG and EWS/FLI1 colocalize with EWS granules in a purified protein droplet assay. This suggests that oncogenic ETS can participate in EWS LLPS. NEAT1, the essential RNA scaffolding of the paraspeckle, has a role in tumor progression in prostate cancer and I have shown that both ERG and EWS/FLI1 interact with NEAT1 through RIP. However, the potential role of paraspeckles in Ewing sarcoma or prostate cancer has not been further investigated. ETS positive prostate cancer and Ewing sarcoma lines showed paraspeckle presence through NEAT1 RNA-FISH. Knock down (KD) of two necessary paraspeckle components, NEAT1 or FUS, in Ewing sarcoma cells reduce paraspeckle presence, colony growth, and EWS/FLI1 activity at the transcriptional level. KD of FUS and NEAT1 also increased migration, which is consistent with EWS/FLI1 loss. Taken together, these data suggest that the paraspeckle has a role in EWS/FLI1 activity in Ewing Sarcoma and that components of the paraspeckle interact with ERG. Because ERG and FLI1 are homologous, there is potential that the paraspeckle acts as a mechanism of oncogenic transcription in prostate cancer as well as Ewing sarcoma. Citation Format: Renee A. Kinne, Peter C. Hollenhorst. The role of paraspeckles in EWS activated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4060.
Abstract 4598: A novel systemic delivery approach for oncolytic adenovirus therapy using tumor-homing mesenchymal stem cells
Authors: Yu Mikane, Nobuhiko Kanaya, Shinji Kuroda, Hitoshi Minagi, Makoto Matsumoto, Tetsuya Katayama, Daisuke Kadowaki, Shunya Hanzawa, Masashi Hashimoto, Yoshihiko Kakiuchi, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara, Yasuo Urata
Journal: Cancer Research (2025)

Abstract Oncolytic viral (OV) therapy is a promising approach for treating metastatic cancer; however, systemic delivery remains a significant challenge due to antiviral immune responses. We previously developed a telomerase-specific OV, Telomelysin (OBP-301), which utilizes the hTERT promoter to drive the expression of E1A and E1B. OBP-301 demonstrated an abscopal effect when combined with anti-PD-1 antibodies in distant metastases in vivo murine colorectal cancer (MC38) mouse models. A p53-armed variant, OBP-702, showed potent tumor-suppressive effects in mouse models of gastroenterological cancers via intratumoral injection. However, these therapies remain limited to accessible lesions. To address these challenges, we investigated three novel approaches for systemic OV delivery. First, we encapsulated the DNA plasmids of GFP-expressing OBP-301 (OBP-401) in liposomes, which effectively reduced the production of neutralizing antibodies compared to naked OVs. Second, we explored extracellular vesicles (EVs) derived from OBP-301-infected tumors as natural carriers. These EVs demonstrated the abscopal effects to non-injected metastatic lesions in preclinical models, achieving promising therapeutic efficacy. Finally, we utilized mesenchymal stem cells (MSCs), known for their tumor-homing properties, as carriers for OBP-702. When MSCs loaded with OBP-702 (MSC-OBP-702) were intraperitoneally injected into an MC38-bearing peritoneal metastasis model, they effectively migrated to metastatic sites, significantly suppressing tumor growth and improving overall survival compared to OBP-702 alone. These findings demonstrate that MSC-OBP-702 has significant potential to overcome the challenges of systemic OV therapy through the tumor-homing capability of MSCs, providing a foundation for future clinical applications. Citation Format: Yu Mikane, Nobuhiko Kanaya, Shinji Kuroda, Hitoshi Minagi, Makoto Matsumoto, Tetsuya Katayama, Daisuke Kadowaki, Shunya Hanzawa, Masashi Hashimoto, Yoshihiko Kakiuchi, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara, Yasuo Urata. A novel systemic delivery approach for oncolytic adenovirus therapy using tumor-homing mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4598.
Abstract 6806: Deciphering the role of BRD2 in acute adaptive response to BET inhibitors across cancers
Authors: Suyakarn Archasappawat, Eunjung Lee, Chang-il Hwang
Journal: Cancer Research (2025)

Abstract Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are a promising therapeutic strategy against cancer, targeting key epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors poses a significant challenge, necessitating a deeper understanding of adaptive mechanisms. Here, we identified the upregulation of BRD2, another member of the BET protein family, as a conserved response to BET inhibition across multiple cancer types. We hypothesize that this upregulation facilitates cellular adaptation to treatment, reducing drug efficacy and potentially contributing to resistance over time. To test this, we performed BRD2 knockdown, demonstrating that BRD2 depletion sensitizes pancreatic cancer cells to BET inhibitors in vitro. Furthermore, a combination of BRD2 knockdown with JQ1 treatment significantly impaired tumor growth in vivo. Mechanistically, ChIP-seq analysis of BRD2 and BRD4 occupancy upon JQ1 treatment revealed that BRD2 and BRD4 share common binding sites. JQ1 caused a substantial loss of BRD4 from chromatin, while BRD2 was modestly affected. Although JQ1 has a higher affinity for BRD4 than for BRD2, our data suggest that higher cellular abundance of BRD2 compensates for BRD4 function under BET inhibitor treatment, thereby contributing to adaptive resistance and sustaining essential transcriptional programs. These findings highlight BRD2 as a key player in the adaptive response to BET inhibition and a potential therapeutic target to enhance the efficacy of BET inhibitors in pancreatic cancer and other malignancies. Citation Format: Suyakarn Archasappawat, Eunjung Lee, Chang-il Hwang. Deciphering the role of BRD2 in acute adaptive response to BET inhibitors across cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6806.
Abstract 7023: A phenotypic screening method identifies a potent anti-cancer PROTAC targeting MAP3K1
Authors: Lelisse T. Umeta, Jayapal R. Mallareddy, Sarbjit Singh, Smitha Kizhake, Lidia Boghean, Amritha Kizhake, Suchita Vishwakarma, Katelyn L. O’Neill, Lisa Humphrey-Brattain, Adrian Black, Xu Luo, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Amarnath Natarajan
Journal: Cancer Research (2025)

Abstract The identification of Thalidomide, Lenalidomide, and Pomalidomide as Cereblon (CRBN) binders spurred the development of proteolysis-targeting chimeras (PROTACs). PROTACs with CRBN-binding moieties are heterobifunctional molecules that form a ternary complex with CRBN, which recruits the CUL4-DDB1 ubiquitin ligase protein complex, and a protein of interest (POI) and targets it for degradation. Despite numerous ongoing efforts, the structure-based design of PROTACs remains elusive. The current approach relies on the synthesis of a PROTAC library and screening the library in the chosen assay format to identify viable hits. Here, we propose a viability-based phenotypic screening system using HCT116 wild type (WT) POI knock-out (POI-/-) and CRBN knock-out (CRBN-/-) cells to identify PROTACs that display activity in both a POI and CRBN-dependent manner. For this study, we selected MAP3K1, an oncogenic signaling activator, as our POI and conjugated an ATP-competitive MAP3K1 inhibitor with thalidomide using various linkers to generate the library. The library was subjected to a 3-day viability screen using the above WT, MAP3K1-/-, and CRBN-/- cell lines. The screen identified 50-008 as a hit that selectively inhibited the viability of the WT cells but not MAP3K1-/- or CRBN-/- cells. 50-008 was chemically validated in a colorectal cancer cell line and organoid model by making single changes that affect either CRBN binding, MAP3K1 binding, or the linker. Follow-up studies showed that 50-008 inhibits cancer cell proliferation, induces apoptosis, and an S-phase cell cycle arrest in a CRBN and MAP3K1-dependent manner. Furthermore, A Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) screen of 50-008 across ∼900 cancer cell lines identified 267 sensitive cancer cell lines (IC50 &amp;lt; 0.1μM), including luminal B breast cancer cell line T47D and 131 resistant cancer cell lines (IC50 &amp;gt; 10 μM). Mechanistic studies in T47D cells demonstrated that 50-008 degrades MAP3K1 and modulates the activation of key downstream effectors, such as ERK and IKKβ. Citation Format: Lelisse T. Umeta, Jayapal R. Mallareddy, Sarbjit Singh, Smitha Kizhake, Lidia Boghean, Amritha Kizhake, Suchita Vishwakarma, Katelyn L. O’Neill, Lisa Humphrey-Brattain, Adrian Black, Xu Luo, Andrew S. Boghossian, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Amarnath Natarajan. A phenotypic screening method identifies a potent anti-cancer PROTAC targeting MAP3K1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7023.
Abstract 6022: YH006: a next-generation CTLA-4×OX40 Treg antagonist, demonstrates superior tumor-infiltrating Treg-depletion efficacy and favorable manufacturability
Authors: Sarah Chan, Baihong Liu, Bahetiyaer Huwatibieke, Jing Zhang, Yang Chen, Minjuan Meng, Wenchao Zheng, Lei Zhang, Yi Yang
Journal: Cancer Research (2025)

Abstract Immune checkpoint inhibitors have revolutionized the treatment of early and advanced cancer. Especially combination of anti-cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody and anti-programmed death-1 (PD-1) antibody, has shown remarkable efficacy against various cancers and approved for 7 indications by the US FDA. However, there are still limitations with regard to response rates and dose-dependent immune related adverse events (irAEs) caused by CTLA-4 antibody for fully achieve the optimal therapeutic effect for the combination strategy. YH006 is a monovalent bsAb with effector enhanced Fc domain, generated from Biocytogen RenLiteTM common light chain mice, designed to deplete tumor-infiltrating Treg cells with better specificity, based on tumor-infiltrating Treg cells consistently exhibit higher expression levels of both CTLA-4 and OX40 compared to T cells in the periphery across multiple cancer types. YH006 potent to selectively depletion of tumor-infiltrating Tregs and increase the intra-tumoral CD8/Treg ratio, outperform the first and other next generation of anti-CTLA-4 agents in vivo efficacy at low dose. Notably, the antitumor activity of PD-1 mAb was significantly enhanced when combined with YH006 in syngeneic MC38 models at high tumor burden. Ongoing CMC process development has a titer of over 6 g/L at the 20 L scale, and the overall purification yield of &amp;gt;80%. YH006 also has consistent quality from research cell bank to passage 90, suggesting excellent developability. Citation Format: Sarah Chan, Baihong Liu, Bahetiyaer Huwatibieke, Jing Zhang, Yang Chen, Minjuan Meng, Wenchao Zheng, Lei Zhang, Yi Yang. YH006: a next-generation CTLA-4×OX40 Treg antagonist, demonstrates superior tumor-infiltrating Treg-depletion efficacy and favorable manufacturability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6022.
Abstract 7010: HDB-82: A promising PROTAC degrader for KRAS G12D mutant cancers
Authors: Mohammad Hassan Baig, Yun Seong Jo, Sagar Dattatraya Nale, Chang Joong Kim, Tae Hwan Park, Ju Han Bok, Dong Min Kim, Hye Mi Kim, Ji Min Park, Jae June Dong, Jae Hee Cho, Sung Ill Jang, Byoung Gon Moon
Journal: Cancer Research (2025)

Abstract KRAS G12D mutations, occurring in approximately 30% of solid tumors, represent a significant therapeutic target. While selective KRAS G12C inhibitors have achieved clinical success, effectively targeting the more prevalent G12D mutation remains an unmet medical need. This study investigates the potential of proteolysis-targeting chimeras (PROTACs) as a promising avenue for KRAS G12D-driven cancers, potentially offering advantages over traditional inhibitors through catalytic protein degradation. Targeted protein degradation of mutant KRAS may yield greater efficacy than simply inhibiting the protein. This study focuses on the design, synthesis, and biological evaluation of novel KRAS G12D-targeting PROTAC degraders. Through rigorous optimization, we developed HDB-82, a highly potent and selective PROTAC compound targeting KRAS G12D. HDB-82 effectively induced degradation of the KRAS G12D protein, leading to significant antiproliferative activity against KRAS G12D-mutant cancer cells in vitro and in vivo. HDB-82 demonstrated potent anti-cancer activity against various KRAS G12D-mutant cell lines, achieving low nanomolar IC50 values. It effectively degraded the KRAS G12D protein in various KRAS G12D-expressing cell lines (DC50 value ranges from picomolar to sub-nanomolar range). Mechanistic studies revealed significant suppression of downstream MAPK and PI3K/AKT signaling pathways, accompanied by robust induction of apoptosis, and superior antiproliferative activity compared to existing inhibitors. Furthermore, HDB-82 exhibited favorable pharmacokinetic and pharmacodynamic properties in mice. Intravenous administration of HDB-82 (10 mg/kg, q.w.) resulted in substantial tumor growth inhibition across multiple KRAS G12D-positive tumor models. These findings establish HDB-82 as a promising therapeutic candidate for KRAS G12D-mutant cancers, warranting further preclinical investigation and potential clinical development. Citation Format: Mohammad Hassan Baig, Yun Seong Jo, Sagar Dattatraya Nale, Chang Joong Kim, Tae Hwan Park, Ju Han Bok, Dong Min Kim, Hye Mi Kim, Ji Min Park, Jae June Dong, Jae Hee Cho, Sung Ill Jang, Byoung Gon Moon. HDB-82: A promising PROTAC degrader for KRAS G12D mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7010.
Abstract 6530: A comprehensive genomic analysis elucidates the microbial landscape of cancer
Authors: Anders B. Dohlman, Robin Mjelle, Henry Wood, Iris Lee, Kevin Jiang, Ethan Shurberg, Alaina Shumate, Blake Sanders, Guanxi Qiao, Jodi Hirshman, Andrew Cherniack, Phil Quirke, Matthew Meyerson
Journal: Cancer Research (2025)

Abstract There is growing evidence that microorganisms are an important component of the tumor microenvironment. However, conflicting reports regarding the cancer microbiome have left the extent of microbial presence across cancer types unclear, highlighting the need for more accurate methods of profiling of tumor-associated microorganisms. Leveraging the new human genome T2T-CHM13, we developed a new host-subtraction and decontamination pipeline for accurately profiling tumor-associated microorganisms in tumor sequencing data and benchmarked it on simulated and real-world datasets. We used this pipeline to perform a pan-cancer analysis of new high-depth whole-genome tumor sequencing data from The Cancer Genome Atlas (n = 8,840) and the UK 100,000 Genomes Project (n = 15,223). Our analysis revealed that in both cohorts, most cancer types do not harbor a detectable microbiome. However, we identified polymicrobial communities in association with nearly all oral, esophageal, gastric, and colorectal cancers, each of which harbored cancer-type specific microbiomes. Within cancer types, microbial communities differed by anatomical site and tumor subtype. Notably, we observed increased bacterial colonization in microsatellite-instable (MSI) cancers of the upper and lower gastrointestinal tract, and a correlation between bacterial colonization and tumor mutational burden in a pattern that persisted after controlling for MSI status. This trend was driven by a specific community of pathogens including Fusobacterium animalis, and was linked to a tumor-specific immune signature using patient-matched RNA-sequencing. Finally, we demonstrate that complete microbial genomes can be assembled from bulk tumor sequencing data, allowing phylogenetic and functional analysis of tumor-resident microorganisms. Together, our analysis helps clarify the microbial landscape of cancer and highlights its potential clinical importance in gastrointestinal malignancies. Citation Format: Anders B. Dohlman, Robin Mjelle, Henry Wood, Iris Lee, Kevin Jiang, Ethan Shurberg, Alaina Shumate, Blake Sanders, Guanxi Qiao, Jodi Hirshman, Andrew Cherniack, Phil Quirke, Matthew Meyerson. A comprehensive genomic analysis elucidates the microbial landscape of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6530.
Abstract 207: snNOMeHiC: joint profiling of 3D genome, DNA methylation, and chromatin accessibility from the same nuclei at flash-frozen tissue and primary tumor sample
Authors: Hailu Fu, Jiayan Ma, Eric Tong, Mark Youngblood, Harrshavasan Congivaram, Mateo Gomez, Juan Wang, Feng Yue, Li Wang, Yaping Liu
Journal: Cancer Research (2025)

Abstract Epigenetic marks, including DNA methylation, chromatin accessibility, and three-dimensional (3D) genome organization, play instrumental roles in gene regulation in mammals. Gene activation or repression potential, however, cannot be entirely predicted by looking at a single modality. Accurate predictive models require multiple modalities simultaneously. We previously developed single-cell Methyl-HiC technology to jointly profile DNA methylation and 3D genome from the same cells. Further, we incorporated an additional footprint of GpC methyltransferase activity (i.e., chromatin accessibility) into the assay, named NOMe-HiC, but at the bulk level. Here, we extended NOMe-HiC technology to the single-cell level to enable the joint profiling of the 3D genome, DNA methylation, and chromatin accessibility from the same nuclei. We performed snNOMe-HiC at IMR-90 cell lines and found high concordance across all three modalities with the bulk NOMe-HiC by pooling the single cells. We further prepared a mixture of GM12878 and IMR-90 cells and processed the cell mixture with snNOMe-HiC. snNOMe-HiC can distinguish the two cell types using each of the three epigenetic features, respectively. To benchmark the performance of snNOMe-HiC at flash-frozen heterogeneous tissues, we generated snNOMe-HiC data from ∼2000 nuclei at flash-frozen mice cortex. We identified all the major known cell types in the previous studies across three modalities and showed reproducible results across replicates. Finally, we applied snNOMe-HiC to a primary meningioma sample. We identified previously known copy number alterations in tumor-related cell clusters and found concordant changes of epigenetic heterogeneity across cell populations, which can potentially reveal the crosstalk between genetics and multiple epigenetic marks during the clonal evolution in cancer progression. In summary, snNOMe-HiC is a robust technology that can profile three epigenetic modalities and genetic aberrations in the same nuclei from flash-frozen tissues and primary tumors. Citation Format: Hailu Fu, Jiayan Ma, Eric Tong, Mark Youngblood, Harrshavasan Congivaram, Mateo Gomez, Juan Wang, Feng Yue, Li Wang, Yaping Liu. snNOMeHiC: joint profiling of 3D genome, DNA methylation, and chromatin accessibility from the same nuclei at flash-frozen tissue and primary tumor sample [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 207.