tbuckley/cabot-search huggingface dataset:
Abstract 3533: Claudin 6 vaccines effectively inhibit tumor growth in a syngeneic mouse colon cancer model
Authors: Na Wang, Melvin Toh, Hong Wang
Journal: Cancer Research (2025)

Abstract Human Claudin 6 (CLDN6) is a member of the Claudin family of proteins, which play a crucial role in the structure and function of tight junctions. The expression of CLDN6 is restricted to stem cells and embryonic tissues. In human adults, CLDN6 mRNA is only detected at very low levels in testis, pancreas, and placenta. However, several types of cancers have been found to express CLDN6 at high levels, suggesting that CLDN6 is an ideal tumor-associated antigen and target for immunotherapy, albeit its precise role in cancer remains to be defined. Here, we designed and produced vaccine proteins consisting of multiple human B- and/or T-cell epitopes of CLDN6, which were selected from computer-predicted sequences, fused with an immune enhancer/carrier, and investigated their immunogenicity and anti-cancer activities in mice. First, C57BL/6 mice were vaccinated subcutaneously once a week for 5 times with the different vaccine proteins. CpG oligodeoxynucleotides were used as the vaccine adjuvant. Using the IFNγ ELISpot assay, we found that splenocytes collected from mice vaccinated with vaccine proteins containing T-cell epitopes displayed potent IFNγ release activity after stimulation with T-cell epitope peptides, suggesting that these CLDN6 vaccine proteins may inhibit the growth of CLDN6-expressing cancer by activating specific cytotoxic T-cells to destroy cancer cells. To explore this potential, we investigated the anti-cancer activity of the vaccine proteins by monitoring the tumor growth of CLDN6-humanized MC38 mouse colon cancer cells inoculated subcutaneously in vaccinated C57BL/6 mice for 4 weeks. We found that the growth of tumors was inhibited 98-100% (compared to the adjuvant-only control group) in two groups of mice (N=8 in each group) vaccinated with proteins containing multiple T-cell epitopes. In the first group, all 8 tumors disappeared within 4 weeks. In the second group, 7 of 8 tumors disappeared within 3 weeks and the last tumor stopped growing after the second week. In mice treated with adjuvant only, all tumors (N=8) displayed the same growth rate and reached an average of ∼1, 000 mm3 in volume, similar to mice treated with PBS. Collectively, our results demonstrate that CLDN6 vaccines effectively inhibited the growth of CLDN6-expressing cancer cells in mice. These findings suggest that CLDN6 protein vaccines hold promise for treating CLDN6-expressing cancers in humans, and this potential will be further explored in future studies. Citation Format: Na Wang, Melvin Toh, Hong Wang. Claudin 6 vaccines effectively inhibit tumor growth in a syngeneic mouse colon cancer model [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 3533.
Abstract 175: Characterising head and neck tumour microenvironment using high plex spatial omics technologies and analyses
Authors: Chin Wee Tan, Naomi Berrell, Meg L. Donovan, James Monkman, Habib Sadeghirad, Vahid Yaghoubi Naei, Jinjin Chen, Alyssa Rossenbloom, Shilah Bonnett, Mark Conner, Brian Filanoski, Christine Kang, Joseph M. Beechem, John F. Fraser, Catherine Barnett, Rahul Ladwa, Brett G. Hughes, Arutha Kulasinghe
Journal: Cancer Research (2025)

Abstract Head and neck squamous cell carcinoma (HNSCC) is the cancer of different parts of the head and neck region originating from epithelial cells of the mucosal layer. Globally, it is the 7th most common cancer with over 89 thousand new cases each year. Its prognosis has not changed significantly in recent years despite improvements in treatments options like immunotherapy, radiotherapy (RT), chemotherapy (CT) and surgery. Using the latest spatial omics technologies and approaches, this work aims to develop a better insight of the tumour microenvironment (TME), particularly the association with typical clinical endpoints including Disease-Free Survival (DFS) and Overall Survival (OS). In this study, we utilised the latest ultra-high plex (580-proteins) spatial protein technology (GeoMx Immuno-Oncology Proteome Atlas, IPA) and full transcriptome profiling (18, 000 transcripts, Whole Transcriptome Atlas, WTA) from Bruker Spatial Biology (Nanostring Technologies) to analysed 84 mucosal HNSCC patient specimens collected during resection. Each patient tissue sample was subdivided into tumour and stromal regions prior to digital spatial profiling. Patients had either underwent CT and/or RT and samples were stratified as either tumour or stromal regions before processing. Till this end, results suggest that patient DFS and OS were associates with anatomical locality and stages of the tumour. We uncovered unique protein and transcript features that’s associated with either DFS and/or OS. We validated these findings (specifically CD34 and CD44) using an independent approach (i.e. single-cell proteomics using PhenoCycler-Fusion from Akoya Biosciences) and uncovered cell types associated with patient survival by applying cell type deconvolution on transcript data. This study demonstrated an integrated analysis workflow using high plex proteomics and transcriptomics profiling data for uncovering markers of clinical significance in mucosal HNSCC. Citation Format: Chin Wee Tan, Naomi Berrell, Meg L. Donovan, James Monkman, Habib Sadeghirad, Vahid Yaghoubi Naei, Jinjin Chen, Alyssa Rossenbloom, Shilah Bonnett, Mark Conner, Brian Filanoski, Christine Kang, Joseph M. Beechem, John F. Fraser, Catherine Barnett, Rahul Ladwa, Brett G. Hughes, Arutha Kulasinghe. Characterising head and neck tumour microenvironment using high plex spatial omics technologies and analyses [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 175.
Abstract 3287: TOX modulates methionine availability and enhances CD8+ T cell anti-tumor function in colorectal cancer
Authors: Yujie Chang, Zhao Hui
Journal: Cancer Research (2025)

Abstract Colorectal cancers (CRC) with high TOX expression exhibit greater infiltration of CD8+ T cells, which display stronger tumor-killing capacity. This study investigates the metabolic mechanisms underlying the role of TOX in shaping the tumor microenvironment (TME) and its impact on CD8+ T cell function. Using LC-MS/MS metabolomics, we found that methionine and its metabolites are enriched in the TME of TOX-high CRC tumors. Further analysis revealed that TOX-high tumor cells express lower levels of the methionine transporter SLC43A2, reducing their methionine uptake. This methionine pool supports CD8+ T cell cytotoxicity and decreases apoptosis. In TOX-low tumors, we tested intratumoral methionine supplementation to assess its effect on tumor growth and CD8+ T cell activity. Supplementing methionine in TOX-low CRC tumors led to a significant reduction in tumor size and an increase in the proportion and activity of infiltrating CD8+ T cells. These results indicate that TOX modulates methionine metabolism by downregulating SLC43A2 in tumor cells, reducing competition with CD8+ T cells and enhancing their anti-tumor function. Our findings highlight TOX as a critical regulator of tumor metabolism and immune cell function, with potential as a therapeutic target for both immunotherapy and metabolic intervention strategies in CRC. Citation Format: Yujie Chang, Zhao Hui. TOX modulates methionine availability and enhances CD8+ T cell anti-tumor function in colorectal 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 3287.
Abstract 1324: MECOM a novel player in AR-driven treatment resistant castration-resistant prostate cancer
Authors: Surendra Gulla, Tej K. Sharma, Ephraim Gardner, Shreya Shyam Sundar, Brian Capaldo, Jonathan E. Bard, Tobi Ogunbowale, Abbas Jawadala, Min Ma, Roberto Pili, Jun Qu, David J. VanderWeele, Remi Adelaiye-Ogala
Journal: Cancer Research (2025)

The androgen receptor (AR) remains a pivotal target in castration-resistant prostate cancer (CRPC), as its continued activity presents a therapeutic vulnerability. Reprogramming of the AR cistrome, shifting from a canonical (typical or standard) to a non-canonical (atypical or non-standard) form, is associated with disease progression. While canonical AR signatures are prevalent in benign and localized prostate cancer, advanced CRPC exhibits a predominance of non-canonical AR elements. This non-canonical AR cistrome is linked to enzalutamide resistance, a standard AR-targeted therapy in the clinic. In preclinical prostate cancer models, non-canonical AR signatures correlate with enzalutamide resistance, and bulk RNA sequencing and AR-ChIP-seq data suggest an association with the EVI1-target gene set. EVI1, a zinc-finger transcription factor and product of the MECOM locus, is associated with poor prognosis and acts as a co-activator in cancer cell survival. Yet, its role in AR therapy resistance remains unclear. Functional assays demonstrated that MECOM expression, confined to CRPC and enzalutamide-resistant models, interacts with AR and influences cell proliferation. MECOM knockdown in CRPC cells inhibited proliferation in 2D and 3D cell cultures and significantly affected noncanonical AR signature profiles. This suggests a potential re-sensitization to AR inhibitors, a finding that could significantly impact the treatment of CRPC. Poly-ADP ribose polymerase inhibitors (PARPi), particularly Talazoparib, effectively reduced tumor growth in vivo and MECOM protein expression in CRPC cells, organoids derived from PDXs, and tumors. Our findings indicate that MECOM is a key driver of non-canonical AR signaling in CRPC. We propose that patients with MECOM expression may benefit from PARPi therapy, regardless of DNA Damage Repair (DDR) or homologous DNA Repair (HDR) gene mutation status. Citation Format: Surendra Gulla, Tej K. Sharma, Ephraim Gardner, Shreya Shyam Sundar, Brian Capaldo, Jonathan E. Bard, Tobi Ogunbowale, Abbas Jawadala, Min Ma, Roberto Pili, Jun Qu, David J. VanderWeele, Remi Adelaiye-Ogala. MECOM a novel player in AR-driven treatment resistant castration-resistant prostate 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 1324.
Abstract 1621: Investigate PARP1-dependent cell death in hepatocellular carcinoma
Authors: Chun Yin YU, Hoi Tang MA
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) is one of the most prevalent types of liver cancer, representing the third-leading cause of cancer-related mortality worldwide. It is typically characterized by an environment of high oxidative stress and persistent DNA damage. The persistent DNA damage in HCC triggers and initiates the ADP-ribosylation signalling pathway, which locates the DNA lesion sites for the recruitment of proteins involved in DNA damage repair. While ADP-ribosylation is critical for DNA damage repair, the impact of disrupting the homeostasis of ADP-ribosylation on HCC remains poorly understood. To explore the impact of dysregulated ADP-ribosylation in HCC, a degron-mediated gene silencing system was employed in HCC cell lines with PARG and ARH3 knockout (KO). With the addition of doxycycline (Dox) and Auxin (IAA), the degron-tagged PARG was degraded, establishing the PARG and ARH3 KO environment. Acute loss of PARG and ARH3 resulted in PARP1 hyperactivation, leading to PAR accumulation in the cells, followed by massive cell death in a time-dependent manner. The PARP1-dependent cell death induced by PARG and ARH3 KO was confirmed using the PARP1 KO model and the supplementation of a PARP1 inhibitor to cells. While activation of apoptosis and parthanatos (canonical PARP1-dependent cell death pathways) was observed, targeting the key enzymes in these pathways failed to suppress PARG and ARH3 KO-mediated cell death, indicating that the underlying mechanism is yet to be identified. Nevertheless, an interconnection between the NAD cycle and PARP1-dependent cell death was also examined. Supplementation of the metabolite in the NAD cycle suppresses PARP1-dependent cell death. Interestingly, targeting the rate-limiting enzyme in the NAD salvage pathway using CRISPR-Cas9-mediated KO or NAMPT inhibitor could suppress cell death. Altogether, these results extend the understanding of PARP1-dependent cell death mediated by the loss of PARG and ARH3 and provide insights into the therapeutic development for targeting the homeostasis of ADP-ribosylation in HCC. Citation Format: Chun Yin YU, Hoi Tang MA. Investigate PARP1-dependent cell death in hepatocellular carcinoma [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 1621.
Abstract 2749: Single-cell 3D genome structure analysis reveals clonal evolution and heterogeneity in acute myeloid leukemia
Authors: Yu Luan, Ye Hou, Yutong Lei, Qiushi Jin, Jie Xu, Bei Jia, Siwei Xu, Ping Wang, Alok Swaroop, Yihao Fu, Juan Wang, Qixuan Wang, Hong Zheng, Jing Zhang, Feng Yue
Journal: Cancer Research (2025)

Abstract Alterations in the 3D genome organization have been reported in different types of cancer and have been linked with gene dysregulation and cancer progression. However, majority of the studies were performed using bulk chromatin interaction assays and therefore, cannot address the heterogeneity and clone evolution in primary human tumors. In this study, we generated single cell Hi-C and single cell ATAC-Seq data in a cohort of AML patients, comprising samples at different disease stages, including diagnosis, remission, and relapse. To our knowledge, this is first large collection of single cell Hi-C data in primary tumor. In total, we profiled 153,517 cells across 13 samples, revealing distinct contact patterns and significant heterogeneity in genome-wide contact features between different samples, as well as within the same sample. We demonstrated the impact of 3D genome alterations on AML-specific gene expression programs, highlighting the role of compartmentalization in driving AML pathogenesis. Moreover, we identified hundreds of AML-specific chromatin domains with decreased heterogeneity during the transition from initial diagnosis to post-treatment relapse, suggesting the emergence and expansion of therapy-resistant subclones. By integrating a clonal evolution model, we delineated the dynamic relationship between somatic mutation, structural variation, and 3D genome architecture alterations. Finally, we discovered a chromatin loop uniquely present in a subclone of the relapse sample, which hijacked a distal enhancer to the known chemo-resistance-related oncogene and led to its upregulation. To summarize, our findings demonstrated the heterogeneity of 3D genome structure in AML and provide insights on the disease progression and relapse mechanisms. Citation Format: Yu Luan, Ye Hou, Yutong Lei, Qiushi Jin, Jie Xu, Bei Jia, Siwei Xu, Ping Wang, Alok Swaroop, Yihao Fu, Juan Wang, Qixuan Wang, Hong Zheng, Jing Zhang, Feng Yue. Single-cell 3D genome structure analysis reveals clonal evolution and heterogeneity in acute myeloid leukemia [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 2749.
Abstract 3129: Fibroblast activation protein directed CAR T cells engineered <i>in situ</i> using targeted lipid nanoparticles inhibit progression of pancreatic ductal adenocarcinoma
Authors: Khuloud Bajbouj, Zebin Xiao, Leslie A. Hopper, Li Huang, Tyler E. Papp, Jayalakshmi Ramani, Adrian Bot, Yanjie Bao, Matthew Butcher, Haig Aghajanian, Carl H. June, Drew Weissman, Hamideh Parhiz, Steven M. Albelda, Ellen Puré
Journal: Cancer Research (2025)

The growth of solid tumors is greatly influenced by stromal components including cancer-associated fibroblasts (CAFs) and desmoplastic matrix through both immune-dependent and immune-independent mechanisms. Fibroblast activation protein (FAP) is a stromal cell target that is selectively expressed at high levels on the cell surface of CAFs. We previously established an ex vivo retroviral-transduced CAR T cell approach to target FAP+ CAFs that resulted in depletion of FAP+ stromal cells, disruption of desmoplastic matrix, enhanced immune infiltration, and inhibition of tumor growth. In this study, we generated FAP-CAR T cells in situ using a novel platform to deliver modified FAP-CAR mRNA encased in anti-CD5 conjugated targeted lipid nanoparticles (tLNPs) and assessed the efficacy of this approach in a preclinical model of pancreatic ductal adenocarcinoma utilizing a cell line derived from a spontaneous pancreatic tumor isolated from a genetically engineered KPC mouse. We found that a single intravenous dose of anti-CD5 tLNP loaded with 30 μg of FAP-CAR mRNA resulted in transient FAP-CAR expression on &amp;gt;45%, &amp;gt;69% and &amp;gt;35% of CD3 T cells in spleen, blood and tumor tissues, respectively. Although CAR expression was more transient, the percentage of FAP-CAR+ T cells generated using this approach was significantly greater than the percentage of FAP-CAR+ cells detected following administration of 1X107 ex vivo retrovirally transduced FAP-CAR T cells. Notably, this in situ mRNA CAR T-cell engineering resulted in significantly increased inhibition of tumor growth, as compared to adoptive transfer of ex vivo retroviral-engineered T cells (74% vs 48%) respectively. Given that this approach circumvents the need for autologous T cell isolation, ex vivo viral transduction and expansion (thereby reducing the potential risk of insertional mutagenesis, while also eliminating the need for pre-conditioning by lymphodepletion), our data indicate a promising therapeutic delivery platform for treating desmoplastic solid tumors using a more accessible and cost-efficient technology. Citation Format: Khuloud Bajbouj, Zebin Xiao, Leslie A. Hopper, Li Huang, Tyler E. Papp, Jayalakshmi Ramani, Adrian Bot, Yanjie Bao, Matthew Butcher, Haig Aghajanian, Carl H. June, Drew Weissman, Hamideh Parhiz, Steven M. Albelda, Ellen Puré. Fibroblast activation protein directed CAR T cells engineered in situ using targeted lipid nanoparticles inhibit progression of pancreatic ductal adenocarcinoma [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 3129.
Abstract 2735: The role of ca2 in regulating 3d chromatin structure in tamoxifen resistant breast cancer
Authors: Lavanya Choppavarapu, Kun Fang, Tianxiang Liu, Aigbe G. Ohihoin, Victor X. Jin
Journal: Cancer Research (2025)

Abstract Background: Estrogen receptor-positive breast cancer frequently develops resistance to tamoxifen in one third of patients, driven by various mechanisms. Our work has linked 3D chromatin alterations to this resistance. However, most of the work in 3D chromatin regulation was mostly conducted in in vitro cell culture system. It is becoming very clear that to expand the characterization of 3D genome organization in patient samples is an emerging task. Hypothesis: We hypothesize that 3D chromatin alterations, including compartment switching, TAD reorganization, and dysregulated chromatin looping, drive tamoxifen resistance (TR) in breast cancer. Looping-mediated genes may play critical roles in resistance and serve as potential therapeutic targets. Methods and Results: To investigate the role of 3D chromatin changes in tamoxifen resistance, we performed Hi-C profiling on normal tissues (NTs), primary tumors (PTs), and tamoxifen-treated recurrent tumors (RTs), uncovering significant chromatin alterations. These included 46.8% A-to-B and 32.8% B-to-A compartment switching from NTs to PTs, and 58.3% B-to-A flipping during PT-to-RT progression. TAD analysis identified RT-specific Neo and Fuse alterations as well as tumor-specific chromatin loops. CA2 was identified as a enhancer-promoter looping (EPL)-mediated gene with its higher expression linked to poor relapse-free survival in endocrine-treated patients. Functional studies using the CA2 inhibitor brinzolamide demonstrated its ability to reduce cell viability, loop intensity, and CA2 expression in MCF7TR and T47DTR cells. In vivo, brinzolamide significantly reduced tumor growth in tamoxifen-resistant cell-derived xenograft (CDX) models. Additionally, CRISPR deletion of CA2 EPL enhancer region in MCF7TR cells resulted in a marked reduction in cellular viability, gene expression and protein expression. Conclusion: Our findings suggest CA2 as a key looping-mediated gene play an oncogenic role in driving tamoxifen resistance in breast cancer. Our study yields significant mechanistic insights into the role and clinical relevance of 3D chromatin architecture in tamoxifen resistant breast cancer. Citation Format: Lavanya Choppavarapu, Kun Fang, Tianxiang Liu, Aigbe G. Ohihoin, Victor X. Jin. The role of ca2 in regulating 3d chromatin structure in tamoxifen resistant breast 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 2735.