tbuckley/cabot-search huggingface dataset:
Abstract 1294: Primed human immune cell and cancer cell co-inoculated model for immuno-oncology drugs evaluation
Authors: Bin Xie, Xin Hou, Pengfei Yang, Yanbing Zhou, Loc Van, Diandong Jiang, Josh Caggiula, Danyi Wen
Journal: Cancer Research (2025)

Systemic peripheral blood mononuclear cell (PBMC) humanized model is a straightforward tool to evaluate therapeutic immuno-oncology (IO) drugs, including immune checkpoint blockers (ICB) and bispecific antibodies (BsAb). However, the model has a limited dosing regimen window due to graft-versus-host disease (GVHD), as seen in most immune deficient recipients. There is also a relative lower responsible rate from insufficient antigen specific immune cells infiltration into tumor microenvironment (TME). Thus, application of this PBMC humanized model is restricted in evaluation of multiple ICBs and myeloid cell- or lymphocyte-mediated BsAbs. To overcome this, LIDE has developed a unique co-inoculation model with primed human PBMC (or/and its derived immune cell subsets) and cancer cells. Cancer-priming human PBMCs are well mixed with fresh cancer cells in MatriGel, co-inoculated into immune deficient mice to form an immune cell relatively warm tumor tissue for late immunotherapy. This model can significantly delay the graft-versus-host-reaction for another month compared with traditional systemic PBMC humanized model, and achieves maximal therapeutic effect of the testing drugs by pre-activating T cells with specific tumor antigens. Considering minimum innate immune cells in TME, dendritic cells or macrophages are expanded ex vivo, then transferred into this co-inoculated system to work together with T cells with a proper survival rate in the dosing period, mimic clinical biopsy complexity, to help determine the overall effect induced by integrated signals. It seems CD40 agonist or CD47 antagonist could well synergize with anti-PD(L)1 to control melanoma and triple negative breast cancer development, respectively. This optimized immune cell humanized cancer-bearing mice models have been tested for various cancer targets, e.g., PD(L)1, Tim3, Lag3, Tigit, PVRIG, TGFβ1, CD73/CD39, CD47/Sirpa, DLL3/CD3, Claudin18.2/4-1BB/CD3, B7H3/CD3/ADC, GPC3/CD3, GPRC5D/CD3, CSF1R, GITR, (Pro)IL2/IL15, to better understand the interaction and modulation between cancer cells and immune cells. Citation Format: Bin Xie,Xin Hou,Pengfei Yang,Yanbing Zhou,Loc Van,Diandong Jiang,Josh Caggiula,Danyi Wen. Primed human immune cell and cancer cell co-inoculated model for immuno-oncology drugs evaluation [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 1294.
Abstract 2823: CHAC1 regulates paraptosis by promoting glutathione degradation in cancer cells
Authors: Ling-Chu Chang, Shih-Kai Chiang, Shuen-Ei Chen
Journal: Cancer Research (2025)

Abstract Paraptosis is a type of programmed cell death characterized by cytoplasmic vacuolation, merging as a potential therapeutic strategy for cancer treatment. Paraptosis has been associated with disruption of proteostasis and redox homeostasis, however, the detailed mechanisms remain to be explored. CPYPP, a known paraptosis inducer, was employed to investigate the underlying mechanisms in breast cancer and melanoma cells. CPYPP significantly increased the production of reactive oxygen species (ROS). Treatment with N-acetyl-L-cysteine (NAC) and glutathione (GSH), but not oxidized glutathione (GSSG), mitigated CPYPP-induced cytoplasmic vacuolation and cell viability inhibition. CPYPP significantly decreased the intracellular GSH/GSSG ratio. Next-generation sequencing analysis indicated that CPYPP upregulates the expression of genes related to the cystine metabolism pathway, including SLC3A2, SLC7A11, cystathionine-γ-lyase (CTH), glutamate-cysteine ligase (GCLC, GCLM), and ChaC glutathione specific γ-glutamylcyclotransferase 1 (CHAC1). CPYPP increased the uptake of cystine. Cystine deprivation attenuated CPYPP-induced protein ubiquitination, cytoplasmic vacuolation, and cell viability inhibition. Furthermore, CHAC1 knockdown ameliorated CPYPP-induced endoplasmic reticulum stress, unfolded protein response, protein ubiquitination, cell viability inhibition, and ROS production. CHAC1 is transcriptionally upregulated by CPYPP via the PI3K-mTOR-CDK7/CDK9 axis. Taken together, these results suggest that the upregulation of CHAC1 mediates paraptosis. CHAC1 enhances the degradation of GSH, resulting in a decline in the GSH/GSSG ratio, a more oxidized intracellular state, and increased ROS production. This leads to the disruption of proteostasis, ultimately inducing paraptosis. Citation Format: Ling-Chu Chang, Shih-Kai Chiang, Shuen-Ei Chen. CHAC1 regulates paraptosis by promoting glutathione degradation in cancer 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 2823.
Abstract 4151: Creatine and GAMT promote tumor stemness and malignancy and can be used as biomarkers for colorectal cancer recurrence
Authors: Zhengran Zhou, Peishan Hu, Zerong Cai, Yufeng Chen, Xiaojian Wu, Xuanhui Liu
Journal: Cancer Research (2025)

Abstract BACKGROUND: The role of creatine, a common nutritional supplement, in tumorigenesis and development has gained increasing attention. Previous studies have shown that it has a dual effect on tumorigenesis and recent studies suggested that it promotes colorectal cancer (CRC) metastasis. However, the role creatine metabolism plays in tumor malignancy and recurrence is still unclear and identifying the mechanism could provide new strategies for the treatment of CRC. METHODS: Targeted metabolomics analysis of creatine was dynamically performed on plasma samples of 160 CRC patients including 30 relapse cases. GAMT, the key enzyme in creatine synthesis, was investigated in TCGA and ICGC-ARGO database (a large multi-omics study of CRC in China conducted by the sixth affiliated hospital of Sun Yat-sen University). The effect of creatine and GAMT on CRC stemness and its mechanism were investigated in CRC cell lines, patient-derived organoids, and patient-derived xenografts. Limited proteolysis-mass spectrometry (LiP-MS) and RNA-sequencing was performed to illustrate creatine-protein interaction and the regulation of relative signal pathways. RESULTS: In recurrent CRC cases, creatine level gradually increased over time after the first radical surgery until recurrence. Meanwhile, GAMT expression was found significantly higher in patients who were going to relapse, both in TCGA and ICGC-ARGO database. Patients with higher GAMT expression had worse prognosis. The addition of creatine inhibitor can effectively restrain CRC activity and proliferation both in vitro and in vivo. GAMT knockdown significantly reduced the self-renewal ability of CRC cells, and tumor stemness pathways were up-regulated, which can be reversed by adding creatine to the culture. CONCLUSIONS: Creatine is associated with CRC recurrence through promoting tumor stemness and malignancy. Therapeutic strategies targeting creatine metabolism have the potential to reduce CRC recurrence. Citation Format: Zhengran Zhou, Peishan Hu, Zerong Cai, Yufeng Chen, Xiaojian Wu, Xuanhui Liu. Creatine and GAMT promote tumor stemness and malignancy and can be used as biomarkers for colorectal cancer recurrence [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 4151.
Abstract 3082: Activation mevalonate pathway via HMGCS2 introduced resistance to molecular targeted therapy for cancer
Authors: Yasuhiro Kato
Journal: Cancer Research (2025)

Introduction: Recently, some oncogenic driver mutations found in any kinds of cancer. NTRK fusion is one of the oncogenic driver mutations express in any kinds of malignancy tumors and neurotrophic tropomyosin receptor kinase (NTRK) tyrosine kinase inhibitors (TKIs) is specific treatment for cancer harboring NTRK fusion. We investigated resistance mechanism of cancer harboring NTRK fusion to NTRK-TKI. Method: We established resistant cells to NTRK-TKIs (larotrectinib, entrectinib and selitrectinib) using KM12 harboring NTRK fusion. We investigated resistant cells for finding resistant mechanism to NTRK-TKI. Results: Whole exome sequence and microarray analysis conducted to resistant cells (KM12-LR, KM12-ER, and KM12-SR). Only KM12-LR have G595R as resistant solvent front mutation previously reported. We confirmed the overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in resistant cell lines from result of microarray, western blotting and quantitative RT-PCR. SREBP2 and PPARα which associated mevalonate pathway showed lower expression correlated HMGCS2 expression in resistant cells. After knocking down of HMGCS2, sensitivity to NTRK-TKI recovered in KM12-ER and KM12-SR. Mevalonic acid reintroduced NTRK-TKI resistance in KM12-ER and KM12-SR. after knocking down HMGCS2. Simvastatin and silibinin showed synergic effect with NTRK-TKIs to resistant cells, and delayed emergence of resistance in KM12 cells. In vivo study, resistant tumor to NTRK-TKI created in mice showed HMGCS2 over expression. NTRK-TKI and simvastatin reduced resistant tumor growth compared with entrectinib alone in vivo. Conclusion: Activation mevalonate pathway via HMGCS2 overexpression introduced resistance to NTRK-TKI. It found novel resistance mechanism to molecular targeted therapy. Statin showed possibly useful for overcoming resistance mechanism introduced by HMGCS2. Citation Format: Yasuhiro Kato. Activation mevalonate pathway via HMGCS2 introduced resistance to molecular targeted therapy for 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 3082.
Abstract 6191: Associations of alcohol consumption with expression of CD44, CD24, and ALDH1A1 stem cell markers in incident benign breast biopsy samples
Authors: Rulla M. Tamimi, Maisey Ratcliffe, Yu Jing J. Heng, Brian Sardella, Lusine Yaghjyan
Journal: Cancer Research (2025)

Abstract Purpose: We investigated the associations of alcohol consumption with expressions of stem cell markers CD44, CD24, and ALDH1A1 in cases of incident benign breast disease. Methods: This study included 721 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses’ Health Study II cohort. Histologically normal breast tissue cores were used to construct tissue microarrays (TMAs). Immunohistochemistry (IHC) was performed on TMA sections to analyze the expression of stem cell markers. For each core, the IHC expression was assessed using semi-automated software and reported as the % of positively stained cells for each of the markers out of the total cell count. All expression measures were log-transformed for analysis. Alcohol consumption was obtained from semi-quantitative food frequency questionnaires. Other covariate information was collected on the initial questionnaire and updated biennially thereafter. We examined associations for recent (at the time of biopsy) and cumulative average alcohol consumption (from all questionnaires before the biopsy), modeled as a continuous variable (drinks/day). Generalized linear regression was used to examine the associations of alcohol with each marker’s expression (within stroma and epithelium), while adjusting for known breast cancer risk factors and BBD subtype. Results: In this study of 721 cancer-free women, the average age at the time of biopsy was 44 (range 27-63), with the majority of participants being premenopausal at the time of biopsy (81.28%). Recent and cumulative average alcohol consumption were not associated with expression of CD44, CD24, or ALDH1A1 in stroma (recent: β per drink/day=0.08, 95% Confidence Interval [CI] -0.16, 0.32; β=-0.03, 95% CI -0.11, 0.05; β=0.01, 95% CI -0.26, 0.29, respectively; cumulative average: β=-0.09, 95% CI -0.38, 0.19; β=-0.01, 95% CI -0.10, 0.08; β=-0.04, 95% CI -0.36, 0.27, respectively) or epithelium (recent: β=0.08, 95% CI -0.04, 0.21; β=0.02, 95% CI -0.01, 0.06; β=0.23x10-2, 95% CI -0.15, 0.15, respectively; cumulative average: β=-0.06, 95% CI -0.08, 0.20; β=0.04, 95% CI -0.01, 0.08; β=-0.01, 95% CI -0.18, 0.17, respectively). Conclusion: Our findings suggest that alcohol use is not associated with the expression of CD44, CD24, and ALDH1A1 in histologically normal breast tissue from benign biopsies. Citation Format: Rulla M. Tamimi, Maisey Ratcliffe, Yu Jing J. Heng, Brian Sardella, Lusine Yaghjyan. Associations of alcohol consumption with expression of CD44, CD24, and ALDH1A1 stem cell markers in incident benign breast biopsy samples [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 6191.
Abstract 4532: Investigating the effects of radiation and anti-PD1 therapy on immune cell tumor infiltration in head and neck cancer
Authors: Katelyn Jansen, Maria Lehn, Nicolas Nassar, Alexis Redmond, Mathieu Sertorio, Vinita Takiar, Dalia El-Gamal, Trisha Wise-Draper
Journal: Cancer Research (2025)

Abstract Head and neck cancer (HNC) is predominantly comprised of head and neck squamous cell carcinoma (HNSCC), ranking as the 6th most common cancer worldwide. There are roughly 450,000 documented annual fatalities with predictions of annual increases in incidence. Despite advances in these intensive anticancer techniques, patient survival remains low. The current standard of care for local recurrence of HNSCC tumors is salvage surgery (SS) or combined modality with adjuvant re-irradiation using (X-ray)-based therapy (XRT). However, due to critical structure dose limits of the head and neck region, adjuvant XRT can cause excess morbidity. Proton radiation (PT), although less researched, may be advantageous to minimize the risk of injury to highly critical structures and minimize the radiation dosage outside of the tumor volume due to its energy course of the Bragg’s Peak, which is thought to also have a higher relative biological effectiveness. While there may be high clinical relevancy of PT, there is currently a lack of translational and clinical data to confirm advantages of its use in HNSCC. Patients with HNSCC have impaired immune surveillance, and higher levels of inhibitory checkpoints such as PD-L1 permitting tumors to evade the immune system. Immunotherapy targeting PD-1, receptor to PD-L1, has greatly enhanced survival rates in these patients, but many patients fail to respond due to other immunosuppressive factors. Here we investigate the immune response effects of RT, with either XRT or PT combined with anti-PD1 antibody (αPD1) in vivo using an established murine oral cavity tumor model. Wild-type C57BL/6 mice were injected into the buccal region with 1.5 x 106 mouse oral cavity (MOC-1) cells. Once tumors reached 50-150mm3, mice were treated over one week with XRT (3 treatments of 5 Gy) or sham. The following week the mice received αPD1 or IgG isotype control antibody. Here we present effects of XRT vs PT on immune infiltration by flow cytometry and immunofluorescence in three independent studies. Growth curves in the studies indicated that proton therapy and αPD1 in combination may be advantageous over αPD1 or PT alone with increased CD8 T cell infiltration, suggesting that PT in combination with αPD1 may offer significant advantages in eliciting a strong anti-tumor immune response. Citation Format: Katelyn Jansen, Maria Lehn, Nicolas Nassar, Alexis Redmond, Mathieu Sertorio, Vinita Takiar, Dalia El-Gamal, Trisha Wise-Draper. Investigating the effects of radiation and anti-PD1 therapy on immune cell tumor infiltration in head and neck 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 4532.
Abstract 6094: Enhanced GPC3-chimeric antigen receptor T cells with secreted bi-specific CD39-PD-L1 antibody for improved liver cancer therapy
Authors: Zhongliang Li, Bing Liu, Huajing Wang, Ke He, Xiaopei Li, Dingjie Liu, Ligong Lu, Xu He, Xiaowen He, Ze Yang, Meixiao Zhan
Journal: Cancer Research (2025)

Abstract Glypican-3 (GPC3)-targeted chimeric antigen receptor (CAR) T cell therapy shows promise for treating liver cancer. However, the immunosuppressive tumor microenvironment (TME), characterized by elevated levels of adenosine and PD-L1 expression, significantly hinders CAR T cell efficacy. We previously demonstrated that a bi-specific antibody, OriA631-B, which targets CD39—an enzyme crucial for converting extracellular ATP into adenosine—and PD-L1, yields significant antitumor effects. Our findings indicate that GPC3 CAR T cells upregulate CD39 upon activation by liver cancer cells, which also express PD-L1.To enhance antitumor efficacy, we engineered GPC3 CAR T cells to secrete a fragment of OriA631-B that targets both CD39 and PD-L1 (termed GPC3 CAR-T-CD39-VHH-PD-L1-ScFv). In a mouse model of liver cancer, GPC3 CAR-T-CD39-VHH-PD-L1-ScFv exhibited superior antitumor activity compared to GPC3 CAR T cells alone. Specifically, while GPC3 CAR T cells inhibited tumor growth, the GPC3 CAR-T-CD39-VHH-PD-L1-ScFv nearly eliminated tumors by day 20, whereas tumors in the GPC3 CAR T group measured around 200 mm3.This enhanced efficacy is attributed to the localized delivery of the bi-specific antibody fragment, which effectively inhibits adenosine signaling and PD-L1-mediated immune checkpoint blockade. Our findings suggest that GPC3 CAR-T-CD39-VHH-PD-L1-ScFv represents a novel therapeutic strategy for liver cancer, offering improved efficacy and potentially reduced side effects associated with systemic antibody administration. Citation Format: Zhongliang Li Bing Liu Huajing Wang Ke He Xiaopei Li, Dingjie Liu, Ligong Lu, Xu He, Xiaowen He, Ze Yang, Meixiao Zhan. Enhanced GPC3-chimeric antigen receptor T cells with secreted bi-specific CD39-PD-L1 antibody for improved liver cancer therapy [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 6094.
Abstract 6071: PD-1xTGFβR2 bispecific Biclonics® antibody INCA33890 augments human T-cell effector functions in vitro and ex vivo
Authors: Jun Guan, Aidan Gilmartin, Kenji Kimura, Estela Noguera-Ortega, Ashwini Kulkarni, Pat Feldman, Michelle Kinder, Cynthia Timmers, Alejandro Amador Arjona, Patrick Mayes, Steven M. Albelda, Evgeniy Erulasnov, Liang-Chuan Wang
Journal: Cancer Research (2025)

Abstract Anti-programmed cell death (PD)-1 and anti PD-ligand1 antibodies have produced durable clinical responses in a wide variety of solid and hematologic malignancies; however, their clinical benefits are often limited to a subset of patients. One of the immune resistance mechanisms that limits the activity of PD-1 axis pathway blockers involves activation of the transforming growth factor beta (TGFβ) pathway within the tumor microenvironment (TME). To overcome this immune suppression, a PD-1 and TGFβ receptor 2 (TGFβR2) dual targeting bispecific Biclonics® antibody, INCA33890, was developed. INCA33890 inhibits TGFβR2 preferentially on PD-1-positive cells (Wang L-C, et al. AACR 2023. Abs 2936). In this study, various in vitro and ex vivo cell-based systems were used to evaluate changes in T-cell effector function induced by INCA33890 compared with the anti-PD-1 antibodies, nivolumab or pembrolizumab. We observed that INCA33890 induced higher interferon gamma (IFNγ) levels than nivolumab with and without exogenous TGFβ in an exhausted T-cell mixed lymphocyte reaction (MLR) assay. Additionally, INCA33890 was superior to nivolumab in enhancing T-cell proliferation in the presence of TGFβ. RNAseq analysis of samples from the exhausted MLR assay revealed that, compared with nivolumab, expression of cytotoxic genes (GZMB, GNLY), proinflammatory cytokines (IFNG), and T-cell activation markers (CD25, 4-1BB) were elevated following INCA33890 treatment in the presence of TGFβ. We next co-cultured T-cell receptor-engineered T cells with non-small cell lung cancer tumor digests to examine the impact of the TME on antigen-specific T-cell responses. INCA33890 increased the percentage of IFNγ-producing T cells compared with pembrolizumab over 72 hours. In summary, our data suggest that co-inhibition of both PD-1 and TGFβR2 by INCA33890 may provide greater therapeutic benefits than an anti-PD-1 antibody alone. Citation Format: Jun Guan, Aidan Gilmartin, Kenji Kimura, Estela Noguera-Ortega, Ashwini Kulkarni, Pat Feldman, Michelle Kinder, Cynthia Timmers, Alejandro Amador Arjona, Patrick Mayes, Steven M. Albelda, Evgeniy Erulasnov, Liang-Chuan Wang. PD-1xTGFβR2 bispecific Biclonics® antibody INCA33890 augments human T-cell effector functions in vitro and ex vivo [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 6071.