tbuckley/cabot-search huggingface dataset:
Abstract 5551: From persistence to resistance: insights into the mechanisms of drug tolerance in cancer therapy using patient-derived organoids
Authors: Yasmine Abouleila, Timo Voskuilen, Mayke Doorn, Roel Verkerk, Joris Maas, Carla Verissimo, Sylvia F. Boj
Journal: Cancer Research (2025)

Abstract Resistance to cancer treatment remains a significant obstacle in curing cancer patients. Despite recent advancements in novel cancer drugs, patients often experience treatment resistance even after initially responding to therapy, leading to tumor relapse. To understand how resistance develops against standard cancer therapies, it is essential to study the gradual changes leading to full resistance. Recent research shows that cancer cells can evade the effects of chemotherapy and targeted therapies by entering a reversible, slow-growing phase called the drug-tolerant persister (DTP) state. In this DTP state, cancer cells survive drug treatment long enough to begin accumulating mutations and eventually develop additional mechanisms of irreversible resistance. Patient-derived organoid (PDO) models, also known as HUB Organoids®, are directly derived from patient tissues, making them more physiologically relevant than traditional cell lines. This study highlights the value of PDO models in studying drug persistence and resistance, as they are more likely to reflect in-vivo conditions. Here, we demonstrate the successful development of colorectal cancer (CRC) PDO models that can persist and resist standard therapies. These models were characterized using whole exome sequencing and bulk RNA sequencing to assess their persistent or resistant state and to identify potential pathways and new drug targets involved in resistance. In conclusion, developing persistent and resistant PDO models is essential for understanding the mechanisms behind drug resistance. This research contributes to developing patient-relevant preclinical models to develop more effective and personalized cancer treatments and expands our overall understanding of how resistance develops in cancer patients. Citation Format: Yasmine Abouleila, Timo Voskuilen, Mayke Doorn, Roel Verkerk, Joris Maas, Carla Verissimo, Sylvia F. Boj. From persistence to resistance: insights into the mechanisms of drug tolerance in cancer therapy using patient-derived organoids [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 5551.
Abstract 4810: Metabolic reprogramming enhances IL15-GPC3-CAR T cell therapy for hepatocellular carcinoma while mitigating cytokine release syndrome
Authors: Kevin Song, Yue Hu, Abhijit Sarkar, Andras Heczey, Xiaotong Song
Journal: Cancer Research (2025)

Abstract Background: This study aims to develop a safer and more effective CAR T cell therapy for hepatocellular carcinoma (HCC). While recent clinical trials have shown promise, IL15-GPC3-CAR T cells demonstrated a 33% partial response rate but were associated with a high incidence of cytokine release syndrome (CRS), occurring in 75% of patients (9/12) compared to 8% (1/12) in GPC3-CAR T cells. Thus, strategies to mitigate CRS while enhancing efficacy are urgently needed. We previously demonstrated that inosine could serve as an alternative energy source for CAR T cells in the glucose-deprived tumor microenvironment (TME) (Nat Metabolism, 2020). More recently, we provided proof of concept that a metabolic reprogramming strategy involving adenosine deaminase 1 (ADA1) enhances T cell survival by converting adenosine to inosine while reducing pro-inflammatory cytokine production (Cell Rep Med, 2024). In this study, we aim to improve IL15-armed GPC3-CAR T cell therapy for HCC by leveraging ADA1 signaling to enhance CAR T cell persistence in the TME while mitigating inflammatory responses, potentially reducing the risk of CRS. Methods: Human PBMCs were transduced with retroviral vectors encoding IL15-GPC3-CAR and ADA1 (designated IL15-GPC3-MRCAR). Antitumor efficacy and toxicity were evaluated in a Huh7 xenograft mouse model. Cytokine levels and mouse survival were measured to assess immune activation and CRS risk. Results: IL15-GPC3-MRCAR T cells demonstrated enhanced proliferation and reduced exhaustion following repeated HCC stimulation in vitro. They also exhibited superior cytotoxic activity compared to IL15-GPC3-CAR or GPC3-MRCAR T cells both in vitro and in vivo. Notably, in the mouse study, IL15-GPC3-CAR T cells resulted in mortality rates comparable to the PBS-treated group, likely due to severe CRS. In contrast, IL15-GPC3-MRCAR T cells significantly extended survival, with outcomes similar to those observed in GPC3-CAR T cells and GPC3-MRCAR T cells groups. Conclusions: IL15-GPC3-MRCAR T cell therapy enhances metabolic fitness and reduces CRS risk, representing a promising advancement in GPC3-targeted therapy for HCC. Further clinical validation is warranted. Citation Format: Kevin Song, Yue Hu, Abhijit Sarkar, Andras Heczey, Xiaotong Song. Metabolic reprogramming enhances IL15-GPC3-CAR T cell therapy for hepatocellular carcinoma while mitigating cytokine release syndrome [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 4810.
Abstract 3865: Targeting MYC high osteosarcoma through EYA2 modulation
Authors: Ryota Shirai, Sydney Hakim, Avery Bodlak, Masanori Hayashi
Journal: Cancer Research (2025)

Abstract Osteosarcoma is the most common bone cancer in children, adolescent and young adults. Recent large scale genomic studies have started to reveal that Osteosarcoma (OS) patients who have tumors that highly express the transcription factor MYC, are significantly at high risk of treatment failure. However, MYC has long been known to be extremely difficult to target with drugs. The EYA protein is an evolutionarily conserved transcriptional co-activator of the SIX1 family of homeobox proteins, which also has phosphatase activity. Multiple studies have shown that EYA is involved in the initiation and progression of various cancers. EYA Tyrosine Phosphatase has been shown to regulate MYC expression and protein stability in Brain tumors. In OS cells, EYA2 is highly expressed and has been indicated to be involved in tumor progression and invasion, but the interaction between EYA2 and MYC is unknown. The major goal of our study is to clarify the effect of EYA2 on the expression of MYC in OS cells, and evaluate it as a therapeutic target. First, EYA2 and MYC expression in various OS cell lines were confirmed using western blotting. Next, we established EYA2 shRNA knock-down in 143B cells and CHCO-OS1 cells, which highly express both EYA2 and MYC. Interestingly, in these cells, EYA2 knock-down led to decreased MYC expression, decreased clonogenicity and proliferation. Furthermore, EYA2 knock-down led to decreased cell migration in 143B cells when measured by a scratch assay using the Incucyte live cell imaging. Next, we also tested 9987, an allosteric EYA2 phosphatase inhibitor. Here, 9987 was shown to inhibit the clonogenicity, proliferation and migration compared to DMSO control. These results indicate that in MYC-high OS cells, EYA2 knockdown leads to decreased MYC expression, decreased proliferation, clonogenicity, and migration, and EYA2 phosphatase inhibition is a promising therapeutic strategy for this tumor. We are currently confirming whether the EYA2 inhibitor 9987 can reduce metastatic rate and extend overall survival in our orthotopic-implantation-amputation mouse model, and further identifying the mechanisms of how EYA2 regulates MYC activation in OS. Citation Format: Ryota Shirai, Sydney Hakim, Avery Bodlak, Masanori Hayashi. Targeting MYC high osteosarcoma through EYA2 modulation [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 3865.
Abstract 6221: Gastric atrophy is associated with increased risk of esophageal squamous cell carcinoma in Lilongwe, Malawi
Authors: Kadiatou Traore, Yingxi Chen, Yukiko Yano, Paul S. Albert, Sung Duk Kim, Sanford M. Dawsey, Shiraz Khan, Christian C. Abnet
Journal: Cancer Research (2025)

Background: Esophageal cancer (EC) is the 7th leading cause of cancer worldwide, with nearly 500,000 annual deaths. Esophageal squamous cell carcinoma (ESCC), the most prevalent subtype, has high incidence in East Asia, South and East Africa. Malawi has the highest EC incidence rate, almost exclusively ESCC, with risk factors including tobacco use, hot beverages, fuel source, moldy grain consumption, geophagia, poor oral health, and possibly HIV. H. pylori’s role in ESCC is unclear, with adverse, null, and protective effects across different populations. Gastric atrophy, a potential result of H. pylori infection, may increase ESCC risk by promoting gastrointestinal bacterial overgrowth that exposes esophageal mucosa to carcinogens (e.g. nitrosamines). HIV, common in Malawi, may interfere with H. pylori antibody tests. Limited data, especially from African populations, leaves a gap in understanding the roles of H. pylori and gastric atrophy in ESCC. Methods: We enrolled 300 ESCC cases and 300 controls, matched by age, sex and region, at two Lilongwe, Malawi hospitals (2017-2020) and collected demographic, health, and behavioral data. We measured H. pylori antibodies and gastric atrophy (pepsinogen I (PGI), pepsinogen II (PGII)) via serology. Atrophy was defined as PGI:II &amp;lt;3 or PGI &amp;lt;30μg/L per kit specifications. We adjusted logistic regression models for design variables, known and potential confounders. Results: H. pylori seropositivity was 68% in cases, 80% in controls and significantly associated with lower ESCC risk (aOR 0.54; 95% CI 0.32-0.92). High HIV positivity in cases (21%) may obscure the association due to assay interference. Having a PGI &amp;lt;30μg/L was significantly associated with higher ESCC risk (aOR 4.92; 95% CI 2.04-11.87) while having a PGI:II &amp;lt;3 was marginally associated (aOR 2.14; 95% CI 0.97-4.70). Conclusion: Serologic gastric atrophy was associated with strongly increased ESCC risk. H. pylori's protective effect may be due to measurement interference. Citation Format: Kadiatou Traore, Yingxi Chen, Yukiko Yano, Paul S. Albert, Sung Duk Kim, Sanford M. Dawsey, Shiraz Khan, Christian C. Abnet. Gastric atrophy is associated with increased risk of esophageal squamous cell carcinoma in Lilongwe, Malawi [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 6221.
Abstract 3845: A matching panel of tumor organoids and patient derived orthotopic xenograft mouse models (PDOX) of high-grade gliomas in EGFP-based SCID mice
Authors: Xin (Alice) Zhai, Milagros Suarez Palacios, Zilu Huang, Jinnan Chen, Tongchao Jiang, Nitin Wadhwani, Michael DeCuypere, Yuchen Du, Xiaonan Li
Journal: Cancer Research (2025)

Background: High grade glioma, also known as glioblastoma multiform (GBM) a highly aggressive brain tumor, requires advanced systems to study tumor-stroma interactions. Paired in vitro and in vivo model systems such as 3D organoids and PDOX models derived from EGFP-SCID mice offered a unique opportunity to precisely and rapidly differentiation of mouse (EGFP positive) from human tumor cells, thereby facilitating the visualization and analysis of tumor/normal cell interactions in vitro and in vivo. Methods: EGFP-SCID mice received intra-cranial implantation of pediatric (n=6) and adult (n=6) GBM tumors to form PDOX. Tumor-bearing mouse brains were dissected, and tumor cells were cultured to generate organoids by seeding at cell densities of 1250, 2500, 5000 cells/well and monitored for size and count over 1-21 or 28 days. Immunohistochemistry (IHC) tracked the distribution of EGFP-positive mouse cells and GBM markers, including GFAP, Nestin, Ki67, GFP, CD276+ and so on. Additional staining for lysosomes and nuclei (Hoechst/DIPA) confirmed cellular localization and interactions. Results: Hybrid organoids were successfully generated, integrating mouse and human GBM cells in 12 PDOX models. Organoid size and count varied by cell density and culture duration, with similar growth patterns between pediatric and adult samples. IHC confirmed expression of cellular proliferation (Ki67), glial cells (GFAP), differentiation (SYN), stem cell (Nestin) as well as normal mouse cells (GFP) that were in and surrounding tumor cells. In organoids, EGFP fluorescence revealed dynamic tumor-stroma interactions, with changing proportions of mouse cells and GBM cells over time, reflecting the organoid’s developmental complexity. Conclusion: This EGFP-based organoid and PDOX model system offers a robust platform for studying tumor-stroma interactions and characterizing cellular dynamics in GBM. The system’s integration of IHC provides a detailed view of tumor and stromal components, making it a valuable tool for biological and translational GBM studies. Citation Format: Xin (Alice) Zhai, Milagros Suarez Palacios, Zilu Huang, Jinnan Chen, Tongchao Jiang, Nitin Wadhwani, Michael DeCuypere, Yuchen Du, Xiaonan Li. A matching panel of tumor organoids and patient derived orthotopic xenograft mouse models (PDOX) of high-grade gliomas in EGFP-based SCID mice [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 3845.
Abstract 3847: APE1 mediates angiogenesis by stabilizing SMAD3 and blocking its ubiquitin induced degradation in esophageal adenocarcinoma
Authors: Farah Ballout, Heng Lu, Nadeem Bhat, Lei Chen, Dunfa Peng, Zheng Chen, Alexander Zaika, Oliver McDonald, Wael El Rifai
Journal: Cancer Research (2025)

Abstract Background: The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. Unfortunately, EAC has one of the lowest survival rates due to limited treatment options. Identifying disease drivers through functional studies is crucial for improving treatment options. This study aimed to explore the role of APE1 in regulating SMAD3 and promoting EAC progression. Methods and Results: Analysis of publicly available datasets revealed that APE1 and SMAD3 are upregulated and positively correlated in EAC compared to normal samples. Immunofluorescence staining of esophageal cancer progression tissue arrays confirmed significantly higher levels of APE1 and SMAD3 in EAC than in normal tissues. Western blot analysis showed that silencing APE1 reduced SMAD3 nuclear expression, which was also confirmed by immunofluorescence staining showing a loss of nuclear SMAD3 accumulation following APE1 knockdown. Immunoprecipitation and proximity ligation assays indicated a direct interaction between APE1 and SMAD3 in the nucleus. Further analysis revealed that APE1 binds to the C-terminal MH2 domain of SMAD3, protecting it from ubiquitin-mediated proteasomal degradation by preventing its interaction with the RING finger protein, ROC1. Notably, inhibiting APE1’s redox or endonuclease activity with pharmacological inhibitors or mutants disrupted APE1-SMAD3 binding, suggesting a conformational regulation. Interestingly, knocking down APE1 reduced angiogenesis in tube formation assays and 3D co-cultures; however, this effect was reversed by overexpressing SMAD3, suggesting that APE1 regulates angiogenesis through SMAD3. Conclusion: The findings establish the role of APE1 in regulating SMAD3 in EAC and suggest a potential therapeutic approach for treating EAC patients. Citation Format: Farah Ballout, Heng Lu, Nadeem Bhat, Lei Chen, Dunfa Peng, Zheng Chen, Alexander Zaika, Oliver McDonald, Wael El Rifai. APE1 mediates angiogenesis by stabilizing SMAD3 and blocking its ubiquitin induced degradation in esophageal 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 3847.
Abstract 1270: An isogeneic Trop-2 expression heterogeneity model for evaluating the bystander killing effect of anti-Trop-2 ADC
Authors: Jingwei Huang, Xiangyi Wang, Zhixiang Zhang, Jingxuan Yan, Jinyan Ma, Man Zhang, Qingyang Gu
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) have recently made significant advancements in cancer treatment, particularly for solid tumors. Among the multiple mechanisms of action of ADC drugs, the bystander effect—where the cytotoxic payloads released by the antibodies diffuse into and kill nearby tumor cells—plays a crucial role, especially in tumors with heterogeneous antigen expression. Therefore, constructing an antigen heterogeneity model for evaluating this bystander killing effect is essential for the preclinical assessment of ADC drugs. To establish a stable Trop-2 antigen expression heterogeneity model, we deleted Trop-2 in the Trop-2-positive NCI-H292 cell line and selected a clone with a similar in vitro proliferation rate to the parental cells. Additionally, to distinguish Trop-2-negative from Trop-2-positive cells in both in vivo and in vitro experiments, we introduced luciferase and mCherry into the Trop-2-negative cells. In vitro, Trop-2-negative and Trop-2-positive cells were mixed in multiple ratios and treated with graded concentrations of anti-Trop-2 ADC. After five days, flow cytometry quantified Trop-2-negative cells to evaluate the bystander killing effect. in vivo, Trop-2-positive and Trop-2-negative cells were mixed in various ratios and implanted subcutaneously in mice, followed by intravenous drug administration. Tumor volume and bioluminescence were measured to assess the efficacy of the anti-Trop-2 ADC and bystander killing activity. The results showed that the anti-Trop-2 ADC exhibited a significant bystander killing effect, significantly inhibiting Trop-2-negative cells both in vitro and in vivo. In summary, we have successfully established an isogeneic Trop-2 expression heterogeneity model and validated the bystander killing activity of anti-Trop-2 ADCs in vitro and in vivo. This model provides a robust platform for the pharmacological and efficacy assessment of anti-Trop-2 ADC therapies. Citation Format: Jingwei Huang, Xiangyi Wang, Zhixiang Zhang, Jingxuan Yan, Jinyan Ma, Man Zhang, Qingyang Gu. An isogeneic Trop-2 expression heterogeneity model for evaluating the bystander killing effect of anti-Trop-2 ADC [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 1270.
Abstract 7296: PF-08046049 synergizes with checkpoint inhibitors to drive CD8+ T cell effector differentiation and tumor clearance in an IO-resistant model
Authors: Laila Shehata, Michelle Ulrich, Lupe Gutierrez, J. Hartsuyker, Raj Giraddi, Ryan A. Heiser, Brian P. O'Connor
Journal: Cancer Research (2025)

Abstract The checkpoint inhibitors anti-PD-1 and anti-CTLA-4 have been clinically successful as therapeutics for melanoma due to their ability to reinvigorate the immune system. However, about half of patients do not benefit from these treatments, suggesting there are still barriers to CD8+ T cell activation or infiltration into the tumor microenvironment (TME). Additionally, while the combination therapy of anti-CTLA-4 and anti-PD-1 (Ipilimumab-Nivolumab) improves response rate and overall survival compared to monotherapies, it also leads to increased toxicity and immune-related adverse events. Recent studies have demonstrated that CD8+ T cell co-stimulation through the 41BB axis is critical for PD-1/PD-L1 blockade efficacy in melanoma, yet those signals may be limited or unavailable to tumor-associated antigen-specific T cells within the TME. However, nontargeted 4-1BB signaling poses a risk of widespread peripheral immune activation and liver toxicity, as was the case for the 4-1BB agonist Urelumab. PF-08046049 (BB228) is a bispecific molecule comprised of a CD228-specific antibody and 4-1BB-directed Anticalin proteins. CD228 is highly expressed in several cancer indications but is low on normal tissues, thus BB228 targets 4-1BB co-stimulation to T cells within the TME. We tested the efficacy of BB228 as a monotherapy and in combination with the current melanoma standard of care (SOC) treatments, anti-PD-1 and anti-PD-1/anti-CTLA-4. In an IO-resistant LL2 model, neither BB228 nor anti-PD-1 monotherapy led to tumor control. However, in combination, BB228 synergized with anti-PD-1 and anti-CTLA-4 to promote tumor clearance. We found that while anti-PD-1 and anti-CTLA-4 can target and expand stem-like CD8+ T cells in both the tumor-draining lymph node and TME, BB228 is able to drive the differentiation of those stem-like cells into effectors, resulting in tumor killing. These data illustrate that BB228 has a distinct and complementary mechanism of action from the current melanoma SOC treatments. Citation Format: Laila Shehata, Michelle Ulrich, Lupe Gutierrez, J. Hartsuyker, Raj Giraddi, Ryan A. Heiser, Brian P. O'Connor. PF-08046049 synergizes with checkpoint inhibitors to drive CD8+ T cell effector differentiation and tumor clearance in an IO-resistant 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 7296.