tbuckley/cabot-search huggingface dataset:
Abstract 6670: Unraveling bone marrow adipocyte-leukemia interactions: Identifying key signaling pathways for improved leukemia therapies
Authors: Janane Rahbani, Minsu Song, Obi Ukomadu, Olivia Arnold, Ella Postich, Arjun Dhar, Caner Saygin
Journal: Cancer Research (2025)

Abstract Bone marrow, the soft tissue within our bones, plays a vital role in blood production and also houses fat cells called bone marrow adipocytes (BMAs), which are a natural component of its structure. However, recent studies suggest that these fat cells might contribute to leukemia growth by fostering an environment that aids cancer cell survival and enhances their resistance to treatments like chemotherapy. This issue could be exacerbated in individuals with obesity, as they have an increased amount of bone marrow fat cells, potentially creating an even more protective environment for leukemia cells. Here, we study two aggressive types of leukemia: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). We believe leukemia cells send specific signals to these fat cells, causing them to change in ways that promote cancer growth and treatment resistance. Our research will investigate these communication signals and the changes in fat cell behavior, with the aim of finding new ways to treat leukemia more effectively. The study has three main goals: (i) understanding how leukemia alters fat cell metabolism; (ii) examining how different eating patterns like calorie restriction and time-restricted feeding affect fat cell activity and (iii) exploring how time-restricted feeding influences leukemia cell survival and metabolism after chemotherapy. Investigating the role of BMAs in leukemia not only deepens our understanding of the bone marrow microenvironment but also opens new avenues for targeted therapies. Over time, this work could revolutionize how we understand and treat leukemia, laying the groundwork for new therapies that target its underlying biochemical mechanisms, and potentially reshaping the future of cancer treatment. Citation Format: Janane Rahbani, Minsu Song, Obi Ukomadu, Olivia Arnold, Ella Postich, Arjun Dhar, Caner Saygin. Unraveling bone marrow adipocyte-leukemia interactions: Identifying key signaling pathways for improved leukemia therapies [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 6670.
Abstract 7236: First successful engraftment of human pancreatic cancer cells in an immunocompromised porcine model to test tumor ablation by high-frequency irreversible electroporation (H-FIRE)
Authors: Manali Powar, Tamalika Paul, Edward Jacobs, Sherrie Clark-Deener, Christopher Byron, Sheryl Coutermarsh-Ott, Katie Orr, Maxx Steinmann, levente Gal, Cassandra Poole, Carley Elliott, Mackenzie Woolls, Madeline Mott, Julio Arroyo, Zaid Salameh, Hannah Ivester, Rafael V. Davalos, Irving Coy Allen
Journal: Cancer Research (2025)

Abstract Pancreatic tumor is difficult to treat due to late diagnosis, critical tumor location, limited surgical options, and high metastatic potential. High-frequency irreversible electroporation (H-FIRE) is a non-thermal ablation technique that uses high-voltage electric pulses to create permanent nanopores in cell membranes, disrupting homeostasis and inducing cell death. This study established the feasibility of using H-FIRE to ablate pancreatic tumors in an immunocompromised porcine model were RAG2/IL2RG double knockout pigs. Panc1 human pancreatic cancer cells were orthotopically injected into the pancreas of these pigs. 3 weeks post-injection, successful tumor engraftment and growth were observed during treatment. We successfully accessed and treated the tumors using H-FIRE, with clear ablation zones and preservation of surrounding tissue confirmed by histopathology. The treatment also showed minimal local muscle contraction. This study demonstrated the first robust large-animal model of H-FIRE-treated human pancreatic cancer with safety and efficacy. Future work will explore the potential of these immunocompromised porcine models for developing advanced therapeutic strategies to enhance tumor ablation by H-FIRE. Citation Format: Manali Powar, Tamalika Paul, Edward Jacobs, Sherrie Clark-Deener, Christopher Byron, Sheryl Coutermarsh-Ott, Katie Orr, Maxx Steinmann, levente Gal, Cassandra Poole, Carley Elliott, Mackenzie Woolls, Madeline Mott, Julio Arroyo, Zaid Salameh, Hannah Ivester, Rafael V. Davalos, Irving Coy Allen. First successful engraftment of human pancreatic cancer cells in an immunocompromised porcine model to test tumor ablation by high-frequency irreversible electroporation (H-FIRE) [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 7236.
Abstract 6660: Fasting-mimicking diet and starvation escape inhibition as novel low-toxic treatments for kidney cancer
Authors: Samuel Lazzeri, Anastasiya Shmahala, Olga Blazevits, Valter D. Longo
Journal: Cancer Research (2025)

Abstract Fasting, or fasting-mimicking diet (FMD), can delay tumor growth and promote tumor regression by making cancer cells more vulnerable to conventional therapies, while promoting protection and resistance in normal cells. FMD, which imitates the beneficial effects of fasting while being more tolerated by patients, activates peculiar survival/growth pathways in different cancer types, which can be identified and inhibited leading to tumor regression with low-toxicity. In the present study, we exploited the beneficial effects of FMD in the treatment of kidney cancer, which remains a major challenge despite the significant therapeutic progress of the past years. We developed a protocol that recapitulates in vitro the main molecular effects of FMD, in which cancer cells are exposed to reduced levels of glucose and serum factors. We observed that renal cancer cells subjected to in vitro FMD up-regulate specific starvation escape pathways, including the ERK-MAPK and the mTOR-S6K signalling. We developed a treatment based on FMD and selective inhibitors of these pathways, which induced cell death in a wide range of renal tumor lines, but not in normal cells, through the impairment of the purine metabolism ultimately leading to oxidative stress. We confirmed that the treatment is very effective in delaying tumor growth and in promoting tumor regression in different kidney cancer subcutaneous xenograft mouse models, attesting its safety and low toxicity on mice. The treatment also reduced metastasis formation upon intravenous injection of renal cancer cells in a syngeneic mouse model. We believe that this study represents a promising start to develop innovative and feasible treatments for kidney cancer, which could potentially also be extended to other cancer types. Citation Format: Samuel Lazzeri, Anastasiya Shmahala, Olga Blazevits, Valter D. Longo. Fasting-mimicking diet and starvation escape inhibition as novel low-toxic treatments for kidney 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 6660.
Abstract 6848: Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy
Authors: Andrei Golovko, Shuang Li, Xiaolei Qiu, Yi Li, Ruilin Sun
Journal: Cancer Research (2025)

Abstract C3 glomerulopathy (C3G) is a rare and progressive kidney disease, encompassing C3 glomerulonephritis and dense deposit disease, both driven by dysregulation of the alternative pathway of complement activation. Approximately 50% of patients progress to end-stage kidney disease (ESKD) within 10 years, with limited treatment options currently available. To address this unmet need, we developed a novel humanized C3 (hC3) mouse model that exhibits a pronounced C3G-like phenotype, characterized by early progression to ESKD and increased mortality. Compared to wild-type mice, hC3 mice display significantly reduced circulating C3 levels, alongside liver and kidney dysfunction confirmed by biochemical and pathological analyses. These mice also demonstrate reduced body weight, elevated morbidity early in life, and a shortened lifespan of approximately 5-6 months. To evaluate potential therapies, we treated hC3 mice with the small interfering RNA drug ARO-C3 at high and low doses. ARO-C3 treatment led to a reduction in serum hC3 levels as early as one week post-administration, with a single dose maintaining suppression for at least five weeks. Importantly, ARO-C3 treatment significantly prolonged survival and improved liver and kidney function, as demonstrated by molecular and histopathological analyses. This hC3 mouse model provides a robust platform for studying complement-mediated diseases such as C3G and for preclinical evaluation of novel therapeutic strategies targeting the complement system. Citation Format: Andrei Golovko, Shuang Li, Xiaolei Qiu, Yi Li, Ruilin Sun. Development of a humanized C3 mouse model for preclinical evaluation of therapeutics in C3 glomerulopathy [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 6848.
Abstract 6672: Lipid droplet accumulation after metformin and 6 aminonicotinamide combinatory treatment of glioblastoma cells
Authors: Cecilia Gasco, Ivan Macharashvilli, Daniela Perez Visñuk, Marina Perona, J. Silvio Gutkind, Marcela Solange Villaverde
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) has the worst prognosis among primary brain cancers. As in many tumors, GBM proliferation is supported by glycolysis and the pentose phosphate pathway (PPP). The PPP enables cancer cells to adapt to anabolic demands, including lipid synthesis, and to restore antioxidant defenses. Metformin (MET), a worldwide prescribed drug for type-two diabetes, impairs the progression of different malignancies by indirectly inhibiting the mammalian target of rapamycin (mTOR). Our previous results showed that the combination of MET and 6-aminonicotinamide (6AN), a PPP inhibitor, strongly potentiates their individual cytotoxic effects on different tumor cells. Thus, the present work aimed to study the effect of MET alone or in combination with 6AN on the mTOR pathway as well as on the activity of acetyl-CoA carboxylase, a key enzyme in lipid synthesis, in the human GBM cell line U251. Results showed that MET (5 mM) alone or in combination with 6AN (25 µM) decreased the mTOR effector, pS6, and increased the presence of the phosphorylated form of acetyl-CoA carboxylase (24 h of treatment, determined by western blot and immunofluorescence, p&amp;lt;0.05). Controversially, we also found an increase in the total cell lipid content (BODIPY and oil red staining, analyzed by flow cytometry (FC), p&amp;lt;0.01) of MET/6AN-treated cells, which was accompanied by a mild increase in the content of the lipid transporter CD36 (FC, p&amp;lt;0.01). In addition, by fluorescence microscopy, we observed an increase in the number and size of lipid droplets of MET/6AN-treated cells. Finally, we also found that MET/6AN promoted a decrease in mitochondrial potential and an increase in oxidative stress and lipid peroxidation (TMRE, DCF and C11-BODIPY respectively, FC, p&amp;lt;0.01). Preliminary results indicated that accumulation of lipids inside lipid droplets may prevent lipid peroxidation. These results deserve to be further investigated to better understand the mechanisms involved in the effectiveness of the combination of MET/6AN as a potential strategy to treat GBM. Citation Format: Cecilia Gasco, Ivan Macharashvilli, Daniela Perez Visñuk, Marina Perona, J. Silvio Gutkind, Marcela Solange Villaverde. Lipid droplet accumulation after metformin and 6 aminonicotinamide combinatory treatment of glioblastoma 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 6672.
Abstract 6847: Development and application of DTR mouse models for immune cell ablation and tumor immunotherapy studies
Authors: Yang Yu, Yi Li, Hechun Ma, Shuang Li, Ruilin Sun
Journal: Cancer Research (2025)

Abstract Inducing the selective ablation of specific cell types is a powerful approach for studying complex cell-cell interactions, particularly within the immune system. While systemic depletion of immune cells can be achieved using chemicals or cytotoxic antibodies, the diphtheria toxin receptor (DTR)-diphtheria toxin (DT) system provides a more targeted, cost-effective, and minimally invasive alternative. The system leverages the fact that human DTR has a 103-105 times higher affinity for DT compared to rodent cells. This allows selective cell ablation in mice by introducing the human DTR gene into specific cell populations and subsequently administering DT in vivo. Using CRISPR/Cas9 technology, we generated a series of DTR mouse models targeting immune cell types, including CD8, Ncr1, Foxp3, CD11c, and seven additional cell-specific targets. These models were created on C57BL/6 or BALB/c genetic backgrounds, with the human DTR coding sequence driven by murine endogenous promoters. Successful gene insertions were validated using GFP or Tomato fluorescent reporter expression. Upon DT administration, these engineered DTR mice exhibited transient immune cell ablation within 48 hours, with cell levels recovering to baseline within 96 hours in the absence of repeated DT dosing. For functional validation, we used the Ncr1-DTR mouse model in an MC38 tumor inoculation study. DT treatment effectively depleted natural killer (NK) cells in the blood, highlighting the model's utility for immune cell depletion in specific experimental contexts. Overall, these results demonstrate that DTR mouse models are robust tools for dissecting immune cell functions, exploring intercellular interactions, and evaluating the mechanisms of immune-based therapies. Citation Format: Yang Yu, Yi Li, Hechun Ma, Shuang Li, Ruilin Sun. Development and application of DTR mouse models for immune cell ablation and tumor immunotherapy studies [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 6847.
Abstract 7444: Automated quantification of small animal liver tumor volume in longitudinal MR imaging using deep learning
Authors: Thomas M. Kierski, Adam M. Aji, Juan D. Rojas, Ryan C. Gessner, Laura Beretta, Suet Ying Kwan, John Hazle, Kiersten L. Maldonado, Charles Kingsley, Richard R. Bouchard, Tomasz J. Czernuszewicz
Journal: Cancer Research (2025)

Abstract In preclinical imaging studies with small animals, tracking tumor growth accurately over time can be challenging due to the time-consuming, labor-intensive, and error-prone nature of manual segmentation of 3D images. Orthotopic and metastatic cancer models can be particularly problematic as additional radiologic expertise is required to detect tumors within the context of deep anatomy, and individual animals may contain many nodules (ten or more) requiring many hours of segmentation effort. Therefore, the goal of this study was to develop and validate a deep learning model for automatic volumetric measurement of murine liver tumors in MR images to increase the practicality and adoptability of longitudinal imaging in preclinical research. We describe a method for automatically quantifying tumor volume over time using a dataset of 4.7T T2-weighted MR images taken from a study involving a genetic model of spontaneous liver cancer. The dataset included 894 images from 198 unique animals collected using a Biospec 47/40 (Bruker, Kontich, Belgium) over a span of 30 weeks. Each image was manually segmented by an expert annotator and tumor burden was tracked longitudinally to generate growth curves. A modified U-Net model built on the MONAI framework was trained to segment tumors. On a held-out test subset of 177 images (20% of the overall dataset), the model's predicted overall tumor burden showed a strong correlation with the human ground truth, achieving an R2 value of 0.88. The model processed each image in 0.34 seconds on a machine with an NVIDIA RTX 3090 GPU, significantly faster than the 5-10 minutes required for manual annotation. This efficiency translates to a substantial reduction in overall annotation time for studies with large datasets. This study demonstrates the feasibility of using deep learning for liver tumor segmentation in MR images. The proposed method offers a reliable and efficient alternative to manual segmentation, potentially improving the accuracy and speed of volumetric measurements in preclinical cancer research. Citation Format: Thomas M. Kierski, Adam M. Aji, Juan D. Rojas, Ryan C. Gessner, Laura Beretta, Suet Ying Kwan, John Hazle, Kiersten L. Maldonado, Charles Kingsley, Richard R. Bouchard, Tomasz J. Czernuszewicz. Automated quantification of small animal liver tumor volume in longitudinal MR imaging using deep learning [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 7444.
Abstract 5487: IndEx-2: An <i>in vitro</i> model to evaluate the impact of target antigen density on antibody and immune therapeutics
Authors: Gavin Meehan, Agapitos Patakas, Hannah Findlay, Vivek Senthivel, Timothy London
Journal: Cancer Research (2025)

Abstract The density of cell-surface receptors targeted by therapeutic agents profoundlyinfluences their safety, efficacy, and pharmacokinetics. Low receptor expression on healthy cells can result in on-target, off-tumor toxicities, while tumor heterogeneity in receptor density may allow low-expressing clones to evade treatment. Traditional invitro evaluation relies on panels of cancer cell lines with varying receptor levels, anapproach that is both logistically challenging and experimentally inconsistent. This limitation is particularly pronounced for therapeutics targeting two receptors.To address this, we developed IndEx-2, an in vitro cell line platform that employs chemical proximity promoters to achieve a high dynamic range of tuneable and independent expression of up to two target antigens within a single, uniform cell line background. We have demonstrated precise control of antigen density for several receptors ranging from a few hundred up to a million receptors, including a cell line thatallows independent control of two target antigens (CD19 and CD22). We report herethree examples of the utility of the system. In the first, we have compared CLN978, a novel CD19- TCE developed for B-cell malignancies and autoimmune diseases, with Blinatumomab and demonstrated that the former retained its activity in terms of cytotoxicity and cytokine production at much lower levels of CD19 expression and estimate the threshold for each molecule in a cohort of 10 healthy donors. In the second, we assessed the ability of two HER2-targeting CAR-T cells, employing high and low antigen binders, and estimate the number of receptors that resulted in half maximal response (R50) for cytotoxicity and IFNγ production, demonstrating the utility of the system as an “on-target, off-tumor” hazard assessment screening tool. Lastly, using our CD19/CD22 dual-antigen cell line, we compared tandem (“OR”) CD19/CD22-CD3zCD28 and dual (“AND”) CD19-CD3z and CD22-CD28 CAR constructs targetingboth antigens. The tandem CAR exhibited enhanced cytotoxicity when either or both antigens were expressed, whereas the dual CAR required co-expression of both antigens for optimal T-cell activation. These results underscore IndEx-2's robustcapability to evaluate the influence of antigen density on therapeutic safety andefficacy, providing a powerful tool for the development of antibody-based and immune-targeting cancer therapies. Citation Format: Gavin Meehan, Agapitos Patakas, Hannah Findlay, Vivek Senthivel, Timothy London. IndEx-2: An in vitro model to evaluate the impact of target antigen density on antibody and immune therapeutics [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 5487.
Abstract 6664: ATF4 is required for PanIN formation and PDAC via effects on nucleotide metabolism and suppression of p53 activity
Authors: Leah M. Ziolkowski, Kay F. Macleod
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence in western society and has a 5-year survival rate of less than 13% which while better than it was several years ago, remains one of the worst for all solid tumors. The development of KRAS inhibitors to block the activity of the dominant activated oncogene in human PDAC brings hope that the mortality rate will improve in the coming years. However, as these new therapeutics enter clinical trials, there is an expectation that resistance to KRAS inhibitors will emerge. Thus, the interrogation of additional pathways and the mechanisms of drug resistance are critical to expand the efficacy of KRAS inhibitors and promote patient survival. Our work focuses on the role of Activating Transcription Factor 4 (ATF4) in PDAC where an ATF4-like gene signature predicts worse survival outcomes for PDAC patients. We show here for the first time that conditional loss of Atf4 in acinar cells of the adult mouse pancreas prevents KRas-driven PDAC, such that neither pre-malignant pancreatic intra-epithelial neoplasia (PanIN) lesions nor PDAC develops over the lifetime of the animal. We also show that loss of Atf4 alone in pancreatic acinar cells (absent KRas activation) causes increased pancreatitis and marked pancreas shrinkage following treatment with cerulein. We show that loss of Atf4 in adult pancreatic acinar cells leads to DNA damage, induction of p53 (and both p21 and Bax) and increased cell death, that is exacerbated by cerulein treatment. The increased DNA damage was associated with nucleotide depletion and decreased levels of metabolites involved in 1C metabolism which we attribute to the observed loss of expression of Atf4 targets, such as Mthfd2. Together, our data point to a critical role for Atf4 in maintaining nucleotide pools necessary for tumor cell growth and that its loss promotes p53-dependent cell death preventing PDAC initiation and progression. Citation Format: Leah M. Ziolkowski, Kay F. Macleod. ATF4 is required for PanIN formation and PDAC via effects on nucleotide metabolism and suppression of p53 activity [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 6664.