tbuckley/cabot-search huggingface dataset:
Abstract 3463: A novel nanobody based IL-18 surrogate cytokine agonist, used alone or combined with immune checkpoint inhibitors, demonstrated synergistic tumor suppression
Authors: Yakun Wan, Min Zhu, Junwei Gai, Yanyang Nan, Yuping Huang, Xuyao Zhang
Journal: Cancer Research (2025)

Abstract IL-18 is a cytokine belonging to IL-1 family regulating both innate and acquired immune responses, acting on innate lymphocytes and antigen-experienced T cells to produce interferon gamma (IFNγ). However, clinical efficacy of IL-18 monotherapy in cancer patients has been proved to be slight, which is mainly caused by the upregulation of IL-18 binding protein (IL-18BP), a decoy protein that binds IL-18 with extremely high affinity, produced in the tumor microenvironment. In this study, we have developed an innovative approach to activate IL-18 receptors without the need for the cytokine itself. We achieved this by employing human IL-18Ra and human IL-18Rb-targeting nanobodies, which mimic the natural IL-18 cytokine. This strategy leads to the formation of functional receptor dimers and initiates the subsequent signaling cascade. IL-18Ra and IL-18Rb nanobodies with high affinity were selected out from the immune libraries constructed from PBMCs isolated from camels immunized with IL-18Ra and IL-18Rb respectively. And then IL-18Ra/IL-18Rb bispecific nanobodies were constructed and evaluated for their induction of IFNγ release in primary peripheral blood mononuclear cells (PBMCs). Modality with best IFNγ stimulation was chosen for further development. And the humanized most potent IL-18Ra/IL-18Rb nanobody was named LQ058. Compared to wild type IL-18, LQ058 demonstrated superior IFNγ stimulation from PBMCs. And CD8+ T cells RNA-sequencing evaluation demonstrated that LQ058 is IL-18BP resistant. In human PK59 and H23 tumor xenograft models, LQ058 illustrated better tumor growth suppression compared with wild type IL-18. Meanwhile, LQ058 showed synergistic tumor inhibition when administrated together with anti-PD-1 or anti-CTLA4 therapies. Besides, LQ058 is designed to have extended half-life which would improve medication convenience. Overall, these positive characteristics of LQ058 make it a promising therapy possible to overcome the limitations of current IL-18 therapies for malignant tumor treatment. Citation Format: Yakun Wan, Min Zhu, Junwei Gai, Yanyang Nan, Yuping Huang, Xuyao Zhang. A novel nanobody based IL-18 surrogate cytokine agonist, used alone or combined with immune checkpoint inhibitors, demonstrated synergistic tumor suppression [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 3463.
Abstract 215: A novel framework for deciphering 3D genome structure in colorectal cancer
Authors: Amin Nooranikhojasteh, Jakob Zerbs, Ghazaleh Tavallaee, Elias Orouji
Journal: Cancer Research (2025)

Abstract Background: The spatial organization of chromatin is a fundamental determinant of epigenomic landscape which is widely investigated using high-throughput chromosome conformation capture (HiC) technique. To address challenges associated with the resolution and variability of HiC technique, we applied a novel workflow, HiC-ECC (HiC Enhance, Compare, and Call). This approach not only enhances HiC data quality but also enables the identification of biologically significant chromatin interactions and genome structural features. By integrating advanced computational tools with a focus on colorectal cancer (CRC) biology, this study sheds light on the 3D genome architecture of CRC organoids and its implications for patient stratification and therapeutic targeting. Methods: We applied the HiC-ECC workflow to a cohort of 15 patient-derived CRC organoid models, including samples derived from primary tumors and metastatic sites in the lung and liver. The workflow involved initial data preprocessing to generate high-quality chromatin contact matrices and ensure rigorous quality control. To enhance the resolution of HiC datasets, we utilized deep learning-based methods, enabling more accurate identification of chromatin interactions. Comparative analyses were conducted to identify differential chromatin interaction patterns and conserved structural features across the cohort. Chromatin architecture was further characterized by delineating topologically associating domains (TADs) and clustering them to reveal common and sample-specific interaction networks, offering insights into the hierarchical organization of 3D genome structures. Results: Our analysis revealed four distinct subtypes of CRC organoids based on their 3D genome architecture, revealing a novel approach to interrogate heterogeneity within CRC. This subtyping was driven by differential chromatin interaction patterns and structural features, including unique TADs and conserved regulatory elements. Comparative analysis highlighted subtype-specific chromatin interaction networks, suggesting distinct epigenomic landscapes that correlate with tumor progression and metastatic potential. Conclusion: This study enhances our understanding of CRC epigenomics and lays the groundwork for integrating chromatin architecture into patient stratification and precision therapy. Citation Format: Amin Nooranikhojasteh, Jakob Zerbs, Ghazaleh Tavallaee, Elias Orouji. A novel framework for deciphering 3D genome structure 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 215.
Abstract 801: Mechanism of oxaliplatin-induced cachexia: A transcriptional and physiological perspective
Authors: Junwei Du, Rachel L. Mintz, Rachael Field, Leland C. Sudlow, John E. Morley, Jonathan R. Brestoff, Gwendalyn J. Randolph, Mikhail Y. Berezin
Journal: Cancer Research (2025)

Abstract Background: Cancer cachexia is a multifactorial, largely irreversible metabolic disorder characterized by skeletal muscle and adipose tissue depletion that is responsible for 20% of cancer-related deaths. Oxaliplatin, a chemotherapeutic agent commonly used to treat colorectal cancer and other malignancies, is associated with weight loss, muscle weaknesses, and metabolic dysregulation. Yet it is unknown whether oxaliplatin mediates these effects independently of cancer. Methods: Non-tumor-bearing immunocompetent C57BL/6 mice were administered a human-equivalent dose of oxaliplatin over 8 weeks. Metabolic parameters were assessed using metabolic cages and EchoMRI, followed by post-mortem bulk RNA sequencing of muscle, adipose tissue, and the hypothalamus. The results were compared to data sets from cachexia models in cancer and fasting. Results: Oxaliplatin induced significant weight loss (∼12%), decreased lean mass, reduced food intake, decreased physical activity, and lowered core body temperature. Adipose tissue exhibited extensive transcriptional dysregulation, with over 2,000 differentially expressed genes (DEGs) affecting metabolic and inflammatory pathways. Muscles exhibited transcriptional evidence of atrophy, supported by histological images. Hypothalamic RNA-seq revealed dysregulated thermogenic and adipocytokine pathways and overexpression of neuropeptides such as neuropeptide Y (NPY), linking peripheral metabolic changes to central regulation. Comparisons with clinical and preclinical cancer and fasting models demonstrated overlapping yet distinct transcriptional signatures. Conclusion: Our study demonstrates that oxaliplatin independently induces cachexia-like symptoms via transcriptional and metabolic disruptions peripherally in muscle, adipose tissue, and centrally in the hypothalamus. The findings point to the importance of identifying early cachexia diagnostic markers and targeted interventions to stop and reverse cachexia during oxaliplatin treatment. Significance: Adipokines such as leptin and GDF15 may be potential biomarkers of oxaliplatin-induced cachexia, and the associated metabolic pathways could be targeted therapeutically to improve cancer patient outcomes. Citation Format: Junwei Du, Rachel L. Mintz, Rachael Field, Leland C. Sudlow, John E. Morley, Jonathan R. Brestoff, Gwendalyn J. Randolph, Mikhail Y. Berezin. Mechanism of oxaliplatin-induced cachexia: A transcriptional and physiological perspective [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 801.
Abstract 1129: Interrogating the molecular profile of pancreatic cancer tumors in Hispanics living in Puerto Rico
Authors: Ingrid M. Montes-Rodriguez, Veroushka Ballester-Vargas, Sol Perez-Martir, Hilamaris Centeno-Girona, Marcia Cruz-Correa, Julie Dutil
Journal: Cancer Research (2025)

Abstract Pancreatic adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the U.S. by 2040. With a low survival rate at advanced stages and an increasing number of patients, PDAC poses a significant public health challenge. The five-year survival rate for localized PDAC is 44%, but it drops to 15% for regional and just 3% for distant disease. There are clear disparities in PDAC outcomes based on race and ethnicity; however, published data often lack racial and ethnic diversity, particularly regarding non-black minority groups like Hispanics. To address this gap, we evaluated the mutational profiles of PDAC tumors from 48 Hispanic patients living in Puerto Rico (PRH) who underwent next-generation sequencing (NGS) testing between 2015 and 2020. Data were provided by the Precision Oncology Alliance (POA) using the CARIS Life Sciences NGS platform. We estimated the prevalence of somatic mutations in PRH PDAC tumors and compared these profiles with those from the TCGA Pan-Cancer Atlas and the AACR Project GENIE, both accessible via the cBioPortal for Cancer Genomics. Notable differences were observed when compared to TCGA and GENIE. For instance, PRH samples exhibited higher mutational frequencies of BRCA1/2, which are actionable genes that could make these patients candidates for targeted therapies such as PARP inhibitors. Additionally, elevated frequencies of mutations in ARID1A and TP53 in PRH suggest a distinct mutational landscape not typically represented in non-Hispanic populations. These findings underscore the need for population-specific molecular profiling to uncover optimal targeted therapeutic approaches for Hispanic patients. Citation Format: Ingrid M. Montes-Rodriguez, Veroushka Ballester-Vargas, Sol Perez-Martir, Hilamaris Centeno-Girona, Marcia Cruz-Correa, Julie Dutil. Interrogating the molecular profile of pancreatic cancer tumors in Hispanics living in Puerto Rico [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 1129.
Abstract 1210: Modeling clonal hematopoiesis of indeterminate potential (CHIP) in solid tumors: genotype-specific effects on tumor growth and immune microenvironment
Authors: Sarah C. Reed, Chad Potts, P. Brent Ferrell, Ben H. Park
Journal: Cancer Research (2025)

Abstract Clonal Hematopoiesis of Indeterminate Potential (CHIP) is characterized by expanded blood cell clones containing somatic mutations in leukemia-associated genes in patients without hematologic malignancies. CHIP incidence increases with age, and it is primarily associated with an increased risk of transformation to myeloid neoplasms and cardiovascular disease. Growing evidence indicates that CHIP is associated with aberrant inflammatory signaling, and retrospective analyses have revealed increased risk or poor outcomes in a wide range of diseases. We hypothesized that CHIP alters the immune response to solid tumors by dysregulating tumor-infiltrating leukocytes, resulting in increased tumor growth. Indeed, CHIP mutations have been identified in tumor-infiltrating leukocytes in patients, and some observational studies have reported an association between CHIP and decreased overall survival among patients with solid tumors. Using multiple solid tumor models, we investigated the impact of CHIP on tumor progression and the functional effects of CHIP mutations on tumor-infiltrating leukocytes. We used bone marrow transplantation to develop chimeric mouse models of CHIP containing mixtures of wild type and CHIP-mutant hematopoietic cells representing the two most common CHIP genotypes observed in patients (Dnmt3a and Tet2). Once transplants were engrafted, CHIP mice were injected with syngeneic melanoma or triple negative breast cancer cells at their orthotopic site. We observed genotype-specific effects on tumor growth, with Tet2-CHIP displaying increased tumor growth and aberrant inflammatory signaling compared to control mice. Immunophenotyping of tumor-infiltrating leukocytes uncovered altered immune infiltrate between control, Dnmt3a-CHIP, and Tet2-CHIP. We further observed a trend towards greater metastatic outgrowth in mice with CHIP, which was similarly observed in a retrospective clinical cohort of patients with breast cancer. These results suggest that while CHIP may mediate differential outcomes in solid tumors via altered immune cell function, the effects of common CHIP genotypes must each be considered independently. They further support the need for additional mechanistic and translational studies into the relationship between CHIP and solid tumors. Citation Format: Sarah C. Reed, Chad Potts, P. Brent Ferrell, Ben H. Park. Modeling clonal hematopoiesis of indeterminate potential (CHIP) in solid tumors: genotype-specific effects on tumor growth and immune microenvironment [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 1210.
Abstract 614: REPYR-SC1: Hemp extract exhibits potent inhibition of squamous cell carcinoma
Authors: Joel Costoya, Sylvia S. Daunert, Sapna K. Deo, Joaquin J. Jimenez
Journal: Cancer Research (2025)

Abstract Squamous cell carcinoma (SCC) is the second most common form of skin cancer in the world, presenting in nearly 1 in 5 US adults by age 70 alongside basal cell carcinoma. Localized low- and high-risk SCC is treated with surgical techniques offering favorable prognoses with recurrence being unlikely. Therapies for non-operable metastatic SCC, such as chemotherapy, possess undesirable side effects, and have yet to achieve similar response rates to surgery. Investigation into pharmacological targeting of cancer using cannabinoids is ongoing, demonstrating pre-clinical efficacy in various cancer models. Additionally, cannabinoids are established immunomodulatory compounds, capable of shifting immune cell populations, regulating immune cell trafficking, and their migration. Our study aimed to investigate the immunomodulatory, and anti-neoplastic capacity of REPYR-SC, a novel hemp extract. SCC-15 cells were used to model SCC, HEKa epidermal keratinocytes were used as a non-cancerous peripheral tissue model, and CTLL-2 T lymphocytes to screen for immune reactivity. REPYR-SC1 was dosed at 0 (control), 0.1, 0.5, 1, and 5 μL/mL and incubated with SCC-15 or HEKa cells for 36 and 72 hours, meanwhile 24 and 48 hours for CTLL-2 cells all at 37°C under 5% CO2 (initial cell density of 2.5 x 105 cells/mL). Cell counts were evaluated pre- and post-treatment with an automated cell counter, and cell viability was determined following treatment via trypan blue exclusion and morphological analysis. REPYR-SC1 induced a significant time- and dose-dependent reduction in proliferation and cell viability (p&amp;lt;0.001) in squamous cell carcinoma cell line SCC-15, as well as T lymphocytes. At a dose of 1 and 5 μL/mL at the 36- and 72-hour mark, 100% inhibition of proliferation was observed in SCC-15 cells and 25% at 5 μL/mL - 72 hours for HEKa cells. At a dose of 1 and 5 μL/mL at the 48-hour mark, 100% inhibition of proliferation was observed for CTLL-2 cells. These results support earlier evidence suggesting the immunomodulatory, and anti-neoplastic activity of cannabinoids. Further testing in-vivo is warranted, and the mechanism of action for REPYR-SC1 remains unknown. Nonetheless, cannabinoid-based compounds may still represent a novel chemotherapeutic modality with a favorable toxicity profile. Citation Format: Joel Costoya, Sylvia S. Daunert, Sapna K. Deo, Joaquin J. Jimenez. REPYR-SC1: Hemp extract exhibits potent inhibition of squamous cell 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 614.
Abstract 1082: A comprehensive platform for stage-specific analysis of colon cancer: integrating transcriptomic and clinical data for biomarker discovery
Authors: Aron Baratha, Balazs Gyorffy
Journal: Cancer Research (2025)

Introduction: Understanding the molecular mechanisms underlying stage-specific colon cancer progression is essential for identifying biomarkers and developing effective therapies. Aim: To address this need, we extended our previously established comprehensive database with stage-specific clinical and transcriptomic data. The new updated database was employed to mine stage-specific patterns and explore functional trends across stage-stratified colon cancer cohorts. Methods: We used data from GEO (gene arrays), TCGA, and GTEx (RNA-seq) databases. A total of 1,926 colon cancer samples from gene chip studies were manually curated from GEO, and RNA-seq data comprising 469 samples were included from TCGA. To identify differentially expressed genes across stages, we first performed ANOVA tests, adjusting p-values using the Benjamini-Hochberg method with a cutoff of 0.01. Effect size was then estimated using the eta squared approach, applying a moderate effect size threshold of 0.06. Results: Stage-specific data were incorporated into our previously established colon cancer dataset, including 37 (array) and 75 (RNAseq) Stage I samples, 291 (array) and 176 (RNAseq) Stage II samples, 197 (array) and 128 (RNAseq) Stage III samples, and 123 (array) and 64 (RNAseq) Stage IV samples. The expanded dataset facilitates a detailed investigation of gene expression changes across colon cancer stages, uncovering stage-dependent molecular signatures. We utilized the integrated database to uncover genes with consistent expression change across tumor progression. We identified 94 stage-specific genes with significant differential expression and at least a moderate effect size. These genes were primarily associated with transcription and phosphorylation. Among them, COG5 (pAdj = 8.17E-09), AMMECR1 (pAdj = 9.76E-10), and SOWAHC (pAdj = 8.51E-10) showed the most consistent differences across stages. The new integrated platform with all transcriptomic and clinical data is accessible at www.tnmplot.com Conclusion: Our enriched platform provides a powerful resource for the comprehensive exploration of stage-stratified colon cancer data, offering valuable insights into cancer biology and supporting biomarker discovery. Citation Format: Aron Baratha, Balazs Gyorffy. A comprehensive platform for stage-specific analysis of colon cancer: integrating transcriptomic and clinical data for biomarker discovery [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 1082.
Abstract 675: Performance of highly sensitive molecular biomarker for pancreatic cancer detection
Authors: Sophia F. Fang, Neng Yang
Journal: Cancer Research (2025)

Background: Pancreatic cancer is one of the most lethal malignancies, with resection being the only potentially curative treatment. However, due to the absence of effective early detection or screening, most patients are diagnosed at an advanced stage with a five-year survival rate of only 3%. Several genetic mutation-based biomarkers are already in use for cancer diagnosis. Epigenetic alterations, recognized as early events in tumorigenesis, also play a critical role in cancer development. The integration of mutational and epigenetic biomarkers has significant potential to enhance the accuracy of diagnostic panels for early cancer detection. By applying advanced mathematical models to integrate multi-level genomic and epigenetic data, Epi One has identified highly accurate biomarker panel for the early detection of pancreatic cancer. We developed pancreaScout - a simple, cost-effective, and highly sensitive qPCR assay for detecting the biomarker panel associated with pancreatic cancer. In this report, we present the performance of pancreaScout for the biomarker panel in human tissue and blood samples. Methods: Eighty-seven human primary tissue samples and 48 blood samples with IRB consent were collected DNA was extracted from human primary samples DNA underwent bisulfite conversion to enable methylation-specific analysis, with quantitative methylation-specific PCR (qMSP) performed to quantify DNA methylation levels. In parallel, quantitative PCR (qPCR) was conducted on untreated DNA to detect genetic mutations. qPCR data analysis was carried out to calculate scores, which reflect the levels of mutation and methylation in samples. Results: Identification of a pancreatic cancer detection panel with two mutation- and four DNA methylation- biomarkers. Validation of the biomarker panel using qPCR in 87 tissue samples (65 pancreatic cancer patients and 22 adjacent normal controls), achieving 87% sensitivity and 90% specificity. Validation of the biomarker panel using qPCR in 41 blood samples (including 41 pancreatic cancer patients and 7 normal individuals) and achieved 69% sensitivity and 100% specificity. Conclusions: pancreaScout is a sensitive and specific diagnostic panel for pancreatic cancer detection for both tissue and blood samples. Compared to sequencing-based methods for early cancer detection, pancreaScout assay achieves comparable sensitivity in blood tests. The simplicity of pancreaScout adds significant value in the fight against pancreatic cancer. Citation Format: Sophia F. Fang, Neng Yang. Performance of highly sensitive molecular biomarker for pancreatic cancer detection [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 675.