tbuckley/cabot-search huggingface dataset:
Abstract 2125: The trispecific T cell engager platform enhances T cell function and therapeutic efficacy via integrated 4-1BB nanobody co-stimulation
Authors: Kaiqing Zhang, Baihong Liu, Liu Yang, Saina Ma, Jiawei Wu, Jinhua Zhao, Yang Chen, Xueyuan Jiang, Peiyan Pan, Jing Zhang, Yi Yang
Journal: Cancer Research (2025)

Abstract CD3 T cell engagers (TCEs) have gained significant clinical interest, with 9 approvals in the past decade. Advances in solid tumor-targeting TCEs, such as DLL3xCD3, GP100xCD3, and STEAP1xCD3, indicate the potential to overcome the challenges posed by solid tumor barriers. However, issues like cytokine release syndrome (CRS), low T cell infiltration, treatment resistance, and limited patient response continue to pose hurdles. To optimize efficacy and minimize adverse effects, CD3 TCEs need further development. The inclusion of the co-stimulatory molecule 4-1BB, which promotes T cell proliferation and upregulates T cell survival genes expression and activation, in the design of trispecific TCE presents an attractive approach. CAR-T cell therapies suggest that combining 4-1BB signaling achieves more robust and durable anti-tumor responses. Therefore, we developed a tumor antigen -dependent CD3×4-1BB trispecific antibody (TriAb) platform by integrating 4-1BB nanobody generated from RenNanoTM mice to maximize T cell activation and sustain the T cell response. Compared with the canonical CD3 TCE, Our TriAb platform features a weaker binding activity to the CD3 receptor through steric hindrance, reducing safety risk relative to canonical CD3 TCEs. We validated the TriAb platform with three targets: Claudin18.2, DLL3 and CDH17. In vitro, TriAbs demonstrated robust antigen-dependent cytotoxic activity against tumor cell lines, surpassing bispecifc antibodies and benchmark counterparts in T cell activation and cytokine production. Importantly, TriAb did not induce cytotoxicity in tumor antigen-negative cells or non-specific cytokine release. In xenograft model with established tumors, TriAbs showed significant tumor growth inhibition. Additionally, TriAbs exhibited an antibody-like PK profile in CD3ε×4-1BB humanized mice, supporting intermittent dosing in human. Taken together, these data indicate our TriAb platform holds promise as a next-generation therapeutic option for clinical development. Citation Format: Kaiqing Zhang, Baihong Liu, Liu Yang, Saina Ma, Jiawei Wu, Jinhua Zhao, Yang Chen, Xueyuan Jiang, Peiyan Pan, Jing Zhang, Yi Yang. The trispecific T cell engager platform enhances T cell function and therapeutic efficacy via integrated 4-1BB nanobody co-stimulation [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 2125.
Abstract 5688: DSTYK dependent regulation of autophagy protects against TNF alpha induced apoptosis in lung cancer
Authors: Andrea Pasquier, Cristina Viu-Idocin, Andrea Arricibita, Mirari Echepare, Beñat Picabea, Ane Álava, Joaquín Fernández-Irigoyen, Enrique Santamaría, Eva Molina, Antonio Pineda-Lucena, Luis Montuenga, Karmele Valencia
Journal: Cancer Research (2025)

Abstract The emergence of immunotherapy has significantly advanced the treatment of non-small cell lung cancer (NSCLC), yet acquired resistance remains a critical challenge. Understanding the molecular mechanisms behind tumor cell sensitivity to T-cell killing is essential to overcome resistance and improve treatment outcomes. Previous studies have indicated the roles of T cell-derived tumor necrosis factor-α (TNFα) and nuclear factor κB (NF-κB) signaling in tumor cell killing, with autophagy inhibiting TNF-α-induced apoptosis.Previous research in our lab has identified DSTYK, a dual serine/threonine and tyrosine kinase amplified in NSCLC, as a key regulator of mTOR. DSTYK plays a critical role in preventing TNF-α-mediated CD8+ T cell killing and impairs the response to immunotherapy in non-small cell lung cancer by inhibiting autophagy. However, the specific mechanism by which autophagy constrains TNF-α-dependent apoptosis remains unclear.In this study, we demonstrate that inhibition of DSTYK disrupts ULK1 phosphorylation, leading to RIPK1 autophosphorylation and promoting proapoptotic signaling through TNFR1 complex II. Furthermore, we demonstrated that ULK1 inhibition replicates the effects of DSTYK inhibition, reducing tumorigenic properties and sensitizing cells to apoptosis and necroptosis. In vivo experiments in syngeneic and xenograft mouse models corroborated these findings, showing significant tumor size reduction upon ULK1 inhibition. In conclusion, our study identifies DSTYK as a key regulator of the TNFR1 pathway via ULK1 phosphorylation, suggesting that targeting ULK1 could be a viable therapeutic strategy for sensitizing DSTYK-amplified NSCLC tumors to cell death. Citation Format: Andrea Pasquier, Cristina Viu-Idocin, Andrea Arricibita, Mirari Echepare, Beñat Picabea, Ane Álava, Joaquín Fernández-Irigoyen, Enrique Santamaría, Eva Molina, Antonio Pineda-Lucena, Luis Montuenga, Karmele Valencia. DSTYK dependent regulation of autophagy protects against TNF alpha induced apoptosis in lung 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 5688.
Abstract 3682: Body mass index impacts blood-based markers signatures in advanced colorectal cancer
Authors: Gabriela Felix, Jun Gong, Francesca Aguirre, Lisa Zhou, Aaron Denmark, Rocio Ramirez, Hayan Lee, Megan Hitchins
Journal: Cancer Research (2025)

Abstract Background: In the USA it is estimated that more than half-million cancer cases are associated with obesity. Colorectal Cancer (CRC) is one of the most common types of cancer, and rising death rates underscores the need for a feasible and tailored algorithm to aid in disease management such as a blood-based test, i.e., liquid biopsy. Here, we investigate a multimodal assessment of blood-based markers, cell-free DNA (cfDNA) methylation signatures, levels of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and Carcinoembryonic Antigen (CEA), and the impact of Body Mass Index (BMI) in CRC cases at presentation. Method: A multimodal assessment was conducted on sixteen treatment-naive CRC cases. The evaluation consisted of a review of clinical records to collect (i) blood levels of CEA, AST, and ALT, and (ii) BMI data. Additionally, cfDNA methylation analysis was performed by Whole Genome Bisulfite Sequencing (WGBS), and methylated SEPTIN9 (mSEPT9) by Real-Time PCR. Statistical analysis was conducted on GraphPad and SPSS. Results: All CRC cases were advanced stages (III and IV), and most had a familial history of cancer. The mean age of diagnosis was 51.50 years (SE ± 3.42). Healthy BMI was observed in most cases (56.3%), followed by overweight/obese (31.3%) and underweight (12.5%). ALT, AST, and CEA levels were abnormal in 25%, 31.3%, and 56.3% of the cases, respectively. Overall cfDNA analysis showed aberrant methylation patterns in all cases, and 75% were mSEPT9 positive. Principal component analysis (PCA) showed a significant correlation among AST (0.93), CEA (0.89), ALT (0.83), mSEPT9 positivity (0.80), and cfDNA overall methylation (0.50) (Kaiser-Meyer-Olkin score 0.60, Bartlett's test p&amp;lt;0.05) but negative correlation with BMI (-0.33) (Kaiser-Meyer-Olkin score 0.50, Bartlett's test p&amp;lt;0.05). Conclusion: Blood-based multimodal assessment could be a valuable method for managing CRC clinically. However, there is an inverse correlation BMI and blood markers. This highlights the importance of considering BMI when evaluating liver function and tumor markers in advanced CRC cases. Citation Format: Gabriela Felix, Jun Gong, Francesca Aguirre, Lisa Zhou, Aaron Denmark, Rocio Ramirez, Hayan Lee, Megan Hitchins. Body mass index impacts blood-based markers signatures in advanced 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 3682.
Abstract 4647: Systematic review and meta-analysis on the prognostic value of circular RNAs in triple-negative breast cancer
Authors: Gessika Lanzillo de Almeida Nunes, Thoa Thi Vu, So-Youn Jung, Yoon-Jung Choi, Sun-Young Kong
Journal: Cancer Research (2025)

Abstract Background: Triple-negative Breast Cancer (TNBC) is known for its aggressive nature, high recurrence rate, poor prognosis and limited treatment options. Currently, the use of non-coding RNAs as diagnosis or prognosis biomarkers or even target treatment options for TNBC are being studied. Among the non-coding RNAs, recent studies show that circular RNAs (circRNAs) levels are differentially expressed in TNBC tumor tissues, they also interact with micro RNAs and regulate multiple intracellular mechanisms involved in tumorigenesis. Furthermore, their distinct shape makes them more stable and resistant. However, the transition from laboratory research to their clinical application as biomarkers is still in progress. In this meta-analysis we compare multiple studies on prognostic values of circRNAs. Methods: After detailed literature search on EMBASE, PubMed, and Web of Science, eligible studies were meta-analyzed to estimate the pooled hazard ratio (HR) and 95% confidence intervals for overall survival (OS) and disease-free survival (DFS) in TNBC patients based on their levels of expression of circRNAs. Results: A total of 1991 patients had their serum or TNBC tumor samples analyzed across 15 different studies and the levels of expression of certain circRNAs were found to be upregulated or downregulated in TNBC compared to normal breast tissues. High expression of upregulated circRNAs also significantly impacts the outcomes of TNBC patients with poor OS (adjusted: HR=2.85, 95%CI: 2.02 - 4.00) and reduced DFS (HR=5.43, 95%CI: 1.82 - 16.21). Moreover, circCRIM1, circEIF6, circTRIO, circCFL1, circGNB1, circRAD18, circ_0001006, circSIPA1L3, circ_0000199, circTBC1D14, circIFI30, circSEPT9, circ_0003528 were upregulated and their high level was associated with worse outcomes. Conversely, circFBXW7 was downregulated in TNBC samples and low levels were significantly associated with bad prognosis. Conclusion: This review showed that circRNAs are abnormally expressed in TNBC tumors, their levels significantly impact the outcome of the patients and their distinct molecular structure is more stable and less prone to degradation which makes them good candidates for prognosis biomarkers and potential therapeutic targets. Citation Format: Gessika Lanzillo de Almeida Nunes, Thoa Thi Vu, So-Youn Jung, Yoon-Jung Choi, Sun-Young Kong. Systematic review and meta-analysis on the prognostic value of circular RNAs in triple-negative 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 4647.
Abstract 4833: Targeting DOT1L to enhance the immune response in ovarian cancer
Authors: Aisha Jamil, Shraddha Gupta, Sangeeta Kumari, Deyana Tabatabaei, Sergey Karakashev
Journal: Cancer Research (2025)

Abstract Epithelial ovarian cancer stands as the second most prevalent cause of death among all gynecological cancers. Current treatment protocols for patients incorporate platinum-based therapy regimens along with PARP inhibitors tailored for HR-deficient high-grade serous ovarian cancers (HGSOC). Despite initial efficacy, patients inevitably develop disease progression as tumor cells acquire resistance. HGSOC is characterized by low immune cell infiltration and reduced anti-tumor immune response. MHC class I mediated antigen presentation by cancer cells to the immune cells is one of the steps required to activate the anti-tumor immune response. Therefore, HGSOC often downregulates MHC class I expression to evade immune surveillance. To identify epigenetic factors negatively regulating MHC class I expression, we conducted a comparative analysis of HGSOC patient cell samples and HGSOC cell lines from the TCGA and DepMap. Our findings indicate that the epigenetic regulator DOT1L is overexpressed in ovarian cancer and negatively correlates with MHC class I expression. DOT1L is an enzyme responsible for the methylation of lysine79 on histone3 that regulates gene expression. However, the role of DOT1L in regulating MHC class I or antitumor immune response has not been previously studied. We hypothesized that DOT1L might regulate the expression of MHC class I in ovarian cancer and block the immune response. To investigate the role of DOT1L in the regulation of MHC class I, we generated a DOT1L knockout in two DOT1L-high EOC cell lines, OVCAR3 and ID8. Genetic inhibition of DOT1L led to enhanced expression of MHC class I on the surface of both cell lines. This suggests that DOT1L inhibition might be a valuable strategy to upregulate MHC class I expression, which could lead to an increased anti-tumor immune response. Importantly, a small-molecule DOT1L inhibitor, Pinometostat, is currently in late-stage clinical trials for other types of cancer. We then tested the effect of Pinometostat on MHC class I expression. In accordance with our hypothesis, DOT1L pharmacological inhibition also promoted upregulation of MHC class I expression in both cell lines. This discovery could potentially pave the way for the development of DOT1L inhibitors for HGSOC to increase anti-tumor immune response in ovarian cancer. The present research indicates that DOT1L inhibitors have the potential to be utilized in the precision medicine strategy for addressing DOT1L-high ovarian cancer patients. Citation Format: Aisha Jamil, Shraddha Gupta, Sangeeta Kumari, Deyana Tabatabaei, Sergey Karakashev. Targeting DOT1L to enhance the immune response in ovarian 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 4833.
Abstract 3308: Use of biosimulation to predict immune checkpoint inhibitor resistance in patients with high microsatellite instability
Authors: Adity Ghosh, Mamatha Patil, Anuj Tyagi, Ansu Kumar, Chandan Kumar, Muthiyah MR, Rahul KR, Swati Khandelwal, Jyoti Chauhan, Michael Castro, Shweta Kapoor, James Wingrove
Journal: Cancer Research (2025)

Abstract Background: Immune checkpoint inhibitors (ICI) have become a standard treatment option in patients with high microsatellite instability (MSI-H). Although immune checkpoint inhibitors are largely effective in these patients, MSI is an imperfect biomarker and other therapies may be warranted. A mechanistic Computational Biology Model (CBM) was developed by Cellworks that can be personalized based on a patient’s tumor-based genomic profile, revealing signaling pathway dysregulation and patient-specific drug response. Model output was used to identify MSI-H patients who may have a poorer response to ICIs. Design: Computational biosimulation was performed using real-world retrospective cohorts of 423 STAD patients and 534 CRC patients (TCGA). MSI measurements were provided by TCGA. Efficacy scores (ES) based on biosimulated composite cell growth in response to disease and therapy were generated on all patients for pembrolizumab. Molecular rationales for ICI resistance were identified for MSI-H patients with low pembrolizumab ES (ES-L). Results: Model efficacy scores for pembrolizumab were significantly higher in MSI-H patients for both STAD (average ES 20.5 vs 3.2 respectively, p-value &amp;lt; 0.001) as well as CRC (average ES 13.4 vs 2.4 respectively, p-value &amp;lt; 0.001). Of the MSI-H patients, 59% and 81% were ES-L (STAD and CRC respectively) MSI-H/ES-L STAD patients showed a significantly higher percentage of NOTCH2, EGFR, and EZH2 amplifications as well as a higher percentage of TP53-SOF mutations, whereas MSI-H/ES-L CRC patients showed a significantly higher percentage of MYC amplifications (p-value &amp;lt; 0.05) Conclusions: In this study, a therapy efficacy score produced through biosimulation was significantly associated with microsatellite instability levels, and markers of ICI resistance were identified in MSI-H/ES-L patients. Future studies will be performed to confirm the hypothesis that biosimulation has utility in deciding which MSI-H patients might benefit from therapies other than ICI. Citation Format: Adity Ghosh, Mamatha Patil, Anuj Tyagi, Ansu Kumar, Chandan Kumar, Muthiyah MR, Rahul KR, Swati Khandelwal, Jyoti Chauhan, Michael Castro, Shweta Kapoor, James Wingrove. Use of biosimulation to predict immune checkpoint inhibitor resistance in patients with high microsatellite instability [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 3308.
Abstract 5569: FBXW7 functional loss enhances IGF2BP1 levels, implicating oncogenic m6A RNA modification dynamics in colon cancer
Authors: Soo-Jin Lee, Sung-Yup Cho
Journal: Cancer Research (2025)

Abstract FBXW7 is an E3 ubiquitin ligase and known as a tumor suppressor gene. Considering the high mutation frequency of FBXW7 observed in colon cancer mutation profiling, it is important to identify the interactive partners of FBXW7 for developing effective colon cancer treatments. Many reports have demonstrated diverse changes in cancer development and progression under FBXW7 mutant conditions at transcriptomic and proteomics levels. However, it is unclear how post-transcriptional modifications, especially RNA modifications, are affected under FBXW7 mutant conditions. To find the candidate targets of FBXW7 in protein level, we performed LC-MS analysis under conditions of FBXW7 functional loss. We analyzed gene ontology biological pathway (GOBP) enrichment analysis with up-regulated genes and found gene terms associated with RNA metabolism (such as mRNA metabolic process, positive regulation of 3’-UTR-mediated mRNA stabilization and mRNA transport). As the RNA metabolism is influenced by various types of RNA modifications, we focused on N6-methyladenosine (m6A) RNA methylation, a prevalent and significant post-transcriptional modification that plays a crucial role in regulating various RNA functions in eukaryotic messenger RNAs. To validate the LC-MS analysis, we profiled m6A regulators (writer, eraser and reader groups) in protein and mRNA level in FBXW7 knock-out and transient knock-down cells. The protein level of IGF2BP1, which belongs to m6A reader proteins, was up-regulated in both FBXW7 knock-out and knock-down conditions, but not in mRNA level. Additionally, the expression of IGF2BP1 increased compared to normal tissue, and expression of IGF2BP1 was associated with decreased survival rates, suggesting that IGF2BP1 plays an oncogenic role, as indicated by the TCGA colon cancer database. Our study suggests that IGF2BP1 is a crucial target in FBXW7 mutant colon cancer. Citation Format: Soo-Jin Lee, Sung-Yup Cho. FBXW7 functional loss enhances IGF2BP1 levels, implicating oncogenic m6A RNA modification dynamics in colon 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 5569.
Abstract 5567: Targeted immunotherapies in multiple myeloma: focus on flow cytometry markers and therapeutic implications
Authors: Haoting Hsu, Elena Bruni, Claudia Carenza, Karolina Pilipow, Paolo Schiavini, Christine Baer, Gilad Silberberg, BanuPriya Sridharan, Mara Gilardi, Stefano Cairo, Brandon Walling
Journal: Cancer Research (2025)

Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of malignant plasma cells. Despite advancements, MM remains one of the most prevalent hematological malignancies with over 30, 000 new cases annually. However, the emergence of immunotherapy through the targeting of specific cell surface proteins has transformed the treatment landscape for MM and highlights the need for the identification and evaluation of unique immunotherapy targets, particularly in relapsed or refractory cases. Drugs to CD38 (Daratumumab &amp; Isatuximab) and SLAMF7 (Elotuzumab) have demonstrated the potency of these therapies, particularly when utilized in combinations. Flow cytometry plays a vital role in diagnosing MM and in evaluating minimal residual disease (MRD), however, it also functions as an excellent method through which to interrogate the expression of unique markers and subpopulations. Here we have utilized Champion Oncology’s cryopreserved primary MM patient samples derived from bone marrow aspirates to generate a platform for the interrogation of novel biomarkers utilizing flow cytometry, sequencing, and ex vivo analysis. We have performed cellular deconvolution on these models to sort and interrogate populations based on numerous factors including tumor type, treatment history, and diagnosis. This provides rapid mechanisms to identify populations of interest for unique signatures. These identified targets may then be utilized via flow cytometry to characterize models with an adaptable “drop-in” panel which facilitates the addition of multiple novel targets for rapid screening. These data can be further stratified utilizing the canonical MM markers to evaluate the expression within subpopulations and how these subpopulations evolve throughout treatment. Finally, those models that have been identified can be utilized in ex vivo assays. Using six unique MM models stratified into refractory, naive, and relapsed, we evaluated the ex vivo response to current standard of care (SOC) treatments allowing for drug sensitivity screening and the evaluation of novel target responses. Collectively, these data demonstrate a robust method for rapid identification and evaluation of unique MM targets. Citation Format: Haoting Hsu, Elena Bruni, Claudia Carenza, Karolina Pilipow, Paolo Schiavini, Christine Baer, Gilad Silberberg, BanuPriya Sridharan, Mara Gilardi, Stefano Cairo, Brandon Walling. Targeted immunotherapies in multiple myeloma: focus on flow cytometry markers and therapeutic implications [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 5567.