tbuckley/cabot-search huggingface dataset:
Abstract 3478: Pre-clinical characterization of AZD0240, a CRISPR-engineered autologous TCR-T cell product targeting KRAS-G12D/HLA-A*11:01 that is multi-armored to increase epitope sensitivity
Authors: Lianne Kok, Sander Eshuis, Xiangjun Kong, Jennifer Ma, Michelle Mojadidi, Paula Kroon, Vanessa Tubb, Ton Schumacher, Arianne Perez, Carsten Linnemann, Mark Cobbold, Jeroen van Heijst, Gavin Bendle
Journal: Cancer Research (2025)

KRAS is one of the most commonly mutated genes in human cancer, with the G12D mutation having the highest frequency, occurring in 33% and 28% of colorectal cancer (CRC) and pancreatic cancer (PDAC), respectively. KRAS G12D-containing peptides are presented by the common HLA allele HLA-A*11:01, making this cancer neoantigen a highly attractive target for the development of adoptive TCR-T cell therapy. However, the levels of cancer neoantigen presentation are typically low and combined with the immunosuppressive tumor microenvironment this compromises the activation and reactivity of TCR-engineered T cells, posing a major hurdle for these cells to eradicate tumor lesions. To establish a TCR-T cell therapy clinically intended for the treatment of solid cancers, including CRC and PDAC, we developed AZD0240, a CRISPR-engineered autologous TCR-T cell product targeting KRAS-G12D/HLA-A*11:01. To improve the reactivity of AZD0240 to the KRAS-G12D neoantigen, we developed a novel multi-armoring strategy, involving the combined disruption of a key negative regulator of T cell function and the introduction of a positive enhancement of TCR signaling. Employing this multi-armoring strategy, we observed enhanced cytokine production in responds to low levels of exogenously loaded KRAS-G12D peptide, as well as HLA-A*11:01+ tumor cells that express the KRAS-G12D mutation. Moreover, assessment of the in vitro and in vivo proliferative and cytotoxic capacity revealed that the AZD0240 armoring strategy can profoundly increase both the proliferative capacity and the anti-tumor efficacy of TCR edited T cells. Notably, the armored AZD0240 T cells were unable to respond to the KRAS G12 wild-type epitope, and no signs of increased TCR cross- or allo-reactivity, or malignant transformation were detected, derisking the clinical use of this armoring strategy. Taken together, AZD0240 is a KRAS-G12D/HLA-A*11:01 targeted TCR-T cell therapy that employs a novel multi-armoring strategy and is currently in preparation for clinical testing, with encouraging signs of pre-clinical efficacy and safety. Citation Format: Lianne Kok, Sander Eshuis, Xiangjun Kong, Jennifer Ma, Michelle Mojadidi, Paula Kroon, Vanessa Tubb, Ton Schumacher, Arianne Perez, Carsten Linnemann, Mark Cobbold, Jeroen van Heijst, Gavin Bendle. Pre-clinical characterization of AZD0240, a CRISPR-engineered autologous TCR-T cell product targeting KRAS-G12D/HLA-A*11:01 that is multi-armored to increase epitope sensitivity [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 3478.
Abstract 5575: Identification of Novel <i>RBBP6</i> transcripts: modulation by <i>Drimia calcarata</i> plant extracts
Authors: Zukile Mbita, Kagiso Laka
Journal: Cancer Research (2025)

Abstract Cancer, an assortment of maladies that are epitomized by deregulated cell proliferation, remains a thorn throughout the world. The soaring cancer cases can be attributed to deregulation of cancer-related genes and lack of effective therapeutics. Thus, this work was aimed at understanding the anticancer mechanisms associated with Drimia calcarata (D. calcarata) plant extracts, targeting cancer-related genes; particularly, Retinoblastoma binding protein 6 (RBBP6) gene. D. calcarata phytochemicals were extracted using both water and methanol, and characterized using Liquid Chromatography Mass Spectrometry (LC-MS). The resultant extracts were used to treat various lung cancer cell lines; namely, H1437, H1573 and A549 cells. The inhibitory effects and half maximal inhibitory concentration (IC50) values of D. calcarata extracts were established using the (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and Muse® Count and Viability assays. Using the IC50 values, induction of cellular apoptosis was evaluated using both fluorescence microscopy, and the Muse® Cell Analyzer, while gene expression analysis was done using Polymerase Chain Reaction (PCR). The D. calcarata extracts, water and methanol, were found to contain a number of compounds with anticancer activities, which include Psoralene (C11H6O3), Limonin-17-beta-D-glucoside (C32H42O14), Oleuropein (C25H31O13), Isorhamnetin derivative (C16H12O7), and various uncharacterized compounds. The anticancer cancer activities were demonstrated to involve apoptosis induction, which was measured by both fluorescence microscopy and flow cytometry. Additionally, and most importantly, PCR showed that the D. calcarata extracts modulated the expression of novel RBBP6 splice variants. Intriguingly, the D. calcarata plant extracts differentially regulated the expression of novel RBBP6 transcripts in different lung cancer cells. D. calcarata extracts down-regulated RBBP6 transcripts 1 and 2; however, subjecting the A549 cells to stress, D. calcarata extracts and curcumin, resulted in the expression of a novel transcript that has not been identified previous. In H1437 and H1573 cells, this novel transcript is down-regulated by the D. calcarata plant extracts. In H1437, the RBBP6 transcripts 1 and 2 were up-regulated by the D. calcarata plant extracts. This suggests that RBBP6 gene can be targeted for development of novel biomarkers, and D. calcarata extracts should be further explored for novel therapeutic targets. Citation Format: Zukile Mbita, Kagiso Laka. Identification of Novel RBBP6 transcripts: modulation by Drimia calcarata plant extracts [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 5575.
Abstract 6230: Meta-analysis with a total of 4,978,125 cancer patients reveals depression as a major mortality risk factor
Authors: Janos Tibor Fekete, Zoltan Ungvari, Monika Fekete, Balazs Gyorffy
Journal: Cancer Research (2025)

Abstract Background: Depression is a prevalent comorbidity in cancer patients, potentially affecting their quality of life, treatment adherence, and biological processes such as immune function and inflammation. Evidence suggests that depression may contribute to poorer outcomes. The objective of our study was to identify studies examining the association between depression and the risk of cancer-specific mortality as well as all-cause mortality in cancer patients. Methods: A comprehensive search of online databases was conducted for studies published up to October 1, 2024. Only cohort studies that assessed clinical depression using established diagnostic criteria and reported risk estimates for mortality (such as relative risk, hazard ratio, or odds ratio) were included. A random-effects model was used for statistical analysis, and heterogeneity was assessed using Cochran's Q and the I2 statistic. The analysis was further refined by conducting cancer-type specific analyses for the most common cancers, including lung, breast, colorectal, and prostate cancers. Statistical analysis was performed using www.metaanalysisonline.com web platform. Results: After screening of 9, 306 studies, we included 65 studies with a total of 4, 978, 125 patients. In these studies, depression was associated with increased cancer mortality in each of the major cancer types. In colorectal cancer, the hazard ratio (HR) was 1.83, 95% CI: 1.47-2.28, indicating an 83% higher risk, while breast cancer showed a 23% higher risk (95%CI: 1.13-1.34). Lung cancer patients had a 59% higher risk (95%CI: 1.36-1.86), and prostate cancer patients faced a 74% higher risk (95%CI: 1.36-2.23). In mixed cancer types, depression was linked to a 38% higher mortality risk (95%CI: 1.20-1.60). Z-score analysis proved sufficient case number to draw a definitive conclusion in each of the sub-cohorts. Conclusions: Our results suggest that the presence of depression is significantly associated with 23%-83% increase of cancer-specific mortality across various cancer types, including colorectal, breast, lung, and prostate cancers. Citation Format: Janos Tibor Fekete, Zoltan Ungvari, Monika Fekete, Balazs Gyorffy. Meta-analysis with a total of 4, 978, 125 cancer patients reveals depression as a major mortality risk factor [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 6230.
Abstract 3880: Functional dissection of the highly plastic basal cell state in pancreatic cancer
Authors: Anupriya Singhal, Hannah Styers, Jonathan Rub, Kate Ryan, Jung Yun Kim, Zeynep C. Tarcan, Jill Hallin, Olca Basturk, Rona Yaeger, James G. Christensen, Yan Yan, Elisa de Stanchina, Tuomas Tammela
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy with a dismal prognosis. Targeting cancer cell plasticity—the capacity to adapt to cell-extrinsic pressure via non-genetic mechanisms—is a promising therapeutic strategy, yet cell states within PDAC harboring high plasticity remain poorly understood. Using genetically engineered mouse models driven by oncogenic KrasG12D and loss of p53 (“KPC” model), we profiled primary PDAC tumors using single-cell RNA sequencing and single cell ATAC sequencing. We find that the KPC model harbors a basal state, which harbors transcriptional signature that aligns with the “basal” signature in human PDAC and is linked to poor prognosis and chemoresistance. The basal state co-expresses both epithelial and mesenchymal programs and has a distinct epigenetic landscape with accessible chromatin across gene sets that mark cancer cell states with divergent phenotypes, suggesting that this cell state is primed for cell state switching. To functionally interrogate the basal state in PDAC progression, we developed a novel lineage-tracing and ablation system. Lineage-tracing experiments revealed that the basal state has a robust capacity for differentiation into epithelial and mesenchymal states, indicating that the basal state is functionally plastic and acts as a source of fixed malignant states. Strikingly, targeted elimination of the basal state over short time periods resulted in tumor collapse, underscoring a critical role in tumor maintenance. Further, we found that the basal state is highly dependent on KRAS activity, with acute KRAS inhibitor treatment leading to a selective depletion of the basal state. Taken together, our data indicates that PDAC harbors a striking dependency on the basal state and encourages therapeutic approaches aimed at eradicating this critical subset of cancer cells. Citation Format: Anupriya Singhal, Hannah Styers, Jonathan Rub, Kate Ryan, Jung Yun Kim, Zeynep C. Tarcan, Jill Hallin, Olca Basturk, Rona Yaeger, James G. Christensen, Yan Yan, Elisa de Stanchina, Tuomas Tammela. Functional dissection of the highly plastic basal cell state in pancreatic 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 3880.
Abstract 4804: RNA binding proteins in CAR-T armoring: Reprogramming T cells for tumor killing
Authors: Augustin B. Biswas, Martin Turner, Romain Lara
Journal: Cancer Research (2025)

Background: CAR T cell therapy uses genetically engineered T cells to express a chimeric antigen receptors (CARs) that trigger detection and killing of target tumor cells. It has been previously shown that a functional screen of mouse RNA binding proteins (RBPs) identifies genes that regulate the abundance of activated plasma cells. Deletion of specific RBP genes was shown to increase the potency of effector CD8 T cell functions. We hypothesized that these observations can be translated as an armoring approach to improve human CAR-T cell functions. Methods: We performed cytotoxicity assays based screening using Her2 CAR T cells with or without 46 RBP knockouts in co-culture with Her2 expressing target cells. The co-culture were set up at a low E:T ratio of 1:32 to evaluate the effect of RBP KO on CAR-T cell exhaustion through engagement in multiple rounds of target cell killing. We validated the modulation of killing with time-course experiments using several Her2 cell lines as HCC-1954, SKOV-3 as well as a control Her2-KO HCC-1954 cell line. We further evaluated the relevance of these findings using patient derived organoid models co-cultured with CAR-T cells bearing specific RBP KOs. Results: Our screen identified several RBPs which upon deletion enhanced Her2 CAR T killing similarly to Med12 deletion which was previously identified as a CAR-T cell armouring candidate. NGS sequencing and FACS analysis validated the KO efficiencies in CAR Ts used for co-culture. Intracellular flow cytometry prior to co-culturing showed that certain CAR T KOs exhibited higher expression of Interferon gamma, Granzyme B and Perforin 1. RBP KOs in CAR Ts also showed increased killing of patient derived organoids in co-culture. Conclusion: Our findings suggest that KO of RBPs may be a good strategy to enhance CAR-T cell cytotoxic function and persistence. They suggest the importance of RBPs as a novel class of armoring targets for CAR-T cell enhancement. Citation Format: Augustin B. Biswas, Martin Turner, Romain Lara. RNA binding proteins in CAR-T armoring: Reprogramming T cells for tumor killing [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 4804.
Abstract 3457: CYLD regulates cGAS-STING pathway and metastasis in HNSCC
Authors: Shiyang Deng, Satoru Shinriki, Yasuhito Tanaka, Hideki Nakayama
Journal: Cancer Research (2025)

Abstract Chromosomal instability, a hallmark of cancer, is related to cancer progression including metastasis and known to promote the activation of the cGAS-STING pathway. Cylindromatosis (CYLD), a well-known negative regulator of NF-kappaB, is down-regulated in aggressive head and neck squamous cell carcinoma (HNSCC), correlating with reduced apoptosis, enhanced invasiveness, and poor prognosis of patients with HNSCC. However, its role in metastasis, immune responses and interaction with the cGAS-STING pathway remain unclear. We found that CYLD protein was rapidly up-regulated and phosphorylated under Poly(dA:dT) or cGAMP stimulation. In addition, by using various cancer cell lines expressing shRNA targeting CYLD, we found that CYLD was essential for sustained phosphorylation of TBK1, a main STING downstream mediator. These results suggest that modulation of the CIN-related activation of cGAS-STING pathway and hence immune responses by down-regulation of CYLD regulates HNSCC progression. Further studies focusing on possible relationship between the NF-kappaB and cGAS-STING pathways would contribute to better understanding of the molecular mechanisms underlying CIN-related metastasis. Furthermore, our preliminary data revealed that CYLD knockdown significantly enhanced metastasis of murine HNSCC cells in immunocompetent mice. Citation Format: Shiyang Deng, Satoru Shinriki, Yasuhito Tanaka, Hideki Nakayama. CYLD regulates cGAS-STING pathway and metastasis in HNSCC [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 3457.
Abstract 7442: Transforming breast cancer treatment decisions: AI tools improve Ki67 risk assessments with 90 pathologists
Authors: Amanda Dy, Ngoc-Nhu Jennifer Nguyen, Melanie Dawe, Dimitrios Androutsos, Susan Done, April Khademi
Journal: Cancer Research (2025)

Abstract A Ki67 proliferation index (PI) of ≥20% determines high-risk status and guides treatment decisions in HR+/HER2− early breast cancer. The Ki67 PI, defined as the ratio of Ki67+ tumor cells to total malignant cells, is labor-intensive and subjective to score. AI support is necessary for routine and reliable clinical use. This is the first large-scale, international study on AI-aided Ki67 PI risk assessments in breast cancer. Ninety pathologists scored the continuous PI from 0% to 100% for 10 breast cancer tissue microarrays (TMA) with and without AI support. The AI tool provided a continuous PI and a Ki67+/- tumor nuclei overlay. The AI tool was developed and validated independently of the pathologists and data used in this study (PMID: 38218973). Using gold-standard manual counts, two pathologists established the ground-truth (GT) PI scores for each TMA, ranging from 7% to 28%. The pathologists’ PI scores were classified into low (&amp;lt;20%) and high risk (≥20%). The risk classification accuracy, sensitivity and specificity relative to the GT were obtained for manual and AI-aided scores, yielding 900 paired classification metrics (90 pathologists × 10 TMAs). Table 1 summarizes the classification metrics showing improvements with AI support for all demographics. The AI tool achieved 100% risk classification accuracy. Manual misclassification and AI-aided correction rates are also summarized in Table 1. The overall manual misclassification rate was 26%, and AI support successfully corrected 95% of these cases. The McNemar’s test, a nonparametric statistical test for paired binary data, assessed statistical differences in risk classification between manual and AI-aided scoring, an asterisk denotes significance (p&amp;lt;0.05). AI support can improve the clinical reliability of PI scoring for risk classification and treatment decisions. AI integration into routine practice can ensure consistent Ki67 use, improving drug response predictions and patient outcomes. Citation Format: Amanda Dy, Ngoc-Nhu Jennifer Nguyen, Melanie Dawe, Dimitrios Androutsos, Susan Done, April Khademi. Transforming breast cancer treatment decisions: AI tools improve Ki67 risk assessments with 90 pathologists [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 7442.
Abstract 7433: Predicting overall survival (OS) differences using longitudinal AI-driven imaging-based prognostication (IPRO) in patients with advanced non-small cell lung cancer (aNSCLC)
Authors: Mohammed A. Alvi, John Riskas, Shahid A. Haider, Vignesh Sivan, Oleksandra Samorodova, Jay Hennesy, Duoaud Shah, Felix Baldauf-Lenschen, Marina Salluzzi, Ronald Bridges, Omar F. Khan
Journal: Cancer Research (2025)

Abstract Background: Early prediction of overall survival benefit associated with cancer treatments remains a key challenge in clinical trials and patient care. Standardized measures such as the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 are used in clinical trials to define tumour response and progression, but are subject to inter- and intra-observer variability, and are infrequently used in day to day clinical practice. Imaging-based prognostication delta (IPRO-Δ) is an artificial intelligence system trained on longitudinal changes in rich features extracted from serial real-world imaging data, automatically predicting survival from pairs of baseline (BL) and follow up (FU) thoracic computed tomography (CT) scans. Methods: IPRO-Δ was evaluated in an external real-world dataset of 194 aNSCLC patients treated with first line systemic therapy at 17 cancer centers, with pretreatment BL and FU (8±4 weeks after treatment initiation) scans. IPRO-Δ generated survival predictions at week 8 for each patient. Kaplan-Meier analyses and hazard ratios (HR) evaluated the association of IPRO-Δ quartiles with OS, with the highest quartile representing progressive disease, the lowest treatment response, and the middle stable disease. Results: The cohort included 19 stage IIIB (9.8%) and 175 stage IV (90.2%) aNSCLC patients, with 94 females (48.5%) and a median age of 64 years. Most tumours were adenocarcinoma (n = 147, 75.8%), followed by squamous cell (n = 18, 9.3%), large cell (n = 5, 2.6%) and other histologies (n = 24, 12.4%). Table 1 shows survival stratification amongst IPRO-Δ quartiles for the overall population and the subgroup of EGFR+ patients. Conclusion: IPRO-Δ successfully predicted survival differences amongst aNSCLC patients using BL and week-8 CT scans. Future work will compare IPRO-Δ to RECIST v1.1, potentially leading to IPRO-Δ's use as a surrogate endpoint in aNSCLC trials. Citation Format: Mohammed A. Alvi, John Riskas, Shahid A. Haider, Vignesh Sivan, Oleksandra Samorodova, Jay Hennesy, Duoaud Shah, Felix Baldauf-Lenschen, Marina Salluzzi, Ronald Bridges, Omar F. Khan. Predicting overall survival (OS) differences using longitudinal AI-driven imaging-based prognostication (IPRO) in patients with advanced non-small cell lung cancer (aNSCLC) [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 7433.