tbuckley/cabot-search huggingface dataset:
Abstract 2188: Enabling sensitivity, repeatability and reproducibility required for immuno-oncology research on the CyTOF XT Pro mass cytometer
Authors: Stephen Li, Rita Straus, Michael Sullivan, Andrea McEwan, Ling Wang, Christina Loh, Alexander Loboda
Journal: Cancer Research (2025)

Understanding the functional phenotype of immune cells from patients with cancer is critical for identifying mechanism of action, determining disease prognoses and monitoring the clinical efficacy of immunotherapies. The ability to reproducibly identify functional markers with low expression and use functional markers to identify rare cell populations can be challenging with fluorescence flow cytometry due to spectral spillover and autofluorescence. Mass cytometry overcomes many challenges of fluorescence-based cytometry, as low signal spillover and the absence of autofluorescence negate the need for spectral compensation and unmixing. To minimize technical variation, metal-tagged antibody cocktails and stained samples can be frozen for later use and acquisition. Antibody panels that detect both surface and intracellular markers can be rapidly designed, conveniently stained and acquired in a single tube to provide streamlined workflows with high consistency. In this study, human whole blood and PBMC samples were stained with antibody panels containing up to 50 surface and cytoplasmic targets. Stained samples were frozen and acquired on a later date using CyTOF™ XT PRO and CyTOF XT systems to assess repeatability and reproducibility, and to ensure data quality was not compromised when samples were acquired at 4x speed with the CyTOF XT PRO system. Population frequencies and resolution indices for markers were assessed by manual gating. There was no significant difference between population frequencies analyzed between the two CyTOF systems. Both the CyTOF XT and CyTOF XT PRO system had high sensitivity and dynamic range for both abundant and low-abundance markers. The cell population frequency and staining intensity results generated from the CyTOF XT and CyTOF XT PRO system were highly repeatable and reproducible across multiple instruments. Overall, these studies find that the CyTOF XT PRO system generates comparable signal resolution to the CyTOF XT system with up to 4x increased event-rate acquisition. Automated acquisition by the CyTOF XT PRO system enables researchers to accurately and reproducibly streamline human immunophenotyping and functional profiling, leading to accelerated discoveries. Citation Format: Stephen Li, Rita Straus, Michael Sullivan, Andrea McEwan, Ling Wang, Christina Loh, Alexander Loboda. Enabling sensitivity, repeatability and reproducibility required for immuno-oncology research on the CyTOF XT Pro mass cytometer [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 2188.
Abstract 3340: A miRNA based signature for the individual assessment of the prognosis of patients with seminoma
Authors: Farzaneh Zohari, Lea Eckhart, Hiresh Ayoubian, Hans-Peter Lenhof, Rainer Bohle, Felix Bremmer, Fabian A. Gayer, Yue Che, Marieke Vermeulen-Spohn, Tim Nestler, Michael Stöckle, Julia Heinzelbecker, Kerstin Junker
Journal: Cancer Research (2025)

Abstract Introduction: Due to the risk of long-term toxicities in young seminoma patients, surveillance regimens nowadays are the standard of care in patients without metastases. Nevertheless, up to 20% will relapse with the necessity of definitive treatment exposing them to an even higher amount of therapy compared to in the adjuvant setting. This study seeks to establish a prognostic miRNA profile on primary tumors utilizing bioinformatics tools to differentiate between metastatic (m) and non-metastatic (nm) seminomas. Materials and methods: MiRNA was extracted from formalin-fixed paraffin-embedded sections. Two cohorts of patients with seminoma (each 24 patients, each 12 nm and 12 m) were investigated by microarray analysis. Validation was performed in 103 patients (47 nm and 56 m) through quantitative PCR (qPCR) using the TaqMan® assay, with RNU48, miR-191-5p, and miR-361-5p serving as references. Statistical and bioinformatics analyses were performed by using the Mann-Whitney U test and machine learning algorithms. Results: The bioinformatics analysis of microarrays identified 16 miRNAs exhibiting an accuracy &amp;gt;70% in differentiating m tumors from nm ones. qPCR analysis of seven selected miRNAs demonstrated significant expression differences between m and nm tumors for miRNA-371a-5p, miR-512-3p and miR-517a-3p (p&amp;lt;0.05), contingent upon the reference used. Analyzing metachronous and synchronous m tumours separately, all 3 miRNAs showed significantly different expression only in synchronous m, although a trend was observed in metachronous m. Conclusions: By employing machine-learning on microarray data, we established a miRNA signature that differentiates metastatic from non-metastatic seminomas with high accuracy. The findings have been validated for 3 miRNAs in independent cohorts by qPCR, reinforcing the potential of miRNAs as prognostic markers in seminomas. Ongoing validation efforts are currently being conducted in independent cohorts to define a robust miRNA signature. Citation Format: Farzaneh Zohari, Lea Eckhart, Hiresh Ayoubian, Hans-Peter Lenhof, Rainer Bohle, Felix Bremmer, Fabian A. Gayer, Yue Che, Marieke Vermeulen-Spohn, Tim Nestler, Michael Stöckle, Julia Heinzelbecker, Kerstin Junker. A miRNA based signature for the individual assessment of the prognosis of patients with seminoma [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 3340.
Abstract 2461: Federated learning enables multi-institution collaboration without sharing Hand E slides
Authors: Kodi Taraszka, Oded Rosolio, Intae Moon, Yevgeniy Semenov, Alexander Gusev
Journal: Cancer Research (2025)

Abstract Hematoxylin and eosin slides provide vital visual information on a collected tissue sample and are a key component of cancer diagnostics. Previous work in computational pathology has utilized deep learning architectures to accurately and efficiently tackle complex tasks such as tumor classification. However, the generalizability of these algorithms is currently limited due to the inherent difficulty of cross institution collaboration. Here, we propose leveraging federated learning (FL) which aggregates model level information between institutions to enable collaboration without exposing sensitive data. This allows the deep learning model to incorporate diverse patient populations and heterogeneous data sources which are needed for generalizability while preserving patient privacy. As a proof-of-concept, we used attention based multiple instance learning within the FL framework to perform cancer subtype classification between lung adenocarcinoma and lung squamous cell carcinoma with three distinct cohorts: Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), and The Cancer Genome Atlas (TCGA). We present comparisons using three approaches: FL, institution specific analyses, and a centralized model where data is combined at one site (gold standard). We find all three approaches have comparable overall AUC. Additionally, we see that there is significant heterogeneity in AUC between cohorts which may indicate FL is more robust to overfitting and more generalizable. Comparing features generated using the foundation pathology model (UNI) to those generated from a ResNet50 model pre-trained on ImageNet (ResNet), we observed more institutional level heterogeneity in the UNI results than in ResNet which may indicate UNI is learning institution specific features that limit its generalizability. Overall our work shows FL enables generalizable deep learning across institutions without risking patient privacy. Citation Format: Kodi Taraszka, Oded Rosolio, Intae Moon, Yevgeniy Semenov, Alexander Gusev. Federated learning enables multi-institution collaboration without sharing Hand E slides [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 2461.
Abstract 2853: Engineered extrachromosomal oncogene amplifications promote tumorigenesis
Authors: Melissa A. Yao, Davide Pradella, Minsi Zhang, Rui Gao, Katarzyna M. Gluchowska, Ylenia Cendon Florez, Tanmay Mishra, Gaspare La Rocca, Moritz Weigl, Ziqi Jiao, Hieu H. Nguyen, Marta Lisi, Mateusz M. Ozimek, Chiara Mastroleo, Kevin Chen, Felix Grimm, Jens Luebeck, Shu Zhang, Andrea Alice Zolli, Eric G. Sun, Bhargavi Dameracharla, Zhengqiao Zhao, Yuri Pritykin, Carlie Siegel, Howard Y. Chang, Paul S. Mischel, Vineet Bafna, Cristina R. Antonescu, Andrea Ventura
Journal: Cancer Research (2025)

Abstract Focal gene amplifications are among the most common cancer-associated mutations but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumour formation in an autochthonous mouse model of hepatocellular carcinoma.These findings offer insights into the role of ecDNA-mediated gene amplifications in tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications. Citation Format: Melissa A. Yao, Davide Pradella, Minsi Zhang, Rui Gao, Katarzyna M. Gluchowska, Ylenia Cendon Florez, Tanmay Mishra, Gaspare La Rocca, Moritz Weigl, Ziqi Jiao, Hieu H. Nguyen, Marta Lisi, Mateusz M. Ozimek, Chiara Mastroleo, Kevin Chen, Felix Grimm, Jens Luebeck, Shu Zhang, Andrea Alice Zolli, Eric G. Sun, Bhargavi Dameracharla, Zhengqiao Zhao, Yuri Pritykin, Carlie Siegel, Howard Y. Chang, Paul S. Mischel, Vineet Bafna, Cristina R. Antonescu, Andrea Ventura. Engineered extrachromosomal oncogene amplifications promote tumorigenesis [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 2853.
Abstract 2898: SS induces BRCA1 reduction and sensitizes breast cancer cells to PARP inhibitor therapy
Authors: Jiaqi Chen, Bin Yi, Yaguang Xi
Journal: Cancer Research (2025)

Abstract Background: PARP inhibitors (PARPi) have demonstrated substantial clinical efficacy in treating BRCA-mutant breast cancers through synthetic lethality, where the inhibition of DNA single-strand break repair in BRCA-mutant cells leads to the accumulation of DNA damage and cell death. However, in the majority of breast cancer patients with BRCA wild-type (BRCAwt) tumors, PARPi therapy has limited effectiveness. Several approaches, such as CRISPR/Cas9-mediated BRCA1 gene editing, have been explored to induce BRCA deficiency in BRCAwt cancers, but these strategies face challenges for clinical application. Our recent work has focused on novel methods to sensitize BRCAwt breast cancer cells to PARPi. Sulindac sulfide (SS), the active metabolite of the FDA-approved NSAID sulindac, has emerged as a potential agent to enhance cancer cell death when combined with DNA-damaging agents, potentially by impairing DNA repair mechanisms. Methods: This study investigates the mechanisms by which SS inhibits DNA repair, potentially through modulating BRCA1 expression. We assessed the effects of SS on BRCA1 protein levels using western blot analysis and examined BRCA1 mRNA levels using RT-PCR. DNA damage and repair were evaluated by γH2AX foci formation, RAD51 recruitment assays, and slot blot assays. To assess the therapeutic potential of combining sulindac sulfide with PARPi, we conducted both in vitro and in vivo studies. Results: Sulindac sulfide treatment resulted in a dose-dependent reduction of BRCA1 protein levels via ubiquitin-proteasomal degradation. This reduction led to impaired homologous recombination repair capacity and increased DNA damage accumulation. In vitro, the combination of sulindac sulfide and olaparib exhibited synergistic cytotoxic effects in BRCA1wt triple-negative breast cancer (TNBC) cells. In vivo, the combination therapy significantly inhibited tumor growth compared to either agent alone. These findings suggest that sulindac sulfide can sensitize BRCA1wt TNBC cells to PARPi therapy by inducing homologous recombination deficiency. Conclusion: This study provides a mechanistic basis for the combination of sulindac sulfide and PARPi as a potential therapeutic strategy for BRCA1wt TNBC. By downregulating BRCA1 and impairing DNA repair, sulindac sulfide induces a synthetic lethality effect, expanding the therapeutic reach of PARPi to BRCAwt cancers. Citation Format: Jiaqi Chen, Bin Yi, Yaguang Xi. SS induces BRCA1 reduction and sensitizes breast cancer cells to PARP inhibitor therapy [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 2898.
Abstract 2880: TM4SF1 as a novel target for different modalities (mAb, bispecific ADC, targeted siRNA) for the treatment of different solid tumor cancers
Authors: Mingquan Xie, Peter Li, Han Lu, ShuTing Dong, Nicole Wilski, Poonam Pandey, Nishida Motohiko, Peter Haytko, Mark Chiu, Maria P. MacWilliams
Journal: Cancer Research (2025)

Background: Transmembrane-4-L-six-family member-1 (TM4SF1) is a tetraspanin superfamily member that is overexpressed in cancers such as breast, colon, lung, liver, and prostate. A contributor to tumor development and progression, TM4SF1 participates in microdomains that regulate cancer cell migration and invasion via induction of the epithelial-mesenchymal transition, and angiogenesis. The overexpression of TM4SF1 makes it an attractive target for the developing novel treatments of GI tract cancers. Methods and Results: We have engineered an anti-TM4SF1 antibody that binds with nM affinity to TM4SF1-expressing cells. The mAb has anti-tumor growth inhibition in gastric, ovarian cancer cell lines. This mAb can serve as an efficacious targeting carrier for toxins in an ADC and for siRNA in an ARC. To broaden the scope of cancer cell engagement, we prepared constructed a TM4SF1-cMET bispecific ADC which showed potent cytotoxicity in multiple GI, lung, ovarian, breast, TNBC, and pancreatic cancer cell lines in in vitro cell cytotoxicity assays. The bispecific TM4SF1-cMET MMAE (DAR=4) treatment led to potent tumor growth inhibition (70% to 95% TGI) in CDX pancreatic and gastric cancer xenograft models. The mice in the TM4SF1-cMET MMAE treatment group maintained normal body weight throughout the treatment course without observed toxicity. The TM4SF1 - MYC siRNA conjugates were stable. Treatment of MYC-dependent cancer lines led to MYC protein knockdown and cell growth inhibition. Conclusions: A bispecific TM4SF1 ADC had activity in multiple cancer cell lines. Notably, the TM4SF1-MMAE molecule showed potent in vivo tumor growth inhibition in ovarian, pancreatic, and gastric cell lines. The TM4SF1 - siRNA ARC had tumor cell proliferation inhibition in lung, pancreatic, and gastric cancer cell lines. Preclinical safety assessment, pharmacokinetics and IND-enabling studies are on-going with the goal of developing TM4SF1 as the “best-in-class” ADC molecule for the treatment of lung, gastric, breast, and pancreatic cancers with significant unmet medical needs. This antibody can be applied to alternative targeting modalities. Citation Format: Mingquan Xie, Peter Li, Han Lu, ShuTing Dong, Nicole Wilski, Poonam Pandey, Nishida Motohiko, Peter Haytko, Mark Chiu, Maria P. MacWilliams. TM4SF1 as a novel target for different modalities (mAb, bispecific ADC, targeted siRNA) for the treatment of different solid tumor cancers [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 2880.
Abstract 3625: Urban-rural and racial disparities in the utilization of immune checkpoint inhibitor (ICI) treatments for non-small cell lung cancer (NSCLC)
Authors: Mary T. Davis, Nikita Nikita, Krupa Gandhi, Scott W. Keith, Sarah Gordon, Rebecca Hartman, Swapnil Sharma, Amy Shaver, Grace Lu-Yao
Journal: Cancer Research (2025)

Abstract Background: While ICIs have revolutionized NSCLC management, studies regarding real-world ICI uptake are limited. Before ICIs became the standard of care, NSCLC research uncovered inequities in treatment outcomes by race and other social determinants, like rurality. It is unclear if similar disparities exist for ICI treatment. This population-based study aims to investigate differences in ICI treatment uptake by race and rurality among late-stage NSCLC patients. Methods: Patients ≥ 66 years diagnosed with stage III or IV NSCLC, with continuous Medicare coverage ≥ 12 months prior to diagnosis, were identified using the SEER-Medicare database. ICI treatment uptake was analyzed between January 1, 2014 and December 31, 2019. A multivariable logistic regression model was used to assess the likelihood of receiving ICI treatment, adjusting for age, year of diagnosis, sex, race, rurality, Charleson comorbidity index, cancer histology, dual eligibility for Medicaid, and state buy-in to Medicaid. Race was self-reported. Rurality was identified using SEER’s Rural-Urban Continuum Codes 04-09. Results: Of the 18, 083 patients identified with NSCLC, 1, 316 (7.38%) were Black and 15, 972 (88.34%) were White; 3, 230 (17.86%) lived in rural areas and 14, 853 (82.14%) in urban areas. ICI treatment uptake increased from 8.70% of patients diagnosed in 2014 to 31.35% in 2017. ICI treatment rates were 15% lower in Black patients compared to White patients, and 25% lower for rural residents compared to urban residents (Table 1). No significant difference was found comparing patients of other races to White patients. (Table 1). Conclusion: This population-based study documented increasing ICI usage over time, with significant rural-urban and racial disparities in treatment. These findings highlight the need to implement initiatives addressing rural and racial differences in both accessing ICI treatment for NSCLC and improving overall treatment equity. Citation Format: Mary T. Davis, Nikita Nikita, Krupa Gandhi, Scott W. Keith, Sarah Gordon, Rebecca Hartman, Swapnil Sharma, Amy Shaver, Grace Lu-Yao. Urban-rural and racial disparities in the utilization of immune checkpoint inhibitor (ICI) treatments for non-small cell lung cancer (NSCLC) [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 3625.
Abstract 185: Alternative NF-kB inhibits MAPK activity to promote quiescence and drug resistance in ovarian cancer
Authors: Cecilia Gallo, Mikella Robinson, Jacqueline Lara, Omar Lujano Olazaba, Carrie D. House
Journal: Cancer Research (2025)

Abstract Ovarian Cancer (OC) is the most lethal gynecological malignancy in the United States and despite good initial response to chemotherapy, approximately 80% of late-stage patients relapse. Recent studies suggest that a subpopulation of tumor cells with stem-like characteristics, called Cancer Stem-like Cells (CSCs), resist treatment and drive recurrence. Several signaling pathways, including MAPK and NF-kB, are known for their roles in tumor initiation, disease progression, and drug resistance in ovarian cancer. We previously showed that the canonical NF-kB factor, RelA, primarily promotes proliferation, while the non-canonical NF-kB factor, RelB, promotes quiescence. Additionally, activation of MAPK/ERK has been implicated in proliferation of ovarian cancer cells. NF-kB and MAPK signaling cascades are both critical for OC progression, although their precise roles in maintaining CSCs remain unclear. Our preliminary data showed that knockdown (KD) of RelB in vivo following chemotherapy did not decrease growth of residual tumors, whereas KD of RelA or inhibition of MAPK alone reduced growth of residual tumors. However, combining RelB KD with MAPK inhibition reduced growth of residual tumors comparable to RelA KD or MAPK inhibition alone. Therefore, we hypothesize that RelB supports quiescence in CSCs by downregulating MAPK activity. Western Blot analysis indicated increased MAPK activity in the absence of RelB in two high grade serous ovarian cancer (HGSOC) cell lines. Moreover, in vitro cell cycle studies revealed an increase in the percentage of CSCs in the S phase following RelB KD and combining RelB KD with MAPK inhibition rescued this phenotype. Taken together, our findings suggest that RelB downregulates MAPK activity to support quiescence in ovarian CSCs. Ongoing studies are investigating the expression of S phase specific cyclins in the absence of RelB to further elucidate mechanisms of proliferation and cell cycle progression regulated by RelB and MAPK. Additionally, immunohistochemistry (IHC) analysis using tissues derived from control, RelB KD, and RelB KD with MAPK inhibition tumors will be used to evaluate changes in NF-kB, MAPK and cell cycle proteins in residual and regrown tumors. This work reveals novel mechanisms of how RelB supports drug resistance in ovarian CSCs and information gleaned from this study could inform future therapeutic studies. Citation Format: Cecilia Gallo, Mikella Robinson, Jacqueline Lara, Omar Lujano Olazaba, Carrie D. House. Alternative NF-kB inhibits MAPK activity to promote quiescence and drug resistance 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 185.