tbuckley/cabot-search huggingface dataset:
Abstract 4551: Increased blood draws for ultrasensitive ctDNA and CTCs detection in early breast cancer patients
Authors: Inaki Comino-Mendez, María Elena Quirós-Ortega, Jesús Velasco-Suelto, Celia Gaona-Romero, Alfonso Alba-Bernal, Ana Godoy-Ortiz, María Emilia Domínguez-Recio, Begoña Jiménez-Rodríguez, Esperanza López-López, Jesús Peralta-Linero, María Victoria Ortega-Jiménez, Estefanía Bellagarza-García, Laura Troyano-Ramos, Guadalupe Dolores Garrido-Ruiz, Alicia Garrido-Aranda, Rocío Lavado-Valenzuela, Martina Álvarez, Nuria Ribelles-Entrena, Javier Pascual, Emilio Alba
Journal: Cancer Research (2025)

Abstract Relapse due to residual disease (RD) is a significant concern for early breast cancer (BC) patients following initial treatment. Liquid biopsy offers a non-invasive approach to detect tumor-derived components in blood; however, detection sensitivity remains limited at early disease stages due to low target concentrations. To improve this, we evaluated 282 high-volume plasma and blood-cell samples for the dual detection of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) using droplet-digital PCR. In pre-treatment samples, ctDNA and/or CTCs were detected in all cases. Post-treatment, positive samples achieved enhanced sensitivity, with a minimum variant allele frequency of 0.003% for ctDNA and a minimum CTCs concentration of 0.069 cells/mL, surpassing detection limits of prior studies. Dynamic ctDNA monitoring allowed accurate prediction of pathological response in the tumor, achieving an area under the ROC curve of 0.92. Moreover, blood detection of disease markers preceded clinical relapse by up to 34.6 months in relapsing patients, providing a significant lead time for intervention. This methodology was also applied to a study of 38 additional BC patients treated solely with surgery to further evaluate its capacity for RD detection in a surgically managed cohort. The findings and implications for RD detection are detailed and presented, underscoring the potential of this sensitive, high-volume approach for real-time monitoring in early-stage BC. Citation Format: Inaki Comino-Mendez, María Elena Quirós-Ortega, Jesús Velasco-Suelto, Celia Gaona-Romero, Alfonso Alba-Bernal, Ana Godoy-Ortiz, María Emilia Domínguez-Recio, Begoña Jiménez-Rodríguez, Esperanza López-López, Jesús Peralta-Linero, María Victoria Ortega-Jiménez, Estefanía Bellagarza-García, Laura Troyano-Ramos, Guadalupe Dolores Garrido-Ruiz, Alicia Garrido-Aranda, Rocío Lavado-Valenzuela, Martina Álvarez, Nuria Ribelles-Entrena, Javier Pascual, Emilio Alba. Increased blood draws for ultrasensitive ctDNA and CTCs detection in early breast cancer patients [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 4551.
Abstract 4539: A new and standardized method to isolate viable, high-quality PBMCs from patient blood samples
Authors: Eleonora Naimo, Lotta Räty, Stefanie Niehues, Migena Kodra, Svetlana Khorkova, Konstantina Kostadinovska, Gregor Winkels
Journal: Cancer Research (2025)

Abstract With the rise of immunotherapy, monitoring patient immune responses during clinical trials has become increasingly critical. Peripheral blood mononuclear cells (PBMCs) serve as a reliable analyte for various cellular analyses, including flow cytometry, ELISpot, and transcriptomics. However, acquiring high-quality PBMCs is traditionally challenging due to long shipment times that compromise cell integrity. Reports indicate that a significant number of patient samples are rendered unsuitable for downstream applications due to these delays. Additionally, traditional gradient centrifugation methods are manual, time-consuming, and require skilled personnel. In this study, we present a novel, standardized, and automation-friendly method for generating PBMCs from whole blood samples. This innovative approach consistently yields high-quality, viable PBMCs, even from older samples, overcoming the limitations of traditional methods. Our method minimizes the need for extensive hands-on training and produces cells ready for immediate use in downstream applications. By streamlining the PBMC isolation process, our method enhances the reliability and efficiency of immune monitoring and biomarker discovery in clinical and research settings. This advancement holds significant potential for improving the quality and consistency of PBMC samples, thereby facilitating more accurate and reproducible immunological analyses. Citation Format: Eleonora Naimo, Lotta Räty, Stefanie Niehues, Migena Kodra, Svetlana Khorkova, Konstantina Kostadinovska, Gregor Winkels. A new and standardized method to isolate viable, high-quality PBMCs from patient blood samples [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 4539.
Abstract 5370: Massively parallel barcoding enables high-throughput single-cell RNA sequencing from formalin-fixed paraffin-embedded tissues for immuno-oncology research
Authors: Fan Zhang, Herbert Gong, Emmanuel Jimenez, Nate Chapin, Bryce Alves, Sanika Vinayak Khare, Bob James
Journal: Cancer Research (2025)

Abstract Formalin-fixed paraffin-embedded (FFPE) tissue samples provide a reliable and long-term storage solution for valuable tumor specimens, enabling future analyses. However, the chemical processes involved can compromise cellular integrity, hindering certain downstream applications such as single-cell RNA sequencing (scRNA-seq). Although recent advancements have enabled scRNA-seq analysis of archival FFPE samples, these techniques are often constrained by limited throughput and reduced sensitivity. Scale Bio provides a solution for profiling single cells/nuclei from FFPE samples at an unprecedented throughput with the flexibility for sample multiplexing by leveraging the power of combinatorial indexing. The probes targeted to the interested regions are hybridized to mRNA inside cells/nuclei extracted from FFPE sample, then released and captured by barcoded beads confined in the individual compartment. The library is finally amplified from the beads, containing the cell barcode and target sequence. The workflow is streamlined to be completed in 2 days from cells/nuclei extraction to sequencing library for ∼1.2M single cells/nuclei. Here we provide an early demonstration of the Scale Bio QuantumScale FFPE scRNA kit in immuno-oncology . We isolated nuclei from 12 bio-banked breast cancer FFPE tumor samples and profiled the transcriptional levels of 1000 clinically actionable genes. QuantumScale FFPE scRNA provides unprecedented insights into the cellular transcriptome at massive scale to analyze the biology of the tumor, microenvironment, and immune response in a single assay. We observed robust cell recovery, with good sensitivity across all samples profiled. Citation Format: Fan Zhang, Herbert Gong, Emmanuel Jimenez, Nate Chapin, Bryce Alves, Sanika Vinayak Khare, Bob James. Massively parallel barcoding enables high-throughput single-cell RNA sequencing from formalin-fixed paraffin-embedded tissues for immuno-oncology research [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 5370.
Abstract 3086: TFAP2C promotes mitochondrial fitness required for sustained kinase reprogramming in endocrine therapy resistance in breast cancer
Authors: Attila Szenasi, Austin Whitman, Santiago Haase, Philip Spanheimer
Journal: Cancer Research (2025)

Abstract Endocrine therapy resistance (ETR) remains a formidable challenge in the treatment of estrogen receptor-positive (ER+) luminal breast cancer, frequently leading to therapeutic failure. Our previous research identified the transcription factor TFAP2C as a key regulator of the antioxidant enzyme glutathione peroxidase 1 (GPX1), as well as c-ErbB2/HER2, RET, and EGFR, which lead to ERK/MAPK activation and promote ETR. Here, we aimed to elucidate the role of TFAP2C in the redox regulation of kinase reprogramming in acquired ETR. Our current study reveals that TFAP2C acts as a metabolic switch, triggering cellular reprogramming and redox modulation of kinase signaling through post-translational cysteine modifications. TFAP2C knockdown in tamoxifen-resistant cell lines and patient-derived organoids induces mitophagy, leading to reduced mitochondrial content, metabolic reprogramming, and altered Reactive oxygen species (ROS) profiles via GPX1 and SOD1 signaling. This disruption enhances phosphatase activity in the PI3K and MAPK pathways, resulting in cell cycle arrest and attenuated HER2- and EGFR-mediated signaling, both of which are pivotal for sustaining ETR. This study not only underscores the role of TFAP2C as a central player in maintaining the metabolic and signaling adaptations required for kinase reprogramming associated with ER+ targeting therapies, but also highlights the broader implications of mitochondrial redox signaling in the etiology of ETR, providing a novel avenue for therapeutic intervention. Citation Format: Attila Szenasi, Austin Whitman, Santiago Haase, Philip Spanheimer. TFAP2C promotes mitochondrial fitness required for sustained kinase reprogramming in endocrine therapy resistance in 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 3086.
Abstract 5982: Mechanisms underlying the anti-cancer activity of new, non-covalent thioredoxin reductase inhibitors
Authors: Abigail Rullo, Brenna Flowers, Keacha Chang, Pavel Petukhov, Irida Kastrati
Journal: Cancer Research (2025)

Abstract Triple negative breast cancer (TNBC) makes up only 15-20% of all breast cancer cases, yet it contributes to 50% of all breast cancer related mortalities. This highlights the urgent need to develop novel therapeutics for the treatment of TNBC. The thioredoxin (Trx) system is an important cellular antioxidant pathway that plays crucial roles in redox homeostasis and supports proliferation, apoptosis, and gene transcription; Thioredoxin reductases (TXNRDs) are the central enzymes in this pathway. Of note, TXNRDs are elevated in TNBC to help tumors cope with excessive redox stress resulting from deregulated metabolism and replicative stress, thus presenting a potential vulnerability. A series of breakthrough studies by our collaborators identified a novel regulatory and druggable “doorstop” pocket in this family of enzymes to which they have developed inhibitors for. These novel TXNRD(i)s show anti-cancer activity in a panel of TNBC lines, by inhibiting proliferation, inducing cell death, inhibiting clonogenic survival, mammosphere forming efficiency and invasion. Importantly, these TXNRD(i)s also inhibit tumor growth in a xenograft model of TNBC. Our goal is to understand the mechanisms underlying the pleiotropic anti-cancer activities elicited by these TXNRD inhibitors. We hypothesize our novel TXNRD(i)s work, in part, by increasing and shifting the balance of redox stress to block proliferation and induce cell death in TNBC cells. To understand major pathways implicated, we conducted transcriptomics (RNAsequencing) in TNBC cells treated with two lead TXNRD(i)s, 8VP101 and 9VP19. Bioinformatic analysis (GSEA) indicates multiple proliferation and mRNA related pathways predominantly enriched by 8VP101. This is consistent with induction of redox stress. To corroborate this finding, cells were treated with 8VP and ROS levels were determined by incubating cells with DCFDA, a ROS sensitive probe, and analyzed by flow cytometry. We find a significant induction in ROS levels comparable to auranofin, a non-specific covalent inhibitor of TXNRDs. Another predominant pathway emerging from GSEA was regulation of cell cycle. Cell cycle analysis in cells treated with 8VP also shows an accumulation in G1. Based on our data, we conclude that our novel TXNRD(i)s elicit anti-cancer activity by elevating intracellular ROS leading to cell cycle arrest and induction of apoptosis and necroptosis. Our findings have important implications for advancing new therapies for TNBC. Citation Format: Abigail Rullo, Brenna Flowers, Keacha Chang, Pavel Petukhov, Irida Kastrati. Mechanisms underlying the anti-cancer activity of new, non-covalent thioredoxin reductase inhibitors [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 5982.
Abstract 6172: PI3K/Akt signaling pathway regulates CD155 expression involved in resistance to cancer immunotherapy
Authors: Katsushige Kawase, Shusuke Kawashima, Tatsuya Nishi, Takashi Inozume, Takao Morinaga, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi
Journal: Cancer Research (2025)

Abstract Although anti-programmed death 1 (PD-1)/PD-1 ligand 1 monoclonal antibodies are effective against various cancers, resistance remains a significant issue in many patients. The immunosuppressive T cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 axis has emerged as one of the crucial mechanisms contributing to this resistance. However, the complexities of CD155 expression remain incompletely understood. In this study, we conducted clustered regularly interspaced palindromic repeats (CRISPR) screening to identify key molecules involved in the regulation of CD155 expression and to investigate their roles in modulating CD155 within the tumor microenvironment (TME). CRISPR screening revealed that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) as one of the key regulators of CD155 expression via the PI3K/Akt signaling pathway. In mouse models, inhibition of Dyrk1a using CRISPR/CRISPR-associated protein 9 (Cas9) technology or treatment with harmine, a DYRK1A inhibitor reduced CD155 expression, resulting in overcoming the resistance to PD-1 blockade. Moreover, in human head and neck squamous cell carcinoma (HNSCC) cell lines, inhibition of the PI3K/Akt signaling pathway reduced CD155 expression, similar to mouse models. In addition, cetuximab-mediated epidermal growth factor receptor blockade reduced CD155 expression by targeting downstream PI3K/Akt signaling in certain HNSCC cell lines. Clinically, patients with HNSCC harboring high CD155 expression exhibited elevated levels of Akt phosphorylation, consistently indicating that the PI3K/Akt signaling pathway is involved in CD155 expression. Furthermore, high CD155 expression contributed to PD-1 blockade resistance especially in patients who had high CD8+ T cell infiltration. These results emphasized the role of the PI3K/Akt signaling pathway in regulating CD155 expression, which may influence resistance to PD-1 blockade therapies in various cancers, particularly those characterized by an inflamed TME. This study suggests that the reduction of CD155 expression by inhibiting the PI3K/Akt signaling pathway could overcome resistance to PD-1 blockade therapies. Citation Format: Katsushige Kawase, Shusuke Kawashima, Tatsuya Nishi, Takashi Inozume, Takao Morinaga, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi. PI3K/Akt signaling pathway regulates CD155 expression involved in resistance to cancer immunotherapy [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 6172.
Abstract 5375: Sex-specific differences in response to exogenous asparagine supplementation during colorectal tumor growth is dependent on aromatase activity
Authors: Oladimeji Aladelokun, Katherine Benitez, Yuying Wang, Abhishek Jain, Domenica Berardi, Georgio Maroun, Xinyi Shen, Jatin Roper, Joanna Gibson, Kaelyn Sumigray, Sajid A. Khan, Caroline H. Johnson
Journal: Cancer Research (2025)

Studies have shown that sex-related differences in asparagine metabolism are associated with gastrointestinal diseases prognosis. However, the effects of exogenous asparagine on the incidence and phenotype of colorectal cancer (CRC) in both men and women remain unclear. This study describes the relationship between exogenous asparagine supplementation and estradiol secretion which is critical for understanding mechanisms of sex-dependent signaling events. We show that asparagine supplementation causes pronounced sex-dependent alteration in cancer metabolomics using in vivo and in vitro approaches. We intraperitoneally administered asparagine to tumor-bearing immunodeficient male and female Rag2/Il2RG (R2G2) mice, at doses of 1 mg/kg and 10 mg/kg body weight. Asparagine supplementation causes a significant increase in cellular asparagine levels in the tumor-bearing male and female R2G2 mice but increases serum estradiol levels and suppresses tumor growth in females R2G2 mice only. Additionally, we combined transcriptome, metabolome and immunochemical analyses and found that asparagine treatment induces intra-tumoral metabolic changes in colorectal cancer cells based on biological sex. We established that in females only, exogenous asparagine exerts a negative feed-back effect on de novo asparagine synthesis and activates a sub-population of macrophages that secretes estradiol via a Cytochrome P450 Family 19 (CYP19)-dependent mechanism, resulting in improved tumor-specific survival. Conversely, in the male mice, asparagine treatment augments tumor growth by decreasing the number of tumor-associated macrophages and reduces CYP19-mediated estradiol secretion leading to worsened tumor-specific survival. Overall, our results revealed a novel role for exogenous asparagine supply during cancer progression and underscores the importance of understanding mechanisms that control asparagine biosynthesis, especially for patients with CRC. Citation Format: Oladimeji Aladelokun, Katherine Benitez, Yuying Wang, Abhishek Jain, Domenica Berardi, Georgio Maroun, Xinyi Shen, Jatin Roper, Joanna Gibson, Kaelyn Sumigray, Sajid A. Khan, Caroline H. Johnson. Sex-specific differences in response to exogenous asparagine supplementation during colorectal tumor growth is dependent on aromatase 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 5375.
Abstract 5369: Characterizing the molecular and clinical implications of<i>NRG1</i>fusions in NSCLC through integrated RNA and DNA sequencing analyses
Authors: Minyi Zhu, Yang Xu, Haimeng Tang, Xue Wu, Qiuxiang Ou
Journal: Cancer Research (2025)

Abstract Background: NRG1 fusions are oncogenic drivers in NSCLC, with therapeutic implications underscored by FDA's designation of Zenocutuzumab for NRG1 fusion-positive cases. Despite this, the molecular characteristics and clinical impacts of distinct NRG1 fusion types remain poorly understood. Methods: We retrospectively enrolled 435 NSCLC patients, comprising 78 with NRG1 fusions and 357 wild-type (WT), from June 2016 to December 2023. We assessed mutational landscapes, tumor mutation burden (TMB), chromosomal instability scores (CIS), and gene expression using broad-panel targeted DNA and RNA sequencing analyses. Survival analyses were conducted in patients from our cohort (N=47) and online TCGA database (N=526). Results: Among the NRG1 fusion-positive patients, 65.8% harbored recurrent fusion partners like CD74-NRG1 and SLC3A2-NRG1, with CD74-NRG1 appearing most frequently (48.1%). These recurrent fusions were associated with significantly fewer EGFR and KRAS mutations and lower TMB and CIS compared to WT (P &amp;lt; 0.01). Additionally, 26 patients had unique singleton fusion partners, with 23 novel fusions identified, including CEBPD-NRG1 and BMP1-NRG1, although validation through tools such as RNA sequencing is warranted in the future. Interestingly, this group showed significant enrichment of mutations in genes like KRAS, MSH2, MSH6, FANCI, and MDM2, impacting key oncogenic and DNA-repair pathways including Fanconi anemia, mismatch repair, PI3K-AKT, and MAPK pathways (P &amp;lt; 0.01). Additionally, the RNA profiling showed upregulation of DNAJB1 (P &amp;lt; 0.01) and LMNA (P = 0.02) in the singleton group versus WT, linked to poorer overall survival (OS) in the TCGA cohort (HR: 1.52 for both). No significant differences in progression-free survival (PFS) were observed between uncommon and WT groups following the first-line anti-EGFR tyrosine kinase inhibitor (TKI) therapy. Conclusion: This study revealed the diversity of NRG1 fusions in NSCLC, identifying novel fusion partners and distinct molecular and clinical features across novel NRG1+ groups, especially the enriched DNA repair/oncogenic signaling pathways and uniquely upregulated transcription profile. Our study highlights the need of subtyping different NRG+ tumors to better understand their tumorigenesis and facilitates more personalized and targeted treatment of NRG1+ NSCLC patients. Citation Format: Minyi Zhu, Yang Xu, Haimeng Tang, Xue Wu, Qiuxiang Ou. Characterizing the molecular and clinical implications ofNRG1fusions in NSCLC through integrated RNA and DNA sequencing analyses [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 5369.
Abstract 3071: Improving the docetaxel-based chemotherapy in therapy resistance prostate cancer
Authors: Md Rakibul Alam, Amos Olalekan Akinyemi, Jianlin Wang, Mithu Howlader, Lixiang Gu, Zhiguo Li
Journal: Cancer Research (2025)

Prostate cancer is known to have a relatively good prognosis, but long-term hormone therapy can lead to castration-resistant prostate cancer (CRPC). Docetaxel, a third-generation chemotherapy drug based on inhibiting depolymerization of microtubules, provide excellent initial response in patients for the CRPC treatment. Despite the improved survival duration and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. In this study, to elucidate the molecular basis of docetaxel resistance, we established docetaxel resistance prostate cancer PC3-TR, C4-2-TR and DU-145-TR cell lines, which exhibited higher LD50 and lower drug uptake against docetaxel than parental PC3, C4-2 and DU-145 cell lines. We employed quantitative high throughput screen with a collection of 2500 FDA approved drugs to identify drugs that can enhance the docetaxel sensitivity of docetaxel resistance cell lines. ML385 has been identified as a potent NF-E2 related factor-2 (Nrf2) synthetic inhibitor, and its treatment of docetaxel resistance cells significantly suppressed the Nrf2 signaling by decreasing the cytosolic and nuclear Nrf2 levels. In addition, docetaxel resistance cell lines showed marked increases in nuclear accumulation of Nrf2 compared to parental cell lines, suggesting that Nrf2 signaling is homeostatically activated in docetaxel resistance cell lines. Here we identified that silencing of Nrf2, docetaxel sensitivity of resistance cell lines was increased, and that of parental cell lines were reduced by activation of Nrf2. Combination treatment of ML385 with docetaxel induced cell death in docetaxel resistance cell lines. Together, these results provide new insight in the understanding of docetaxel resistance and direct a therapeutic approach to overcome docetaxel resistance in CRPC treatment. Citation Format: Md Rakibul Alam, Amos Olalekan Akinyemi, Jianlin Wang, Mithu Howlader, Lixiang Gu, Zhiguo Li. Improving the docetaxel-based chemotherapy in therapy resistance prostate 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 3071.