tbuckley/cabot-search huggingface dataset:
Abstract 5885: Streck Urine Preserve provides cell-free DNA stabilization in whole urine for liquid biopsy
Authors: Jing Li, Sama Mehta
Journal: Cancer Research (2025)

Abstract Urinary cell-free DNA (ucfDNA) has gained recognition as a critical biomarker for liquid biopsy, as it provides comprehensive and invaluable insights for cancer researchers, especially for urological cancers such as bladder, kidney, and prostate cancers. While urine as a sample matrix offers appealing advantages over blood, including large sample volume and truly non-invasive and easy self-collection, ucfDNA is a challenging and unstable analyte, as it is vulnerable to DNase degradation and contamination from bacterial and genomic DNA. Here, we describe the use of Streck Urine Preserve to minimize pre-analytical variables before ucfDNA extraction and downstream analysis. To determine whether Streck Urine Preserve effectively stabilizes ucfDNA and limits DNA contamination, second void urine was collected from donors, treated with Streck Urine Preserve, and stored at 2 °C to 37 °C for up to 7 days. Following storage, ucfDNA was isolated from 4 or 8 mL urine using a modified automated extraction method with MAGicBead cfDNA Isolation Kit (Zymo Research) on a KingFisher Apex System. Target human ucfDNA concentrations were monitored by ddPCR or dPCR using a housekeeping gene (ACTB) as a surrogate marker. The total bacterial burden in the extracted ucfDNA sample was analyzed using qPCR targeting 16S rRNA. While unpreserved urine samples exhibit rapid ucfDNA degradation during ambient temperature storage, samples stored in Streck Urine Preserve (at a preservative-to-urine ratio range between 1:20 to 1:5) maintained the void-time human ucfDNA target concentration for up to 7 days regardless of temperature (2 °C to 37 °C). Further, a marked increase in bacterial cfDNA contamination was observed in the unpreserved urine sample, whereas samples treated with Streck Urine Preserve displayed minimal changes in Cq values of 16S rRNA in the extracted ucfDNA from void time to day 7. Taken together, these data indicate that Streck Urine Preserve protects ucfDNA targets in the sample from DNase degradation and genomic and bacterial DNA contamination during storage. Streck Urine Preserve ensures sample integrity and minimizes pre-analytical variables, providing cancer researchers and assay developers flexibility in sample handling and enhanced confidence in the validity of downstream ucfDNA analysis results. Streck Urine Preserve is for Research Use Only. Not for use in diagnostic procedures. Streck Urine Preserve should only be used for research or the development of new assays. Citation Format: Jing Li, Sama Mehta. Streck Urine Preserve provides cell-free DNA stabilization in whole urine for liquid biopsy [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 5885.
Abstract 1156: Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors
Authors: Zhengyan Kan, Ji Wen, Vinicius Bonato, Jennifer Webster, Wenjing Yang, Vladimir Ivanov, Kimberly Hyunjung Kim, Whijae Roh, Chaoting Liu, Xinmeng Jasmine Mu, Jennifer Lapira-Miller, Jon Oyer, Todd VanArsdale, Paul A. Rejto, Jadwiga Bienkowska
Journal: Cancer Research (2025)

Abstract To better understand the molecular mechanisms of drug resistance to CDK4/6 inhibitors (CDK4/6i) and inform precision medicine strategies, we retrospectively analyzed a multi-omics dataset of 400 HR+/HER2- mBC patients who received CDK4/6i plus endocrine therapies in routine clinical practice, including 200 pre-treatment (Pre), 227 post-progression (Post) samples. Integrative clustering analysis identified three subgroups of tumors harboring different drug resistance mechanisms: ER driven, ER co-driven and ER independent. The ER independent subgroup increased the most in prevalence from 4% pre-treatment to 23% post-progression and is characterized by down-regulation of estrogen signaling and enrichment of drug resistance markers including TP53 and RB1 mutations, Basal-like and Her2-like subtypes and CCNE1 over-expression. We deconvoluted bulk tumor expression profiles to derive cancer-specific expression (CSE) profiles for investigating tumor intrinsic mechanisms that give rise to ER independent drug resistance. We then performed trajectory inference analyses often used in single-cell transcriptomics on CSEs and identified a latent pseudotime variable strongly correlated with ER independence and disease progression. Elastic principal graph (EPG) analysis further revealed bifurcated evolutionary trajectories for drug resistance that correspond to ER-dependent vs. ER-independent mechanisms. Using elastic net models trained on in vitro CRISPR knockout screen data, we predicted a shift in therapeutic dependency on ESR1 and CDK4 among ER-dependent tumors to CDK2 among ER-independent tumors. These predictions were experimentally validated using genetically modified isogenic models. Citation Format: Zhengyan Kan, Ji Wen, Vinicius Bonato, Jennifer Webster, Wenjing Yang, Vladimir Ivanov, Kimberly Hyunjung Kim, Whijae Roh, Chaoting Liu, Xinmeng Jasmine Mu, Jennifer Lapira-Miller, Jon Oyer, Todd VanArsdale, Paul A. Rejto, Jadwiga Bienkowska. Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 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 1156.
Abstract 5278: Spatial and temporal analysis of the metastatic breast cancer tumor microenvironment: from primary tumors to liver metastasis
Authors: Diana Gaete-Alvarez, Joseph Nolff, Deborah Altomare
Journal: Cancer Research (2025)

Abstract Metastasis is a leading cause of mortality in breast cancer, with the liver being a common site for secondary tumor formation. Previous studies have demonstrated the potential to predict breast cancer liver metastases (BCLM) by identifying tumor microenvironment (TME) characteristics, including immune markers (e.g. CD8, PD1, CD206) and stromal components (e.g. αSMA, MMP8). However, the dynamic changes in the TME during metastatic progression remain elusive due to the limitations of the current tumor models. Here, we propose a longitudinal approach to monitor the temporal evolution of TME in both primary and BCLM. Using two tumor engraftment techniques, orthotopic injection of mouse breast cancer cells in a mouse mammary fat pad for primary tumor development, and portal vein injection, we modeled metastatic seeding and colonization in the liver. Live imaging (bioluminescence) of tumor progression captured the temporal dynamics of metastatic growth for early and late-stage BCLM. Tissue analysis of the primary tumor and metastatic lesions was performed using multiplex fluorescent imaging (MACsima, Miltenyi) to spatially map cellular and molecular players (e.g. immune and stromal compartments). Flow cytometry was used to quantify changes in immune cell populations. Collectively, we identified microenvironmental shifts that facilitate metastatic seeding, adaptation, and outgrowth by comparing the TME of primary tumors and liver metastases at early and late stages. Our results showed therapeutic targets within the TME, thereby offering potential strategies to disrupt the immune suppression that allows metastatic progression of breast cancer. By identifying temporal-specific alterations and key cellular players, these findings open opportunities for personalized therapies to address the evolving progression of metastatic breast cancer. Citation Format: Diana Gaete-Alvarez, Joseph Nolff, Deborah Altomare. Spatial and temporal analysis of the metastatic breast cancer tumor microenvironment: from primary tumors to liver metastasis [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 5278.
Abstract 5127: Metastatic organotropism in small cell lung cancer
Authors: Manan Krishnamurthy, Anjali Dhall, Christopher W. Schultz, Michelle Baird, Parth A. Desai, Jacob Odell, Sarthak Sahoo, Nobu Takahashi, Michael Nirula, Sophie Zhuang, Yue Huang, Brett Schroeder, Yang Zhang, Christophe Redon, Christina Robinson, Lai Thang, Lilia Ileva, Nimit L. Patel, Joseph D. Kalen, Alice-Anaïs Varlet, Noam Zuela-Sopilniak, Ankita Jha, Darawalee W. Zong, Donna Butcher, Tamara Morgan, Alyah Afzal, Raj Chari, Karim Baktiar, Suresh Kumar, Lorinc Pongor, Simone Difilippantonio, Mirit I. Aladjem, Yves Pommier, Mohit K. Jolly, Jan Lammerding, Ajit K. Sharma, Anish Thomas
Journal: Cancer Research (2025)

Abstract Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized well-annotated rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive transcriptomic, epigenomic, and single cell multi-omic analyses, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease. Citation Format: Manan Krishnamurthy, Anjali Dhall, Christopher W. Schultz, Michelle Baird, Parth A. Desai, Jacob Odell, Sarthak Sahoo, Nobu Takahashi, Michael Nirula, Sophie Zhuang, Yue Huang, Brett Schroeder, Yang Zhang, Christophe Redon, Christina Robinson, Lai Thang, Lilia Ileva, Nimit L. Patel, Joseph D. Kalen, Alice-Anaïs Varlet, Noam Zuela-Sopilniak, Ankita Jha, Darawalee W. Zong, Donna Butcher, Tamara Morgan, Alyah Afzal, Raj Chari, Karim Baktiar, Suresh Kumar, Lorinc Pongor, Simone Difilippantonio, Mirit I. Aladjem, Yves Pommier, Mohit K. Jolly, Jan Lammerding, Ajit K. Sharma, Anish Thomas. Metastatic organotropism in small cell 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 5127.
Abstract 6062: A novel bi-specific antibody targeting CD39 and PD-L1 for enhanced cancer immunotherapy
Authors: Ze Yang, Xiaopei Li, Zhongliang Li, Yongfa Chen, Huajing Wang, Xu He, Hongwei Sun, Xiaowen Lin, Ligong Lu, Xiaowen He, Meixiao Zhan, Ke He, Wei Zhao
Journal: Cancer Research (2025)

Abstract While immune checkpoint inhibitors have revolutionized cancer treatment, there remains a significant unmet need for more potent strategies to bolster anti-tumor immunity. This study introduces OriA631-B, a pioneering bi-specific antibody designed to simultaneously engage CD39 and PD-L1. By disrupting both the metabolic checkpoint CD39 and the immune checkpoint PD-L1, OriA631-B aims to amplify therapeutic efficacy.Leveraging advanced antibody engineering, OriA631-B was meticulously crafted to exhibit optimal binding affinity and specificity for its intended targets. In vitro studies revealed that OriA631-B, rooted in a clinically validated PD-L1 antibody, effectively suppressed CD39-mediated adenosine generation, thereby invigorating effector T cell function and proliferation. In vivo investigations utilizing syngeneic tumor models demonstrated that OriA631-B treatment significantly curtailed tumor growth compared to monotherapy or combination therapies. Safety assessments indicated a favorable toxicity profile, with no substantial adverse events observed.Collectively, these findings highlight the promising potential of OriA631-B as a novel immunotherapeutic agent in cancer treatment. By concurrently targeting CD39-mediated immune suppression and PD-L1-mediated T cell exhaustion, this bi-specific antibody may circumvent resistance mechanisms and enhance T cell engagement with tumor cells, ultimately improving patient outcomes. Further clinical evaluation is warranted to fully assess the therapeutic potential of this innovative bi-specific antibody in cancer immunotherapy. Citation Format: Ze Yang, Xiaopei Li, Zhongliang Li, Yongfa Chen, Huajing Wang, Xu He, Hongwei Sun, Xiaowen Lin, Ligong Lu, Xiaowen He, Meixiao Zhan, Ke He, Wei Zhao. A novel bi-specific antibody targeting CD39 and PD-L1 for enhanced 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 6062.
Abstract 5869: Exploring chronic stress-induced hippocampal changes in murine ovarian cancer models and their relevance to depressive-like behaviors
Authors: Luinet Lee Melendez-Rodriguez, Luis M. Rivera-Perez, Yadiel A. Rivera-Lopez, Melanie Ortiz-Leon, Jaydiel Casiano-Martinez, Alanis P. Torres-Rosado, Zuliann S. Galarza-Ruiz, Nemesis J. Torres-Rivera, Orlando I. Torres-Rodriguez, Guillermo N. Armaiz-Pena
Journal: Cancer Research (2025)

Abstract Patients with ovarian cancer (OC) often experience depression, which can negatively impact their quality of life and overall prognosis. Our research group has demonstrated that chronic stress (CS) induces systemic inflammation, contributing to disease progression. Other studies have also highlighted its role in the development of depressive symptoms. Microglia are key regulators of brain inflammation and serve as a primary source of brain-derived neurotrophic factor (BDNF), which is crucial for maintaining synaptic plasticity, neuronal survival, and reducing symptoms of depression. However, the influence of CS and OC on the development of depressive symptoms in OC patients remains poorly understood. This study aims to investigate whether CS and OC can induce changes in the hippocampus (HPC) that may lead to depressive-like behavior in mice with OC. We hypothesize that CS will increase microglial infiltration and inflammatory markers, while reducing BDNF levels and neuronal activity in the HPC of mice with OC. To test our hypothesis, we inoculated 8- to 12-week-old C57BL/6 mice with ID8luc or IG10luc OC cells and subjected them to daily restraint stress for four weeks. Upon sacrifice, we collected and processed their brains for immunofluorescence analysis of BDNF, IBA1, and c-Fos. Our data suggest that CS accelerated tumor growth and led to increased microglial infiltration, decreased BDNF levels, and reduced neuronal activity in the HPC. These findings align with the BDNF hypothesis, which posits that a loss of BDNF in the HPC is directly involved in the development of depression. This study lays the groundwork for further research on how OC and CS can modulate brain activity and behavior. Citation Format: Luinet Lee Melendez-Rodriguez, Luis M. Rivera-Perez, Yadiel A. Rivera-Lopez, Melanie Ortiz-Leon, Jaydiel Casiano-Martinez, Alanis P. Torres-Rosado, Zuliann S. Galarza-Ruiz, Nemesis J. Torres-Rivera, Orlando I. Torres-Rodriguez, Guillermo N. Armaiz-Pena. Exploring chronic stress-induced hippocampal changes in murine ovarian cancer models and their relevance to depressive-like behaviors [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 5869.
Abstract 5884: Cancer subtype classification by cfDNA fragmentomics analysis
Authors: Lisha Zhu, Chao Dai, Shuang Gan, Shidong Jia, Pan Du
Journal: Cancer Research (2025)

Introduction: Nucleosome occupancy patterns at transcription factor binding sites (TFBS) exhibit differences between circulating tumor DNA (ctDNA) in cancer patients and normal plasma controls, as well as among different tumor subtypes. Therefore, cell-free DNA (cfDNA) fragmentomics can be employed for cancer subtyping analysis. The tumor fraction in cfDNA can affect the performance of nucleosome profiling, and a minimal tumor fraction is required to obtain high sensitivity of cancer subtyping. This study investigated the detection sensitivity - specifically, the minimal tumor fraction required - for different TFBS analyses. Methods: We utilized the Griffin framework to classify tumor subtypes based on nucleosome profiling of cancer-specific TFBS from low-pass whole genome sequencing data of cfDNA. Androgen receptor (AR) and ASCL1 binding sites were used to distinguish between AR-dependent prostate cancer (ARPC) and neuroendocrine prostate cancer (NEPC). Estrogen receptor (ER+) ATAC-seq peaks were employed for subtyping of ER-positive breast cancer. For each tumor type, we selected three tumor samples with highest nucleosome profiling abnormality scores for simulation studies. Each cancer sample was down-sampled at various percentages and mixed with six down-sampled normal samples, with three replicates per normal sample using different random seeds, to obtain simulated cancer samples with a serious of predetermined tumor fractions. Results: The specificity of nucleosome profiling at AR, ASCL1 and ER binding sites was high (&amp;gt; 95%) for all 87 normal samples. The limit of detection (LoD) for tumor fraction of AR binding sites ranged between 10% and 14%, with the average of 12% and standard deviation of 0.0098. Similarly, the LoD for ER binding sites was between 10% and 13%. The LoD of ASCL1 binding sites was higher, ranging from 20% to 25%. When genome-wide DNA methylation data were incorporated, both the specificity and sensitivity of nucleosome profiling increased. Interestingly, we observed methylation loss at AR and ER binding sites in prostate and breast cancer patients respectively. Conclusion: Prostate and Breast Cancer cfDNA samples sequenced by low-pass whole-genome sequencing can be assigned to subtypes according to nucleosome profiling of AR, ASCL1 and ER binding sites. The minimum tumor fraction required for AR and ER is at least 10%, while for ASCL1 it is as high as 20%. Integrating DNA methylation data into nucleosome profiling analysis can enhance sensitivity and lower the limit of detection, which we are actively investigating. Citation Format: Lisha Zhu, Chao Dai, Shuang Gan, Shidong Jia, Pan Du. Cancer subtype classification by cfDNA fragmentomics analysis [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 5884.
Abstract 6064: Multiomics preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy
Authors: Julien Tessier, Joon Sang Lee, Ingeborg M. Langohr, Caroline Morel, Xiangming Li, Seth Garren, Virna Cortez-Retamozo, Dinesh Bangari, Donald Jackson, Donald Shaffer, Angela Hadjipanayis
Journal: Cancer Research (2025)

Abstract Mechanism of action studies are imperative for translating oncology therapeutics into the clinic informing testable hypotheses and potential combination partners. One class of oncology therapeutics, immune-stimulatory cytokines can augment the antitumor efficacy of checkpoint blockade, but further translational work is required to understand beneficial treatment effects versus unwanted immunotoxicities. SAR445877 (SAR’877, formerly KD050), is a novel antibody-cytokine fusion protein consisting of an Fc silenced human anti-PD-1 IgG1 fused to a mutated interleukin-15 (IL-15)/IL-15 receptor alpha sushi domain fusion, which can cis-activate effector T cells by biasing IL-15 stimulation to T cells expressing PD-1. Here we used immunohistochemistry (IHC), flow cytometry and spatial transcriptomics to characterize SAR’877 treatment effects on residual tumors in a B16-OVA mouse model. Mice were treated with isotype control, anti-mPD-1 (anti-murine PD-1), mntSAR’877 (mIgG2a-mutmIL15) or mSAR’877 (murine surrogate anti-mPD-1-mutmIL15). The mSAR’877 treated animals showed regression of tumors, decreased necrosis and increased tumor immune cell infiltration compared to isotype control, mntSAR’877, and anti-mPD-1. IHC performed on residual tumors treated with mSAR’877 displayed a further decrease of PD-L1+ cells compared to anti-mPD-1 or mntSAR’877. Spatial transcriptomic profiling using the GeoMx DSP instrument revealed significant infiltration of innate immune cells (NK, monocytes, and neutrophils) and adaptive immune cells (CD8 T and CTL cells) into the tumor leading-edge compartment when compared to anti-mPD-1. CD8 T cell and NK cell increases were orthogonally validated by IHC and flow cytometry. Pathway analyses showed these changes were also associated with an upregulation of cytotoxic pathways when compared to controls. Together, these data elucidated the mechanism of anti-PD-1/IL15 showing contributions of NK and CD8 T cells associated with anti-tumor activity observed in mice. These findings suggest that mSAR’877 shows superior efficacy to single agent PD-1 or untargeted IL-15 in mouse tumor models. Note: all authors are employed by Sanofi and may hold stock and/or stock options Citation Format: Julien Tessier, Joon Sang Lee, Ingeborg M. Langohr, Caroline Morel, Xiangming Li, Seth Garren, Virna Cortez-Retamozo, Dinesh Bangari, Donald Jackson, Donald Shaffer, Angela Hadjipanayis. Multiomics preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy [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 6064.