tbuckley/cabot-search huggingface dataset:
Abstract 3372: Building precision oncology via real-world data standardization, privacy preserving infrastructures, and collaboration among IT and clinical experts: The DIGICORE network experience
Authors: Alberto Traverso, Giovanni Tonon, Piers Mahon, Gennaro Ciliberto, Andre Dekker, Xosé Fernández, Adriana Albini
Journal: Cancer Research (2025)

Abstract Precision oncology necessitates personalized treatments maximizing efficacy while minimizing toxicity. Real-World Data (RWD) presents a powerful resource to achieve this, offering insights to clinical trials and facilitating cross-national comparisons of treatment effectiveness. However, significant obstacles persist: data sparsity, unstructured formats, and limited digitization; complex and internationally diverse data privacy regulations; heterogeneous IT infrastructures and expertise across institutions. The DIGICORE (Digital Institute for Cancer Outcome Research) consortium—a network of European hospitals and companies—directly addresses these challenges. Its initiatives, among the DIGIONE research plan, include: (1) the definition of a set of minimum data elements related to electronic health record systems required to setup RWD studies (MEDOC) (2) a standardized survey assessing the digitalization of these key cancer-related data elements; (3) AI-based tools such as natural language processing to support data digitization; (4) a federated learning infrastructure for privacy-preserving clinical research; (4) the development of standards for comprehensive cancer center infrastructure, (5) the establishment of disease-focused working groups to foster collaboration, and (6) dedicated training programs for clinicians to enhance their IT knowledge. To date, three projects have been completed, with additional 10 projects underway. DIGICORE's multi-faceted approach promises to unlock the transformative potential of RWD in advancing personalized cancer care. (https://digicore-cancer.eu/) 1. Mahon P, et al. A federated learning system for precision oncology in Europe: DigiONE. Nat Med. 2024 doi: 10.1038/s41591-023-02715-8. 2. Mahon P, et al. Harnessing oncology real- world data with AI. Nat Cancer. 2023 doi: 10.1038/s43018-023-00689-7. Citation Format: Alberto Traverso, Giovanni Tonon, Piers Mahon, Gennaro Ciliberto, Andre Dekker, Xosé Fernández, Adriana Albini. Building precision oncology via real-world data standardization, privacy preserving infrastructures, and collaboration among IT and clinical experts: The DIGICORE network experience [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 3372.
Abstract 397: Combinatorial use of VHL and KEAP1-based PROTACs reveals unexpected synergy and hook effect relief
Authors: Sehbanul Islam, Haihong Jin, Dong Liu, Dan Lu, Yunkai Zhang, Renxu Chang, Joel Austin, Thomas Beer, Hsin-Yao Tang, Lan Huang, James Tonra, Luca Busino
Journal: Cancer Research (2025)

Abstract Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules bridging a target protein with an E3 ubiquitin ligase, promoting its ubiquitylation and degradation. Unlike traditional inhibitors, PROTACs exploit transient interactions, enabling the selective degradation of “undruggable” proteins, thereby expanding the landscape of druggable targets. However, PROTACs are not without limitations. The “hook effect”—a phenomenon where high PROTAC concentrations reduce efficacy due to inactive binary complex formation—compromises their clinical utility. Additionally, single PROTACs may fail to achieve complete degradation due to insufficient polyubiquitination or suboptimal E3 ligase recruitment, limiting their therapeutic efficacy. These challenges highlight the need for strategies to enhance PROTAC performance and so therapeutic applicability. In this study, we introduce a novel dual-PROTAC strategy that recruits two distinct E3 ligases, such as KEAP1 and VHL, to cooperatively degrade KRAS(G12D) and Androgen Receptor (AR). Our data demonstrate that combining KEAP1- and VHL-recruiting PROTACs synergistically enhances target degradation, reduces the required dosing, and minimizes off-target effects. Notably, KEAP1 recruitment offers the unique advantage to favour polyubiquitin chains elongation, thereby improving proteasomal recognition. In conclusion, dual-targeting approach represents a promising avenue for optimizing PROTAC-based therapeutics. Citation Format: Sehbanul Islam, Haihong Jin, Dong Liu, Dan Lu, Yunkai Zhang, Renxu Chang, Joel Austin, Thomas Beer, Hsin-Yao Tang, Lan Huang, James Tonra, Luca Busino. Combinatorial use of VHL and KEAP1-based PROTACs reveals unexpected synergy and hook effect relief [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 397.
Abstract 3116: High-definition spatial transcriptomics reveals microenvironment features associated with resistance to anti-PD1 therapies in lung cancer
Authors: Corinne Ramos, Sandra Delebecq, Richard Ruez, Victor Senechal
Journal: Cancer Research (2025)

Abstract Introduction: Primary resistance to immune checkpoint inhibitors (anti PD1) presents a significant hurdle in lung cancer treatment. Tumor microenvironment (TME) features, particularly within the immune compartment, are central to shaping therapeutic response. This study employs high-definition spatial transcriptomics to identify biomarkers and mechanisms underlying resistance. Methods: Formalin-fixed, paraffin-embedded (FFPE) lung cancer tissues from patients resistant to anti PD1 therapies were analyzed using the Visium HD spatial transcriptomics platform. Unsupervised clustering of spatial transcriptomics data was performed to identify distinct gene expression patterns within the immune compartment. Tissue morphology was integrated with gene expression profiles to map spatial heterogeneity. Results: Our in-depth analysis of lung cancer tumor samples, utilizing high-throughput spatial transcriptomics and multiplexed immunohistofluorescence (IHF), revealed that primary resistance to PD1 PDL1 therapies is associated with a distinct tumor microenvironment. Unsupervised clustering of spatial transcriptomics data identified clear groupings that differentiated responders from resistant patients, based on immune compartment gene expression profiles. This analysis highlighted a suppression of immune-activating pathways and enrichment of immunosuppressive signals in resistant tumors, particularly within peritumoral regions. These findings underscore the pivotal role of the tumor microenvironment in modulating the likelihood of response to PD-1 blockade. Conclusion: This study underscores the transformative potential of high-definition, single-cell scale spatial transcriptomics in revealing microenvironmental features associated with primary resistance to PD1 therapies in lung cancer. By enabling precise spatial evaluation of the tumor microenvironment, the identified biomarkers offer a robust foundation for developing predictive tools and personalizing immunotherapy strategies for improved patient outcomes. Citation Format: Corinne Ramos, Sandra Delebecq, Richard Ruez, Victor Senechal. High-definition spatial transcriptomics reveals microenvironment features associated with resistance to anti-PD1 therapies in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3116.
Abstract 3438: The CD24-SEC14L2 drives the neoplastic progression of oral squamous cell carcinoma
Authors: Shi-Rou Chang, Chung-Hsien Chou, Kuo-Wei Chang, Shu-Chun Lin
Journal: Cancer Research (2025)

Abstract Immune stimulation or escape are critical factors determining the survival of malignancies, including oral squamous cell carcinoma (OSCC) and head and neck SCC (HNSCC). CD24 is a glycoprotein anchoring on cell membranes, modulating macrophages' immune responses and tumor stemness. However, its roles in the neoplastic progression are still controversial. As the inhibition of multiple oncogenic miRNAs downregulates CD24 expression, but not other immune checkpoint molecules, in murine OSCC cell lines, the functional roles of CD24 are investigated using a knockdown approach and the stable CD24 tet-off expression cell subclones. CD24 expression modulates the increase of migration and invasion and the upregulation of phosphatidylcholine/phosphatidylinositol transfer protein SEC14 Like 2 (SEC14L2) expression. CD24 expression enriches the orthotopic growth of syngeneic tumor grafts. This is accompanied by the slight change in the myeloid lineage of immune cell infiltration within tumors and the mild disruption of cell profile in recipient mice's neck lymph node and spleen. The shutdown of CD24 with doxycycline treatment drastically suppresses the growth of CD24 tet-off tumors. Concordance in CD24 and SEC14L2 expression is noted in murine tumors. SEC14L2 is upregulated in TCGA-HNSCC tumors and our OSCC tumors. High SEC14L2 expression defines the decreased B cells and myeloid cell population. The integrative analysis of combined TCGA-HNSCC and our OSCC cohort using random effect mode illustrates SEC14L2 as an unfavorable survival predictor of tumors. The oncogenic potential of the CD24-SEC14L2 axis being elucidated in this study may signify the therapeutic efficacy of CD24 targeting for oral cancer. Citation Format: Shi-Rou Chang, Chung-Hsien Chou, Kuo-Wei Chang, Shu-Chun Lin. The CD24-SEC14L2 drives the neoplastic progression of oral squamous cell carcinoma [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 3438.
Abstract 2566: Dissecting PDAC cell-microenvironment interplay in liver metastasis by single cell analysis
Authors: Claudia Fioravanti, Arianna Vallerga, Giulia Garattini, Ilaria Craparotta, Federica Di Leva, Chiara Grasselli, Fabio Sangalli, Andrea Resovi, Raffaella Giavazzi, Marco Bolis, Giulia Taraboletti, Dorina Belotti
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumors. Because most PDAC patients are diagnosed with an already advanced and metastatic stage of the disease, only 15% are suitable for surgical intervention. Thus, an improved understanding of the metastatic mechanism is critical to improve the outcome of these patients. The most common target for PDAC metastasis is the liver. Outgrowth of metastases requires acquisition of tumor genetic alterations in conjunction with alterations in the pancreas and liver microenvironment. The aim of the study was to investigate the role of the tumor microenvironment and the molecular alterations in tumor and stroma cells leading to PDAC liver metastasis formation. To this purpose a metastatic cell variant was established from the FC1199 pancreatic cancer cell line, derived from tumors arisen in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice and growing orthotopically in C57BL/6 mice. The FC199LV metastatic variant was obtained by successive rounds of in vivo selection of cells implanted in the pancreas, isolated from liver metastases and re-implanted in the pancreas for a total of 5 rounds. IHC and in vivo MicroCT analysis of livers at different time points after tumor cell injection highlighted the presence of metastases only in mice transplanted with FC1199LV. Single cell RNA-sequencing analysis of dissociated primary tumors and livers of mice transplanted with FC1199 and FC1199LV highlighted differences in the microenvironmental transcription profile between the two tumor variants. The spontaneous metastatic model of PDAC is an important tool to study the interplay between tumor and stroma in PDAC metastatic process and to identify a tumor and tumor microenvironment gene expression signature associated with PDAC liver metastasis. Supported by AIRC IG 2019 ID23443 Citation Format: Claudia Fioravanti, Arianna Vallerga, Giulia Garattini, Ilaria Craparotta, Federica Di Leva, Chiara Grasselli, Fabio Sangalli, Andrea Resovi, Raffaella Giavazzi, Marco Bolis, Giulia Taraboletti, Dorina Belotti. Dissecting PDAC cell-microenvironment interplay in liver metastasis by single cell 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 2566.
Abstract 398: Systematic identification and translation of novel targeted protein degradation mechanisms
Authors: Christian Dillon
Journal: Cancer Research (2025)

Abstract The rise of Targeted Protein Degradation (TPD) is rapidly changing perceptions about therapeutic target druggability and drug design. However, the majority of degraders in clinical and preclinical development rely on the recruitment of a single E3 ligase, Cereblon, highlighting a pressing need to identify and translate novel mechanisms. Moreover, the discovery of molecular glue degraders is hampered by the prevailing serendipitous nature of their discovery. To unlock the potential of this modality we have developed proprietary cell-based screening platforms, SITESEEKER® and GlueSEEKER™, to uncover novel TPD mechanisms. These technologies exploit vast libraries of computationally-derived coded peptide fragments within the context of a pooled degradation-based phenotypic screen. Specifically, SITESEEKER® screens have identified a cache of degrader mechanisms that rely on hijacking components of the UPS machinery. GlueSEEKER™ utilizes peptide libraries to create a diverse suite of surface-edited E3 ligases to systematically explore neo-substrate degradation across a variety of E3 ligases and Proteins-of-Interest (POI).PhoreMost is progressing a pipeline of monovalent and heterobifunctional oncology degrader programmes arising from its platforms. We describe a novel set of small molecule heterobifunctional degraders that operate via an E3 ligase distinct from Cereblon or VHL-based PROTACs. Mechanistically, these degraders function via a CUL1-SKP1 SCF complex FBOX substrate receptor and demonstrate potential for enhanced cancer-selective degradation of POIs. Finally, we uncover neomorphic interactions revealed by GlueSEEKER™ that provide translational insights for the degradation of both precedented and unprecedented substrates of the E3 ligase, Cereblon. Citation Format: Christian Dillon. Systematic identification and translation of novel targeted protein degradation mechanisms [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 398.
Abstract 3462: Novel delivery platform for temporally-controlled release of immunocytokines and immune checkpoint inhibitors to enhance cancer therapy
Authors: Pilar O'Neal, Julia Lu, Yicheng Zhang, Marek Kovar, Hai-Quan Mao, Jamie Spangler
Journal: Cancer Research (2025)

Abstract Interleukin-2 (IL-2) is a multifunctional cytokine that plays a critical role in the differentiation, proliferation, activation, and survival of immune cells and has been used therapeutically for over 30 years as a cancer treatment. Unfortunately, the cytokine’s narrow therapeutic window and its short circulation half-life have severely limited its clinical application. Strategies designed to bias the activities of IL-2 represent emergent and promising avenues in the treatment of cancer, as they afford the opportunity to selectively target and stimulate certain immune cell subtypes. Recently, our lab has developed one such therapy, termed an immunocytokine (IC), which fuses IL-2 to an anti-IL-2 antibody that biases the cytokine towards immunostimulatory activities while also extending its persistence in the bloodstream. Additionally, we further established that the IC was able to synergize with immune checkpoint inhibitors (ICIs) to effectively clear tumors through expansion of CD8+ T cells and stimulation of their effector functions. Interestingly, it was observed that the therapeutic effects of this combination treatment were highly sensitive to dosing regimen; specifically, robust antitumor activity was observed when IC was delivered after ICI, but not when the order was reversed. Building on this observation of time-dependent anti-cancer activity, here we expand upon this work through the development of a biomaterial system that will enable further exploration of the kinetics surrounding the combinatorial delivery landscape using IC and ICIs. Our biomaterial system involves formulation of nanoparticles that encapsulate IC and ICIs using a flash nano complexation and flash nanoprecipitation system. These particles are further enclosed within a hydrogel system for protection and sustained release within the tumor environment, controlling both the temporal and spatial distribution of the encapsulated immunotherapies. We have successfully designed and characterized the delivery platform and established time-dependent release of the therapeutic cargo. In vivo immune stimulation and tumor clearance studies are ongoing to further evaluate our approach. Overall, our work introduces an innovative and highly versatile bioengineering approach that can be tuned to optimize immunotherapy strategies in a wide range of cancer types. Citation Format: Pilar O'Neal, Julia Lu, Yicheng Zhang, Marek Kovar, Hai-Quan Mao, Jamie Spangler. Novel delivery platform for temporally-controlled release of immunocytokines and immune checkpoint inhibitors to enhance cancer 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 3462.
Tri‐Layered Bioactive Cutaneous Scaffold with Integrated Bioactive Metal Organic Frameworks to Promote Full‐Thickness Infected Diabetic Wound Healing: Multifaceted Therapeutic Strategies
Authors: Ayse Gunyakti Mujtaba, Ayşe Karakeçili, Berna Topuz, Barış Batur, Okan Onar, Mehmet Eray Elçiğir, Çağdaş Oto, Alireza Hanifehnezhad, Kaan Orhan
Journal: Advanced Healthcare Materials (2025)

Abstract Chronic infected diabetic wounds are complex and often lead to severe clinical outcomes such as sepsis, gangrene, and amputation. To address these challenges, herein we developed a novel tri‐layered scaffold to provide multi‐functional therapeutic support. The bottom poly (lactic‐co‐glycolic acid) (PLGA) fibrous layer contains doxycycline loaded CuBDC nanosheets for rapid antibacterial action. The porous PLGA/gelatin middle layer offers mechanical support and γ‐tocotrienol loaded ZIF‐8 nanocrystals mitigates oxidative stress in the wound. The PLGA top sealing fibrous layer delivers insulin and Transforming growth factor beta (TGF‐β1) from Zeolitic Imidazolate Framework‐8 (ZIF‐8) nanocrystals to promote epithelialization and modulate inflammation. Comprehensive in vitro and in vivo evaluations demonstrated that the scaffold effectively filled deep wounds, reduced bacterial load, controlled inflammation, and accelerated the tissue regeneration. Histopathological analyses showed enhanced epithelialization and partial granulation tissue remodeling. Biochemical assays indicated an increase in glutathione peroxidase (GPx) activity and a reduction in lipid peroxidation. Gene expression analysis revealed decreased levels of the pro‐inflammatory TNF‐α and increased levels of the anti‐inflammatory IL‐10, facilitating the transition to the proliferative phase. This multi‐layered composite scaffold, with its antimicrobial, antioxidant, and anti‐inflammatory activities, controlled release capabilities, presents a promising solution the healing process of deep, infected diabetic wounds.
Abstract 1200: FET fusion oncoproteins disrupt physiologic DNA repair and create a targetable opportunity for ATR inhibitor therapies
Authors: Shruti Menon, Daniel Gracilla, Marcus Breese, Filemon Dela Cruz, Asmin Tulpule
Journal: Cancer Research (2025)

Abstract The FET family of intrinsically disordered proteins (FUS, EWSR1, TAF15) are frequent 5’ oncogenic transcription factor (TF) fusion partners in a diversity of sarcomas and leukemias. These TF fusion oncoproteins are often the sole oncogenic driver alteration in these cancers and due to the difficulty in pharmacologic targeting of TFs, precision medicine approaches have been lacking. Here we focus on the pediatric bone tumor Ewing sarcoma (ES) as a model for the class of FET rearranged cancers. ES patients with relapsed or metastatic disease continue to have dismal outcomes, yet decades of clinical experience and laboratory testing of ES cancer cell lines have shown ES to be among the most chemo- and radiosensitive cancers, at least initially. In this study, we address the long-standing hypothesis that ES tumors harbor an intrinsic DNA repair defect by studying the role of the ES fusion oncoprotein EWSR1-FLI1 in regulating the DNA damage response (DDR). Native FET family members are among the earliest factors that localize to DNA double-strand breaks (DSBs). Here we discover that EWSR1-FLI1 (and other FET) fusion oncoproteins are aberrantly recruited to DNA DSBs and interfere with native FET (EWSR1) protein function in activating the DNA damage sensor ATM. We demonstrate the functional importance and therapeutic relevance of ATM suppression in ES through increased reliance on a compensatory DDR kinase, ATR, and FET fusion oncoprotein-dependent synthetic lethality with ATR inhibitors (nanomolar range IC50’s). Lastly, we tested ATR inhibition in PDX models across the class of FET rearranged cancers as a synthetic lethal therapeutic strategy to specifically target functional ATM defects induced by FET fusion oncoproteins themselves. We demonstrate significant anti-tumor responses to ATR inhibitor monotherapy in all 5 PDX models including those derived from multiply relapsed ES and clear cell sarcoma patients. In summary, our study provides a new mechanism for how an oncogene can impair physiologic DNA repair (i.e., aberrant recruitment of an oncogenic fusion protein to sites of DNA damage) to create functional states akin to genetic DDR pathway loss, and rationale for a new targeted therapeutic strategy (i.e., ATM/ATR synthetic lethality) in ES and the broader class of undruggable FET fusion-driven cancers. Citation Format: Shruti Menon, Daniel Gracilla, Marcus Breese, Filemon Dela Cruz, Asmin Tulpule. FET fusion oncoproteins disrupt physiologic DNA repair and create a targetable opportunity for ATR inhibitor therapies [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 1200.