tbuckley/cabot-search huggingface dataset:
Abstract ND05: The discovery of BMS-986449, a highly potent and selective degrader of the transcription factors Helios (IKZF2) and Eos (IKZF4) for the treatment of solid tumors
Authors: Aaron Balog
Journal: Cancer Research (2025)

Abstract Regulatory T (Treg) cell abundance in the tumor microenvironment is associated with poor responses to immunotherapies, such as nivolumab. The transcription factors Helios (IKZF2) and Eos (IKZF4) are abundantly expressed in Treg cells and contribute to the immunosuppressive phenotype associated with this T-cell subset. We and others have postulated that degradation of Helios and Eos could re-polarize Treg cells towards a less suppressive, more inflammatory phenotype that would result in an enhanced antitumor effector T cell response. This presentation will describe the discovery and characterization of BMS-986449, a Cereblon E3 Ligase Modulatory Drug (CELMoD™) molecular glue degrader of Helios and Eos. BMS-986449 is a potent and orally bioavailable degrader of IKZF2/4 with minimal impact on IKZF1/3 levels in regulatory T-cells as assessed by global proteomics. BMS-986449 affects in vitro reprogramming of Treg cells to have a more effector-like phenotype that results in promising in vivo efficacy in syngeneic tumor models. In cynomolgus monkeys, oral administration of BMS-986449 (0.3 mg/kg, QD) was well-tolerated and maintained ≥80% degradation of Helios in circulating Treg cells over 24h. Given the positive outcomes from these pre-clinical studies and an acceptable safety profile, BMS-986449 was advanced into Phase I/II clinical trials for patients with advanced solid tumors. Citation Format: Aaron Balog. The discovery of BMS-986449, a highly potent and selective degrader of the transcription factors Helios (IKZF2) and Eos (IKZF4) for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND05.
Abstract ND07: FXX489, a FAP targeting ligand with best-in-class potential for radioligand therapy
Authors: Markus Reschke, Danielle Park, Sarah Choi, Takeru Ehara, Andrei Golosov, Philipp Grosche, Dominik Hainzl, Philipp Holzer, Patrick Klein, Lukas Leder, Shiva Malek, Eloisa Jimenez Nunez, Patrick Reid, Holger Sellner, Quincey Simmons, Therese Stachyra, Hayato Yanagida, Alexei Karpov
Journal: Cancer Research (2025)

Abstract FAP (Fibroblast Activation Protein) is expressed on cancer-associated fibroblasts (CAFs) and is a highly attractive target in Radioligand Therapy (RLT) due to its pan cancer potential. The penetrating nature of β radiation is hypothesized to drive a ‘cross-fire effect’ from CAFs to tumor cells resulting in DNA damage and tumor cell death. Known FAP targeting ligands show excellent and selective tumor uptake in the clinic but suffer from short tumor retention which limits their application as a therapeutic modality. Herein we describe FXX489 (FAP targeting ligand) which improves tumor retention and is currently undergoing clinical evaluation in Phase 1 (NCT06562192) in patients with PDAC, NSCLC, Breast Cancer, and CRC. Importantly, FXX489 demonstrates BiC potential for anti-tumor efficacy in translationally relevant models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs, thus relying on the cross-fire mechanism. Multiple starting points were identified using mRNA display platform, co-crystallized with FAP and assessed for biodistribution in vivo. The series with the best tumor/kidney ratio was selected for further optimization. Optimization was enabled by the co-crystal structure and was focusing on maximizing compound affinity and proteolytic stability. FXX489 binds to both human and mouse FAP with the affinity &amp;lt; 10 pM; shows exquisite selectivity over other proteases (such as DPP4); is stable in blood and plasma. Citation Format: Markus Reschke, Danielle Park, Sarah Choi, Takeru Ehara, Andrei Golosov, Philipp Grosche, Dominik Hainzl, Philipp Holzer, Patrick Klein, Lukas Leder, Shiva Malek, Eloisa Jimenez Nunez, Patrick Reid, Holger Sellner, Quincey Simmons, Therese Stachyra, Hayato Yanagida, Alexei Karpov. FXX489, a FAP targeting ligand with best-in-class potential for radioligand therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND07.
Abstract ND03: ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant prostate cancer
Authors: Regina M. Reilly
Journal: Cancer Research (2025)

Abstract Prostate cancer is the second leading cause of male cancer deaths in the US. There is currently no curative therapy available for advanced prostate cancer, indicating an urgent need for novel therapeutics. ABBV-969 is intended to address this critical need by delivering cytotoxin to tumor cells highly expressing prostate tumor antigens, STEAP1 (six transmembrane epithelial antigen of the prostate-1) and PSMA (prostate specific membrane antigen). STEAP1, minimally expressed on normal tissue, is highly enriched in over 85% of prostate tumors, where it promotes proliferation and invasion. As a prostate lineage marker PSMA expression is up to 100-fold higher on tumor versus healthy prostate tissue and correlates with tumor stage, aggressiveness, and recurrence. High expression and prevalence in prostate cancer identifies both antigens as attractive targets for antibody drug conjugates (ADCs). Since heterogeneous expression throughout and among tumors may limit effectiveness, a bispecific antibody that binds both STEAP1 and PSMA was designed using a dual variable domain immunoglobulin (DVD-Ig) format. This format enables bivalent engagement of both targets, potentially increasing tumor coverage and durability of therapy. ABBV-969 is a conjugate of the DVD-Ig with a proprietary topoisomerase-1 (Top1) inhibitor linker-drug identical to that used in two assets in clinical development, ABBV-400, targeting c-Met, and ABBV-706, targeting SEZ6. ABBV-969 binds to STEAP1 and PSMA with high affinity and is cytotoxic to cells expressing either or both antigens. ABBV-969 exhibits favorable drug-like properties, pharmacokinetics, and efficacy against patient-derived xenografts from castrate resistant prostate tumors and has broader activity than standard ADCs targeting either STEAP1 or PSMA. Furthermore, ABBV-969 is well tolerated in cynomolgus monkeys with bone marrow and gastrointestinal toxicities common to other Top1 inhibitor ADCs. ABBV-969 is currently in dose escalation in a Phase 1 clinical study (NCT06318273). Citation Format: Regina M. Reilly. ABBV-969: A first-in-class dual-targeting PSMA-STEAP1 drug conjugate for the treatment of metastatic castrate-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND03.
Abstract ND06: Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor
Authors: Anne Edwards
Journal: Cancer Research (2025)

Abstract The RAS G12V mutation is among the most common oncogenic drivers in pancreatic, colorectal, and non-small cell lung cancers. Within a tumor cell, RAS G12V exists predominantly in the active, GTP-bound (“RAS(ON)”) state leading to excessive downstream oncogenic signaling. The intrinsic GTP hydrolysis rate of RAS G12V is about 12-fold lower than that of KRAS G12C, biasing the cellular RAS G12V pool to the ON state and emphasizing the importance of targeting RAS G12V(ON) for maximal suppression of this oncogenic driver. Additionally, achieving selectivity for RAS G12V over wild-type RAS has, to date, been extremely challenging using conventional small molecules because the Val-12 residue is neither amenable to covalent inhibition nor to formation of polar, noncovalent interactions.The investigational agent RMC-5127 is a potent, orally bioavailable, RAS (ON) G12V-selective, noncovalent tri-complex inhibitor. In KRAS G12V mutant cancer cells, RMC-5127 forms a tri-complex between KRAS G12V(ON) and cyclophilin A (CypA), driving near-immediate disruption of RAS effector binding through steric occlusion and extinction of KRAS G12V(ON) signaling.RMC-5127 suppressed ERK phosphorylation and cell growth in multiple human KRAS G12V-addicted cancer cell lines in vitro, and a single dose induced dose-dependent, deep, and durable suppression of RAS pathway activation in vivo in subcutaneous xenograft models of KRAS G12V mutant cancers in mice. Across a panel of preclinical PDAC and NSCLC models harboring KRAS G12V, RMC-5127 monotherapy induced tumor regressions in the majority of models and was well-tolerated. In addition, dose-dependent exposure of RMC-5127 was observed in the whole brain of naïve mice, indicating the compound is brain penetrant, and RMC-5127 exhibited profound antitumor activity in relevant intracranial KRAS G12V mutant tumor xenograft models, with regressions observed at well-tolerated doses. Citation Format: Anne Edwards. Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND06.
CellWalker2: Multi-omic discovery using hierarchical cell type relationships
Authors: Zhirui Hu, Pawel F Przytycki, Katherine S Pollard
Journal: Cell Genomics (2025)

Tissues are composed of cells with a wide range of similarities to each other, yet existing methods for single-cell genomics treat cell types as discrete labels. To address this gap, we developed CellWalker2, a graph diffusion-based model for the annotation and mapping of multi-modal data. With our open-source software package, hierarchically related cell types can be probabilistically matched across contexts and used to annotate cells, genomic regions, or gene sets. Additional features include estimating statistical significance and enabling gene expression and chromatin accessibility to be jointly modeled. Through simulation studies, we show that CellWalker2 performs better than existing methods in cell-type annotation and mapping. We then use multi-omics data from the brain and immune system to demonstrate CellWalker2's ability to assign high-resolution cell-type labels to regulatory elements and TFs and to quantify both conserved and divergent cell-type relationships between species.
Sleep and the recovery from stress
Authors: Xiao Yu, Mathieu Nollet, Nicholas P Franks, William Wisden
Journal: Neuron (2025)

The relationship between stress and sleep is multifaceted, with stress capable of both disrupting and promoting sleep depending on the nature, intensity, and duration of the stressor. While stress commonly leads to sleep fragmentation and arousal in both humans and animals, certain selective stressors, such as immune challenges and psychosocial stress, promote sleep in rodent models. Specific neural circuits, such as those involving the ventral tegmental area and lateral habenula, mediate this stress-induced sleep. Post-stress sleep may facilitate recovery, reduce anxiety, and enhance stress resilience, but the extent to which sleep versus wakefulness post-stress aids long-term adaptation is unclear. Both human and animal studies highlight a bidirectional relationship, where stress-induced changes in sleep architecture may have adaptive or maladaptive consequences. Here, we propose that post-stress sleep contributes to resilience and discuss potential mechanisms underlying this process. A deeper understanding of these pathways may provide new strategies for enhancing stress recovery and improving mental health outcomes.
Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers
Authors: Palmira Llorens-Giralt, Marina Ruiz-Romero, Ramil Nurtdinov, Macarena Herranz-Itúrbide, Guillermo P Vicent, Florenci Serras, Isabel Fabregat, Montserrat Corominas
Journal: Cell Genomics (2025)

The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.
E. coli prophages encode an arsenal of defense systems to protect against temperate phages
Authors: Lucas R Brenes, Michael T Laub
Journal: Cell Host & Microbe (2025)

In recent years, dozens of anti-phage defense systems have been identified. However, efforts to find these systems have focused predominantly on lytic phages, leaving defense against temperate phages poorly understood. Here, we isolated 33 temperate phages from a diverse collection of E. coli to create a library of single lysogens, which were tested for defense against the same set of temperate phages. We found that the majority of lysogens offer protection against at least one additional phage from the collection, often displaying broad defense against various phages. Defense efficacy varies based on growth media and host background, suggesting that some systems are context dependent. Using an iterative deletion-based strategy, we identify 17 systems responsible for the prophage-encoded defense, including 5 toxin-antitoxin modules. Collectively, our work uncovers a diverse array of phage-phage interactions and indicates that temperate phages encode a previously unrecognized arsenal of anti-phage defense systems.
Semaglutide effects on energy balance are mediated by Adcyap1+ neurons in the dorsal vagal complex
Authors: Júlia Teixidor-Deulofeu, Sebastian Blid Sköldheden, Ferran Font-Gironès, Andrej Feješ, Johan Ruud, Linda Engström Ruud
Journal: Cell Metabolism (2025)

The use of the GLP-1R agonist semaglutide is revolutionizing the treatment of obesity, yet its mechanistic effects on energy balance remain elusive. Here, we demonstrate that reactivation of semaglutide-responsive dorsal vagal complex neurons mimics the drug's effects of reducing food intake and body weight and promoting fat utilization and conditioned taste aversion. We observe that many of the semaglutide-activated area postrema (AP) and nucleus of the solitary tract (NTS) neurons express Adcyap1 mRNA, and ablation of AP/NTS Adcyap1+ neurons largely reverses semaglutide's effects on energy balance acutely in lean mice and in subchronically treated obese mice. Semaglutide-activated AP/NTS Adcyap1+ neurons promote the loss of fat rather than lean mass, with only a modest effect on conditioned taste aversion. Furthermore, NTS Adcyap1+ neurons are engaged by GLP-1R-expressing AP neurons and are necessary for semaglutide-induced activation of several downstream satiety-related structures. Selective targeting of semaglutide-responsive Adcyap1+ neurons holds potential for improved future anti-obesity treatments.
A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo
Authors: Fanghui Zhang, Javier Celis-Gutierrez, Lichen Zhang, Valentin Mellado, Léna Gelard, Sophie Panigot, Daiki Mori, Liaoxun Lu, Guillaume Voisinne, Carine Vilarnau Wolek, Marielle Mello, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Frédéric Fiore, Romain Roncagalli, Yinming Liang, Marie Malissen, Bernard Malissen
Journal: The Journal of Experimental Medicine (2025)

Naive T cell activation requires both TCR and CD28 signals. The CARMIL2 cytosolic protein enables CD28-dependent activation of the NF-κB transcription factor via its ability to link CD28 to the CARD11 adaptor protein. Here, we developed mice expressing a mutation named Carmil2QE and mimicking a mutation found in human T cell malignancies. Naive T cells from Carmil2QE mice contained preformed CARMIL2QE-CARD11 complexes in numbers comparable to those assembling in wild-type T cells after CD28 engagement. Such ready-made CARMIL2QE-CARD11 complexes also formed in CD28-deficient mice where they unexpectedly induced most of the functions that normally result from CD28 engagement in a manner that remains antigen-dependent. In turn, tumor-specific T cells expressing Carmil2QE do not require CD28 engagement and thereby escape to both PD-1 and CTLA-4 inhibition. In conclusion, we uncovered the overarching role played by CARMIL2-CARD11 signals among those triggered by CD28 and exploited them to induce potent solid tumor–specific T cell responses in the absence of CD28 ligands and immune checkpoint inhibitors.
Trends and Disparities in Rates of Hypoglycemia Among Hospitalized Patients With Type II Diabetes
Authors: Paul A. Heidenreich, Shoutzu Lin, Robert J. Gallo, Anju Sahay, Mary Burkhardt, Peter Glassman, Daniel Fang, Von Moore
Journal: Diabetes Care (2025)

OBJECTIVE Hypoglycemia is a common complication of inpatient care for patients with diabetes. We sought to determine recent trends and demographic disparities in the rate of inpatient hypoglycemia. RESEARCH DESIGN AND METHODS We used data from the Veterans Affairs (VA) health care system to identify all patients with type 2 diabetes hospitalized from 2016 to 2022. We determined rates of inpatient hypoglycemia (&amp;lt;70 mg/dL) and discharge diagnosis coding for hypoglycemia. We determined differences in rates of hypoglycemia by age, gender, and race/ethnicity, adjusting for other patient diagnoses, laboratory values, vital signs, and insulin use. RESULTS Among 512,261 patients hospitalized with diabetes, 6.8% (34,918) had an episode of hypoglycemia (&amp;lt;70 mg/dL). This rate decreased by 17% from 2016 to 2022 (7.4% to 6.3%), while the rate of discharge diagnosis among those with hypoglycemia increased. After adjustment for other patient characteristics, the youngest and oldest patients, and those hospitalized in earlier years (vs. 2022) had significantly higher rates of hypoglycemia. Black (adjusted odds ratio [aOR] 1.42, 95% CI 1.36–1.49) or Hispanic patients (aOR 1.26, 95% CI 1.17–1.35) had a greater risk of hypoglycemia compared with non-Hispanic White patients, and women had borderline less hypoglycemia than men (aOR 0.95, 95% CI 0.89–1.00). CONCLUSIONS Inpatient hypoglycemia in the VA health system has been declining, although there are race, age, and gender differences that remain unexplained. Recognition of hypoglycemia, defined as a discharge diagnosis, is increasing.
Gut dysbiosis from high-salt diet promotes glioma via propionate-mediated TGF-β activation
Authors: Chae Won Kim, Hyun-Jin Kim, In Kang, Keun Bon Ku, Yumin Kim, Jang Hyun Park, Juhee Lim, Byeong Hoon Kang, Won Hyung Park, Jeongwoo La, Sungwoo Chang, Inju Hwang, Minji Kim, Stephen Ahn, Heung Kyu Lee
Journal: The Journal of Experimental Medicine (2025)

The purpose of this study is to investigate the impact of a high-salt diet (HSD), which is commonly found in Western countries, on the progression of glioma. Our research shows that the alterations in gut microbiota caused by an HSD facilitated the development of glioma. Mice fed an HSD have elevated levels of intestinal propionate, which accelerated the growth of glioma cells. We also find that propionate supplementation enhanced the response of glioma cells to low oxygen levels. Moreover, we identify a link between TGF-β signaling, response to low oxygen levels, and invasion-related pathways. Propionate treatment increases the expression of HIF-1α, leading to an increase in TGF-β1 production. Additionally, propionate treatment promotes glioma cell invasion through TGF-β signaling. Our findings suggest that an HSD-induced increase in propionate plays a crucial role in glioma progression by facilitating invasion through the hypoxic response and TGF-β signaling pathways, thereby establishing a significant connection between gut microbiota and the progression of glioma.
Innovative Medicines Initiative public–private partnerships to enhance translational safety
Authors: Salah-Dine Chibout, Dominique Brees, Magda Chlebus, Philippe Detilleux, Loic Laplanche, Jonathan Moggs, Shashi K. Ramaiah, Jacques Richard, Gunnar Schütz, Nathalie Seigneuret, Thomas Steger-Hartmann, Elisabetta Vaudano
Journal: Nature Reviews Drug Discovery (2025)
Analyzing the relationship of RNA and DNA methylation with gene expression
Authors: Shangqian Xie, Darren Hagen, Gabrielle M Becker, Kimberly M Davenport, Katie A Shira, Morgan R Stegemiller, Jacob W Thorne, Sarem Khilji, Denise Konetchy, Patricia Villamediana, Brenda M Murdoch, Stephanie D McKay
Journal: Genome biology (2025)
Tumor-associated macrophage-derived exosomes modulate the immunotherapeutic sensitivity of SHH-medulloblastoma by targeting m6A-modified FOXD1
Authors: Yantao Liu, Yu Peng, Chen Song, Zongran Liu, Xiaolong Yang, Shuqing Bian, Xiaolin Xiao, Haishuang Li, Jing Wang, Ziwen Sun, Xiaodan Liu, Bao Yang, David J H Shih, Jianyuan Luo, Hui Liang, Qing Chang
Journal: Neuro-Oncology (2025)

Abstract Background Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Infiltration of tumor-associated macrophages (TAMs) and m6A modification of RNA are correlated with poor prognosis and tumor progression in the Sonic Hedgehog (SHH) subtype (SHH-MB). However, the relationship between TAMs infiltration in SHH-MB and m6A modification status during tumor progression remains unclear. Methods Expression of m6A modification-related proteins was assessed in 40 cases of SHH-MB. Genes affected by TAM-derived exosomes were identified with methylated RNA immunoprecipitation sequencing. Mechanisms of m6A modification of FOXD1 were evaluated and combinatorial treatment with AAV2/9-shFOXD1 and PD-1 inhibitors was investigated in the NeuroD2:SmoA1 mouse model. Results TAMs infiltration led to decreased METTL14 expression, which was mediated by TAM-derived exosomes containing METTL14-specific microRNAs. In turn, this led to lower levels of m6A modifications. Through a screen, FOXD1 was identified as a critical downstream target of TAM-derived exosomes, and its expression level was correlated with poor prognosis in SHH-MBs. Importantly, knockdown of FOXD1 in SHH-MB cells significantly promoted the release of chemokines CXCL10/11, resulting in CD8+ T cell recruitment. Furthermore, treatment with AAV2/9-shFOXD1 significantly enhanced the antitumor effect of the PD-1 inhibitor in transgenic SHH-MB mice. Conclusion Our study revealed for the first time that TAM-derived exosomes modulate m6A levels in SHH-MB, which promotes tumor progression via FOXD1. We identified FOXD1 as a novel therapeutic target whose inhibition sensitizes SHH-MB to immune checkpoint blockade.