tbuckley/cabot-search huggingface dataset:
Abstract 2914: The WEE1 inhibitor Debio 0123 is synergistic with the PKMYT1 inhibitor lunresertib in preclinical models of ovarian and breast cancer
Authors: Luke Piggott, Diana Bianca Rocha Gomes, Paula Martinez Sanz, Violeta Serra
Journal: Cancer Research (2025)

Background: Debio 0123 is a highly selective and brain penetrant WEE1 inhibitor that has previously shown significant preclinical efficacy in combination with DNA damaging agents and is currently being investigated in several phase 1 clinical studies either as a monotherapy or in combination. WEE1 plays an important role in regulating the cell cycle during the S-phase and at the G2/M transition. Lunresertib (RP6306) is a selective and potent PKMYT1 inhibitor currently in phase 1 clinical studies as a monotherapy or in combination. Like WEE1, PKMYT1 regulates the G2/M transition, arresting cells with DNA damage to permit repair before progressing into mitosis. Herein, we present pre-clinical data that demonstrates the synergistic activity of the lunresertib and Debio 0123 combination in breast and ovarian tumor models. Methods: Knockdown studies were performed utilizing siRNA against PKMYT1 and WEE1 to explore potential synergistic relationship of these targets in different cancer cell types. In vitro, combination efficacy of the selective WEE1i (Debio 0123) and PKMYT1i (lunresertib) was assessed by cytotoxicity in cell lines across different cancer types. Additionally, combination efficacy of lunresertib and Debio 0123 was further assessed in vivo in subcutaneous breast and ovarian cancer cell line-derived and patient-derived xenograft models. Results: Knockdown of either PKMYT1 or WEE1 alone resulted in minor decrease in cell viability, however, concomitant knockdown of both targets resulted in no surviving cell populations. In vitro, combination of lunresertib and Debio 0123 resulted in significant synergy (Bliss) at low nM doses of both compounds. In vivo, in models of ovarian or breast cancer, monotherapy treatments with either Debio 0123 or lunresertib only resulted in minor tumor growth inhibition. Strikingly, the combination of Debio 0123 and lunresertib at all dose levels and schedules tested across all 5 models resulted in complete and sustained regression of all tumors. Conclusions: These results demonstrate, in preclinical models of ovarian and breast cancer, the WEE1 inhibitor, Debio 0123, is synergistic with the PKMYT1 inhibitor, lunresertib, and consistently leads to deep and sustained regressions in vivo. Citation Format: Luke Piggott, Diana Bianca Rocha Gomes, Paula Martinez Sanz, Violeta Serra. The WEE1 inhibitor Debio 0123 is synergistic with the PKMYT1 inhibitor lunresertib in preclinical models of ovarian and 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 2914.
Has This Child Experienced Physical Abuse?
Authors: Sonal N. Shah, Hiu-fai Fong, Suzanne B. Haney, Nancy S. Harper, Mary Clyde Pierce, Mark I. Neuman
Journal: JAMA (2025)

Importance Nearly 100 000 children experience physical abuse each year in the US. Among approximately 2000 annual deaths related to child maltreatment, more than 40% resulted from physical abuse, and half of those children were younger than 1 year. Many of these young children had unidentified abusive injuries before the fatal event. Objective To determine the accuracy of clinical and radiologic findings for identifying physical abuse among children who have sustained an injury. Data Sources and Study Selection MEDLINE, PubMed Central, and Embase were searched for articles published from 1970 to September 2024. Three authors identified studies describing clinical and radiologic characteristics in children and adolescents undergoing assessment for physical abuse. Data Extraction and Synthesis The number of children with and without each clinical or radiologic finding, and the presence or absence of physical abuse, which had been determined by expert panels, predefined criteria, or standardized scales that quantify the level of concern for abuse, were recorded. Main Outcomes and Measures The sensitivity, specificity, and likelihood ratios (LRs) of each finding for the presence of physical abuse were calculated and the range or calculated summary measures were reported when the finding was evaluated in more than 1 study. Results Of 7378 unique articles, 18 studies met inclusion criteria. The prevalence of physical abuse in these 18 studies ranged from 5% to 79%. Studies that were focused on skin findings in children evaluated for trauma showed that the presence of oral injury such as a torn frenulum (positive LR, 6.6 [95% CI, 3.2-14.0]), bruising on the buttocks (positive LR range, 15-83) or neck (positive LR range, 2.2-84), patterned bruises (positive LR range, 2.0-66), and subconjunctival hemorrhage (positive LR range, 5.4-130) were associated with increased likelihood of physical abuse. In studies of hospitalized children with head injury, the presence of retinal hemorrhages (positive LR, 11.0 [95% CI, 4.0-32.0]), seizures (positive LR, 3.9 [95% CI, 2.4-6.5]), hypoxic ischemic injury (positive LR, 3.4 [95% CI, 1.8-6.4]), or a subdural hematoma (positive LR, 3.2 [95% CI, 2.6-3.8]) increased the likelihood of physical abuse. In studies examining children who underwent skeletal surveys, a single fracture (positive LR, 5.9 [95% CI, 2.9-12.0]) or multiple fractures (positive LR, 3.8 [95% CI, 2.4-6.0]) increased the likelihood of physical abuse. Conclusions and Relevance A detailed physical examination that reveals oral injury, bruises on the buttocks or neck, patterned bruises, and subconjunctival hemorrhage in young children should alert clinicians to the possibility of physical abuse. Findings on neuroimaging and ophthalmologic evaluation in infants and young children with head trauma can help clinicians determine the likelihood of physical abuse.
Abstract 1867: Development and validation of fluorescent lipid nanoparticles for RNA delivery applicable to personalized in vitro oncology models
Authors: Xavier Warnet, Célia Bosso-Lefèvre, Erica Cirri, Eric Mennesson, Marie Morin, Mélanie Sapateiro, Maxime Rochet, Laetitia Edmond, Alexandra Foucher, Armelle Vindrios, Alzbeta Komarkova, Flavien Carpenier, Romain Cordonnier-Goulay
Journal: Cancer Research (2025)

Abstract Tebubio offers contract services in RNA-based therapeutic discovery, in vitro modeling, biomarker mapping, and data analysis. Leveraging these platforms, we have developed innovative lipid nanoparticles (LNPs) designed to encapsulate and deliver RNA. This advancement features a fluorescent lipid, created by Echelon Inc., which enables imaging-based tracking of the LNPs. Using this fluorescent lipid, we formulated LNPs encapsulating a mRNA Coding for a fluorescent protein. We validated the distribution of these LNPs within 2D mammalian cell line model and confirmed RNA expression in these cells through imaging techniques. This technology is applicable to in vitro oncology models, including patient-derived spheroids and tumoroids, which allow for a personalized approach to therapeutic testing. Ultimately, Tebubio’s platform provides end-to-end support, from RNA optimization and custom LNP formulation to efficacy validation in vitro, enabling personalized medicine models for RNA-based therapeutics. Citation Format: Xavier Warnet, Célia Bosso-Lefèvre, Erica Cirri, Eric Mennesson, Marie Morin, Mélanie Sapateiro, Maxime Rochet, Laetitia Edmond, Alexandra Foucher, Armelle Vindrios, Alzbeta Komarkova, Flavien Carpenier, Romain Cordonnier-Goulay. Development and validation of fluorescent lipid nanoparticles for RNA delivery applicable to personalized in vitro oncology models [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 1867.
Abstract 5032: Discovery of XPO1 as a therapeutic target in TNBC: Mechanistic insights and preclinical validation
Authors: Amy L. Paulson, Robert F. Gruener, Adam M. Lee, R. Stephanie Huang
Journal: Cancer Research (2025)

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment options. The nuclear export protein XPO1 has emerged as a potential therapeutic target in cancer, but its role in TNBC hasn’t been fully characterized. OBJECTIVES: This study screens, nominates, and investigates the potential of repurposing selinexor, an FDA-approved XPO1 inhibitor, as a novel therapeutic option for TNBC. METHODS: We utilized a computational drug repurposing pipeline to predict breast cancer patient tumor responses to hundreds of drugs. We then stratified patient tumor’s predicted sensitivities by breast cancer subtype and focused on drugs preferentially sensitive towards TNBC. We identified XPO1 inhibitors as the top candidate drug and its efficacy validated in an independent patient dataset and across various TNBC cell line. Additionally, we conducted RNA-sequencing after longitudinal XPO1 inhibition in a panel of TNBC cell lines to explore the mechanism contributing to the preferential sensitivity of TNBC cells to XPO1-inhibition mediated cell death. Further mechanistic studies were conducted to validate our RNA-sequencing findings. RESULTS: Selinexor was found to significantly reduce the viability of a variety of TNBC cell lines. Mechanistically, we reveal that selinexor induces TNBC cell death by inhibiting the NF-kB pathway through nuclear retention of NFKBIA, a key regulator of this pathway. This effect was consistent across multiple TNBC cell lines of differing TNBC subtypes, confirming the broad applicability of XPO1 inhibition in TNBC treatment. CONCLUSION: This study identifies XPO1 inhibitors as a promising therapeutic candidate for TNBC patients by inhibiting the XPO1-mediated export of NFKBIA and blocking the NF-kB pathway. These findings pave the way for more personalized treatment strategies and provide a potential alternative to conventional chemotherapy. IMPLICATIONS FOR PRACTICE: Repurposing selinexor for the treatment of TNBC could accelerate the availability of targeted therapies for patients with this aggressive cancer. New mechanistic insight into the causes leading to TNBC cell specific sensitivity to XPO1-inhibition mediated cell death warrant further clinical trials to evaluate the safety and efficacy of selinexor in TNBC patients. Citation Format: Amy L. Paulson, Robert F. Gruener, Adam M. Lee, R. Stephanie Huang. Discovery of XPO1 as a therapeutic target in TNBC: Mechanistic insights and preclinical validation [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 5032.
Removable Boot vs Casting of Toddler’s Fractures
Authors: Ariane Boutin, Keith Colaco, Jennifer Stimec, Mark Camp, Unni Narayanan, Maala Bhatt, Naveen Poonai, Andrew R. Willan, Ramona Cook, Marie-Lyne Nault, Sasha Carsen, Kathy Boutis
Journal: JAMA Pediatrics (2025)

Importance Toddler’s fractures (TF) of the tibia are commonly treated with casts and fracture clinic follow-up. However, a prefabricated removable boot might be sufficient and reduce unnecessary follow-up. Objectives To determine whether pain in children with TF treated with a removable boot is not worse than those managed with a circumferential cast at 4 weeks postinjury. Design, Setting, and Participants This pragmatic, multicenter, assessor-blinded, noninferiority randomized clinical trial was conducted between October 2019 and February 2024 at 4 urban, tertiary care, pediatric Canadian emergency departments. Children aged between 9 months and 4 years with a radiograph-visible TF were eligible for inclusion. Interventions Prefabricated walking boot for up to 3 weeks (removable at caregivers’ discretion) vs circumferential cast immobilization (site standard of care) for 3 weeks. Main Outcomes and Measure The primary outcome was pain score, measured with the Evaluation Enfant Douleur (EVENDOL) scale (maximum score: 15). Additional outcomes included return to baseline activities, complications, parental satisfaction and care burden. Results In 129 enrolled children, the mean (SD) age was 2.2 (0.8) years, and 56 children (43%) were female. Of these, 118 children (92%) completed the 4-week follow-up, and the boot (n = 64) vs cast (n = 54) groups demonstrated mean (SD) EVENDOL pain scores of 1.21 (1.54) and 1.76 (2.13), respectively (difference, −0.55; 95% CI, −1.23 to 0.13). The percentage of participants who returned to baseline activities “almost all of the time” was 49 of 64 children (77%) in the boot group and 22 of 54 (41%) in the cast group (difference, 36%; 95% CI, 9%-63%). Skin complications occurred in both groups (boot: 46 total complications [72%], with 5 stage 1 pressure sores; cast: 27 total complications (50%), with 1 pressure sore]; difference, 22%; 95% CI, −6% to 50%). There was no statistically significant difference in the percentage of caregivers who were satisfied or very satisfied with the treatment (difference, 9%; 95% CI, −24% to 43%). Fewer caregivers reported bathing care burden (difference, −32%; 95% CI, −47% to −18%) and challenges with carrying the child (difference, −21%; 95% CI, −27% to −15%) in the boot vs cast group. Conclusions and Relevance In this multicenter randomized clinical trial examining the management of children with TF, a removable boot without physician follow-up was noninferior to circumferential casting with respect to pain recovery. While there was a clinically relevant but not statistically significant trend toward more skin complications in the boot group, there was no difference in caregiver satisfaction, and the boot strategy demonstrated reduced childcare-related challenges. Trial Registration ClinicalTrials.gov Identifier: NCT03971448
Abstract 2889: Multabodies: A next-generation approach for cancer immunotherapy and 4-1BB agonist therapy
Authors: Joanne Hulme, Peter Bayliss, Abilasha Rao, Shrayasee Saha, Xinwen He, Debbie Jin, Yvonne Tsao, Amy Berkley
Journal: Cancer Research (2025)

Abstract 4-1BB agonism represents a promising strategy in cancer immunotherapy, targeting the 4-1BB receptor (CD137, TNFRSF9) expressed on activated T cells and NK cells. This co-stimulatory receptor, when activated by receptor multimerization, enhances immune cell proliferation, survival and effector functions. Agonistic antibodies against 4-1BB, optimized for FcγR cross-linking, have demonstrated potent anti-tumor activity in preclinical models. However clinical development has been hindered by severe liver toxicity (i.e., urelumab), or insufficient single agent activity, as seen with utomilumab. Here we describe a novel MULTi-specific, multi-Affinity antiBODY (Multabody™, MB) platform that exploits multi-valency to deliver an innovative 4-1BB Multabody™ with broad therapeutic potential. To understand the impact of epitope on 4-1BB agonism, we generated a panel of 4-1BB Multabodies to unlock comprehensive comparisons of potency and maximal activity of these molecules in a suite of assays including a 4-1BB Jurkat reporter assay vs urelumab and utomilumab. We identified 4-1BB MBs that demonstrated a range of Fc-independent agonistic profiles, including those mimicking the natural ligand, 4-1BBL. Identified lead 4-1BB MB candidate, RBT101, was further evaluated in vivo using the syngeneic MC38 murine tumor model. RBT101 demonstrated robust in vivo efficacy resulting in durable complete tumor regressions. Unlike urelumab which demonstrated splenomegaly and liver inflammation, RBT101 showed no signs of spleen or liver toxicity. Furthermore, RBT101 also provided long-term protection in a tumor rechallenge study, suggesting generation of a durable immunological memory response driven by RBT101. These data suggest the Multabody™ platform provides a novel approach to delivering a 4-1BB therapeutic with a differentiated profile to address an unmet clinical need in cancer immunotherapy for patients with solid malignancies. Citation Format: Joanne Hulme, Peter Bayliss, Abilasha Rao, Shrayasee Saha, Xinwen He, Debbie Jin, Yvonne Tsao, Amy Berkley. Multabodies: A next-generation approach for cancer immunotherapy and 4-1BB agonist 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 2889.
Abstract 4682: Elucidating the mechanisms of 2-deoxy-D-glucose (2-DG) and 2-deoxy-D-glucose phoaphate (2-DG-P) in maintaining gastrointestinal homeostasis
Authors: Rao V. Papineni, Shahid Umar, Prashanthi Karyala, Kavya Ramesh, Badal Roy
Journal: Cancer Research (2025)

Abstract 2-Deoxy-D-glucose (2-DG), a polypharmacological agent, has shown promise in treating various pathological conditions, including cancer, bacterial and viral infections, and as an adjuvant to radio-chemo-therapy. 2-DG exerts its effects by inhibiting glycolysis, disrupting protein N-glycosylation, inducing endoplasmic reticulum stress, autophagy, and apoptosis. Our recent studies demonstrated that 2-DG mitigates bacterial infection-induced inflammation and colitis, and proposed its potential as a radiation countermeasure agent. Utilizing a colonoid model, we investigated the mechanisms underlying 2-DG's maintenance of gastrointestinal homeostasis. Specifically, we explored its interaction with Doublecortin-like kinase 1 (DCLK1), a protein with two major isoforms, DCLK1-L and DCLK1-S.Here, 2-DG-Phosphate (2-DG-P), the non-metabolizable product of 2-DG, is also implicated in this process. Combining in silico molecular docking of 2-DG and 2-DG-P with DCLK1, we propose that 2-DG-P, along with 2-DG, may serve as potential candidates for radioprotection and mitigation of irradiation-induced gastrointestinal acute radiation syndrome (GI-ARS). Citation Format: Rao V. Papineni, Shahid Umar, Prashanthi Karyala, Kavya Ramesh, Badal Roy. Elucidating the mechanisms of 2-deoxy-D-glucose (2-DG) and 2-deoxy-D-glucose phoaphate (2-DG-P) in maintaining gastrointestinal homeostasis [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 4682.
Abstract 5071: Spatially resolved gene expression analysis of primary and metastatic fibrolamellar hepatocellular carcinoma (FLC)
Authors: Waqar Arif, Luciane Kagohara, Robert A. Anders, Kiyoko Oshima, Mark Yarchoan
Journal: Cancer Research (2025)

Abstract Fibrolamellar carcinoma (FLC) is a rare and aggressive malignancy of the liver that predominantly affects adolescents and young adults. These tumors are distinct from conventional hepatocellular carcinomas and are characterized histologically by thick fibrous collagen bands. The transcriptome of FLC is characterized by a recurrent oncogenic fusion between DNAJB1 and PRKACA. Liver resection is a potentially curative treatment option for early-stage FLC, but there are no standard systemic therapies available for advanced FLC. Most patients present with unresectable disease or relapse after surgery; for these individuals, outcomes are dismal with a median survival of only 12 months. This highlights the urgent need to understand the natural evolution of FLC, which in turn will support the development of effective targeted therapies. To investigate the evolution of FLC, we leveraged FLC tissue samples from n=5 patients with paired primary and distant metastatic surgical biopsies. Among these patients, 4/5 received systemic therapy including immunotherapy in the interval between primary resection and resection of the distant metastatic lesions. A histological view of the cases revealed notable morphological differences between the primary and metastatic tumors. Primary tumors showed the characteristic oncocytic tumor cells separated by thick cords of collagen fibrosis. However, the metastatic lesions exhibited reduced fibrosis or lacked it entirely, suggesting malignant progression of the tumor and loss of a key histological hallmark of FLC over time. To date, most transcriptomic analysis of FLC has been performed on bulk tissue which neglects the heterogeneity of the tumor. To capture the complexity of the lesion, we performed spatial transcriptomic analysis of our paired samples (n = 10, primary and metastatic lesions) using the VisiumHD platform by 10x Genomics. Furthermore, we succeeded in labeling the neoplastic cells using a custom-designed probe against the DNAJB1-PRKACA chimeric transcript which we included in the standard probe library. Spatially resolved gene expression analysis and neighborhood analysis using the Seurat workflow revealed marked differences in transcriptional networks coinciding with the progression of the tumor. Here we present a spatially and temporally resolved transcriptome atlas of FLC. This rich and valuable resource will be critical for understanding FLC biology and ultimately developing novel therapeutics. Citation Format: Waqar Arif, Luciane Kagohara, Robert A. Anders, Kiyoko Oshima, Mark Yarchoan. Spatially resolved gene expression analysis of primary and metastatic fibrolamellar hepatocellular carcinoma (FLC) [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 5071.
Abstract 4752: The combination of GLP1-R agonists and progestins enhances endometrial cancer cell killing through membrane receptor crosstalk
Authors: Lane E. Smith, Jamie L. Padilla, Geneva L. Williams, Kristina Thiel, Kimberly K. Leslie
Journal: Cancer Research (2025)

Obesity is a major risk factor for endometrial cancer, and glucagon like peptide-1 receptor (GLP-1R) agonists such as semaglutide may be helpful to achieve weight loss. Conservative treatment of endometrial cancer includes hormone therapy with progestins for women who wish to preserve their uterus. Our previous work showed a significant reduction in viability of multiple endometrial cancer cell line and organoid models in response to the combination treatment of semaglutide and levonorgestrel, and identified a positive feedback loop between GLP-1R and progesterone receptor (PR) signaling. Here, we further explored mechanisms underlying the enhanced signaling, using confocal microscopy to show the co-localization of membrane PR (Progesterone Receptor Membrane Component 1; PGRMC1) and GLP1-R in response to semaglutide + progesterone combined treatment. We also found that semaglutide alone (100nM) induces the translocation of PR to the nucleus within 30 minutes. We are undergoing microarray analyses to assess specific phosphorylation events as well as RNA sequencing occurring downstream to identify the signaling molecules and transcripts activated by dual treatment. These studies highlight the potential of semaglutide to improve the anti-cancer effects of progestins, and, importantly, may reduce recurrences that can occur with progestin therapy alone. Citation Format: Lane E. Smith, Jamie L. Padilla, Geneva L. Williams, Kristina Thiel, Kimberly K. Leslie. The combination of GLP1-R agonists and progestins enhances endometrial cancer cell killing through membrane receptor crosstalk [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 4752.