Citations

Abstract INTRODUCTION: Cholangiocarcinoma (CCA) is a deadly cancer of the hepatic bile duct epithelial cells. Loss-of-function mutations of epigenetic regulator ubiquitin C-terminal hydrolase deubiquitinase BRCA1-associated protein 1 (BAP1) occur in 26-32% of human CCA and are associated with worse prognosis and resistance to cytotoxic therapy. The goal of this study is to identify how BAP1 loss promotes cell death evasion through metabolic rewiring. MATERIALS & METHODS: Isogenic wild-type and BAP1-deficient human and murine CCA cell lines were generated with shRNA/siRNA or CRISPR/Cas9 and were used to assess ferroptosis sensitivity by treatment with ferroptosis inducers. In vitro, ferroptosis was assessed by phospholipid peroxidation (C-11BODIPY), mitochondrial phospholipid peroxidation (MitoPeDPP, MitoCLox), iron oeverload (MitoFerro green) and cell death (CellTiter-Glo). Phospholipidomics and proteomics were performed in isogenic cells by LC-MS/MS. Isogenic liver orthotopic CCA murine models were used for in vivo pre-clinical studies. RESULTS: Our findings indicate that BAP1 loss confers CCA ferroptosis resistance. BAP1 loss protects CCA against mitochondrial iron overload, ROS accumulation, and phospholipid peroxidation. Strikingly, BAP1 loss protects from mitochondrial phospholipid peroxidation and cardiolipin oxidation. Unbiased phospholipidomic profiling revealed that BAP1 loss remodels membrane phospholipid composition, enriching for ferroptosis-blocking monounsaturated phospholipids (MUFA-PLs) at the expense of ferroptosis-inducing polyunsaturated (PUFA-PLs). We found that BAP1 loss upregulates TLCD1, a phosphatidylethanolamine acyltransferase that incorporates MUFAs into membrane phospholipids, thereby stabilizing membranes against peroxidation. TLCD1 knockdown in BAP1-deficient CCA cells, restored ferroptosis sensitivity Notably, TLCD1 is significantly upregulated in human BAP1-mutant CCA as compared to WT tumors. We identified TLCD1 in the endoplasmic reticulum, Golgi and by mitochondrial outer membrane. In syngeneic liver orthotopic CCA murine models, engineered EpCAM-aptamer-coated lactosomes carrying GPX4 siRNA selectively targeted CCA cells, inducing ferroptosis and robustly suppressing tumor growth without systemic toxicity. Lastly, BAP1-mutant patient-derived xenografts (PDXs) and organoids were resistant to ferroptosis inducers, as compared to WT controls. CONCLUSIONS: Our findings reveal that BAP1 loss rewires mitochondrial phospholipid metabolism thus conferring CCA resistance to ferroptosis, identifying TLCD1 as a targetable metabolic vulnerability in BAP1-mutant CCA. Citation Format: Yu Zhao, Peyton Classon, Danielle Marie Carlson, Jayla Millender, Irene K. Yan, Sumera Ilyas, Rory L. Smoot, Gregory J. Gores, TUSHAR PATEL, Davide Povero. BAP1 loss confers ferroptosis resistance to cholangiocarcinoma via TLCD1-mediated membrane phospholipid remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2433.

Abstract Background: Prostate cancer (CaP) is among the most common cancers in U.S. men, with Black men experiencing a 1.7-fold higher incidence and nearly twice the mortality rate compared with non-Hispanic White men. While early detection has improved survival, differences remain in recovery and quality of life (QoL). Sexual dysfunction after treatment affects identity, relationships, and well-being, yet stigma, cultural norms, and limited access to patient-centered care prevent open discussion. Few initiatives address the intersection of identity, stigma, and survivorship in this population. Community town halls provide a trusted, culturally responsive space for shared learning, peer connection, and open dialogue on survivorship and sexual health. Methods: Two community-engaged CaP town halls were convened by the Multidisciplinary Health Outcomes Research and Economics (MORE) Lab at the University of Oklahoma Health Campus (OUHC) to explore survivorship issues among Black CaP survivors. The first, held virtually in June 2024, included watch parties in Georgia and Texas. The second, in November 2024, was hybrid, hosted at OUHC and via Teams with a watch party at the Willa D. Johnson Recreation Center, a community center in Oklahoma City. Panelists included oncologists, psychologists, survivors, partners, and Community Advisory Board members. Both town halls featured survivor storytelling, provider Q&A, and interactive discussion. Post-event surveys captured demographics, satisfaction, and impact. Open-discussion transcripts were analyzed using Braun and Clarke’s reflexive thematic analysis, guided by a constructivist framework. Results: A total of 124 participants attended both town halls. Survey respondents (n=17; 13.7%) provided demographic and satisfaction data; remaining insights came from all participants who engaged in open dialogue. Respondents ranged in age from 19-76 years (mean=48.7 ± 21.8). Of the 17 respondents, 93% rated the events as very good or excellent; 23.5% were CaP survivors, all identifying as Black. Five themes emerged: (1) Masculinity, stigma, and silence limit help-seeking; (2) Sexual dysfunction and identity loss cause major emotional burdens; (3) Navigation challenges highlight systemic barriers; (4) Spousal and psychological support aid coping; and (5) Survivorship empowerment. Participants valued hearing “real stories from real men,” validating their experiences. Conclusions: Community town halls are a feasible and culturally relevant strategy to engage Black CaP survivors in survivorship and sexual health discussions. By centering lived experiences and facilitating two-way communication between survivors, clinicians, and researchers, these events build trust and reduce stigma. Future work will assess changes in knowledge, engagement, and confidence in care navigation and explore scaling this community-academic model to improve survivorship QoL. Citation Format: Parisa Ghasemi, Gaurav Kumar, Ernest T. Kaninjing, Adanma Ayanambakkam, Yaw A. Nyame, Amy Siston, Jordan M. Neil, Adam C. Alexander, Andrew G. McIntosh, Yan Zhao, Zsolt Nagykaldi, Kathleen A. Dwyer, Mary Ellen Young, Sabrina Dickey, Daniel Morton, Opeyemi Bolajoko, Darla E. Kendzor, Motolani E. Ogunsanya. Survivorship and sexual health: What we learned from Black men in community town halls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2483.

Abstract Background: Cholangiocarcinoma (CCA) is a highly lethal epithelial cell malignancy of the hepatic biliary tract. Efficacy of current standard-of-care therapy is limited. Ferroptosis, an iron-catalyzed, caspase-independent cell death driven by phospholipid peroxidation, has emerged as a novel therapeutic target. Our goal is to develop a tumor-selective therapeutic approach targeting ferroptosis in CCA using siRNA-based nanotherapeutics. Materials & Methods: Milk-derived nanovesicles (lactosomes) coated with EpCAM aptamer and packaged with siRNA against Glutathione Peroxidase 4 (siGPX4-lactosomes) and Ferroptosis Suppressor Protein 1 (siFSP1-lactosomes), were used to induce ferroptosis in murine CCA cells (FAC) and in syngeneic liver orthotopic CCA-bearing mice. In vitro, lactosome uptake and efficacy were assessed by fluorescence-based, cell-viability and molecular biology assays. In vivo, target engagement, tissue distribution, safety and efficacy were assessed. Results: EpCAM (epithelial cell adhesion molecule expressed on CCA cells)-coated lactosomes showed robust uptake by FAC cells in a EpCAM-dependent manner. EpCAM knockdown via siRNA reduced lactosome uptake, confirming aptamer selectivity. Dose-dependent siGPX4/siFSP1-lactosome treatment led to GPX4/FSP1 knockdown and induced ferroptotic cell death in up to 60% of FAC cells after 72 hours (p<0.001 vs. siNC). In CCA-bearing mice, intravenous administration of siRNA lactosomes was well-tolerated with no liver or systemic toxicity observed and demonstrated robust tumor distribution compared to non-tumorous tissues. Efficacy studies demonstrated that siGPX4/siFSP1-lactosomes significantly reduced intratumor Gpx4 and FSP1 mRNA expression by 40-60% and induced significant upregulation of ferroptosis markers Ptgs2 and Acsl4 (p<0.01 vs. siNC). Ferroptosis in siRNA-lactosome treated tumors was confirmed by immunohistochemistry for phospholipid peroxidation markers oxPAPC and 4-HNE. Additionally, proliferation marker Ki67 was significantly downregulated in siGPX4/siFSP1-lactosome treated tumors (p<0.05 vs. siNC), indicating ferroptosis-mediated tumor suppression. Importantly, siGPX4/siFSP1-lactosomes reduced tumor burden and expression of CCA markers CK19/7 in treated mice, as compared to control mice. Conclusions: siRNA-based nanotherapeutics targeting CCA can effectively and safely induce ferroptosis in vitro and in vivo, representing a potential therapeutic strategy for CCA treatment. Citation Format: Peyton Classon, Danielle Marie Carlson, Jayla Millender, Irene Yan, Sumera Ilyas, Rory L. Smoot, TUSHAR PATEL, Gregory J. Gores, Davide Povero. Targeting cholangiocarcinoma with ferroptosis-inducing siRNA-based nanotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5664.

Abstract Background. Mitophagy plays a crucial role in removing dysfunctional mitochondria to maintain cellular homeostasis but also has been implicated in cancer tumorigenesis. Previously, we showed that genetic variation in mitophagy pathway genes holds a predictive value in metastatic CRC (mCRC) patients (pts) treated with bevacizumab-based chemotherapy. In this study, we analyzed the correlation between tumor expression profiles of genes associated with PINK1/Parkin and BNIP3/NIX/FUNDC1 mitophagy pathways with clinical outcome in a large phase III randomized clinical trial CALGB SWOG 80405. Method. We analyzed 433 pts with mCRC treated with first-line chemotherapy in combination with the targeted agents bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207). Tumor RNA isolated from FFPE samples was sequenced using the HiSeq 2500 platform (Illumina). Median Overall survival (mOS) and median progression-free survival (mPFS) were compared across pts groups divided into high, medium, and low tertiles based on mitophagy-related gene (BNIP3, BNIP3L, PINK1, PRKN) expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazards models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, Consensus Molecular Subtypes, and treatment arm. Results: Overall, BNIP3L demonstrated significant prognostic value for both PFS and OS after adjustment for multiple testing (false discovery rate [FDR] < 0.05). Tumors with low BNIP3L expression showed longer PFS and OS compared to those with medium or high expression levels (mPFS 14.8 vs. 10.0 vs. 9.2 months, HR 1.16, 95% CI 1.04 - 1.29p = 0.0182; mOS: 37.4 vs. 30.2 vs. 24.4 months, HR 1.22, 95% CI 1.09 - 1.38, p = 0.0036), independent of treatment. In pts treated with Cet, high PRKN expression was associated with improved PFS and OS (mPFS: 8.9 vs. 10.3 vs. 14.6 months, HR 0.79; 95% CI 0.69 - 0.91, p = 7.3e-05; mOS: 21.2 vs. 27.7 vs. 41.1 months, HR 0.87; 95% CI 0.75 - 1.01, p = 0.00084), whereas low PINK1 expression was significantly associated with longer OS (mOS: 24.9 vs. 30.9 vs. 39.2 months, HR 1.23; 95% CI 1.04 -1.46, p = 0.013). No significant associations were observed in Bev-treated patients for PRKN or PINK1. No significant results were found for BNIP3 expression analysis. Conclusion. Mitophagy is a crucial player in CRC biology due to its tumor-intrinsic (mitochondrial bioenergetics) and microenvironment (interacts with immune components) effects. Our study highlights the prognostic value of BNIP3L and predictive potential of PINK1 and PRKN, suggesting a potential combinatorial therapeutic approach using mitochondrial targeting drugs and targeted agents e.g Cet, which warrants further investigation. Support: Genentech; Clinicaltrials.gov Identifier: NCT00265850 Citation Format: Shivani Soni, Yan Yang, Michela Bartolini, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Steve Soto Trujillo, Yitzhar Goretsky, Wu Zhang, Alan P. Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Correlation of mitophagy related genes expression and clinical outcome in metastatic colorectal cancer patients enrolled in CALGB (Alliance)/SWOG 80405 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1011.

Abstract Background and Aims Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. Methods Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. Results Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P < .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P < .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2–9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. Conclusions Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

Abstract Background Robotic left pancreatectomy (RLP) is increasingly adopted worldwide. Current guidelines suggest a learning curve of 21 cases, yet its impact on major morbidity and oncological quality remains uncertain. Methods A retrospective multicentre international study was undertaken across 10 centres in the UK, Spain, Germany, the USA, and Australia (2014–2025). Consecutive patients undergoing RLP were categorised into competency (first 21 cases per centre) or proficiency phase (>21). The primary outcome was major morbidity (Clavien–Dindo grade ≥ IIIa), and secondary outcome was the R1-margin rate. Mixed-effects logistic regression and risk-adjusted cumulative sum (RA-CUSUM) analyses were performed. Results 521 patients underwent RLP, including 200 (38.4%) in the competency phase and 321 (61.6%) in the proficiency phase. Median age was 63 years (IQR 54–73), and 56.4% were female. Rates of major morbidity were similar between phases (14.5% versus 14.0%, P = 0.981), as were R1 margin rates (21.6% versus 19.7%, P = 0.092). Independent predictors of major morbidity included male sex (OR 1.76, P = 0.037), preoperative pancreatitis (OR 2.23, P = 0.031), and multivisceral resection (OR 2.29, P = 0.034). Among patients with adenocarcinoma (n = 110), prolonged operative time (OR 1.39 per hour, P = 0.004) and nodal positivity (OR 2.62, P = 0.047) predicted R1 resection, while learning phase was not associated with margin status. RA-CUSUM demonstrated no excess morbidity over time in any centre. Conclusions In this first multicentre international analysis, the learning phase of RLP did not increase the risk of major morbidity or compromise oncological quality. These findings support the safe global adoption of RLP with appropriate training and case selection.

ABSTRACT Cataract is a leading cause of visual impairment worldwide, and its prevalence is increasing with population aging. The majority are age‐related cataracts (ARC), clinically classified into nuclear, cortical, and posterior subcapsular cataracts (PSC) by opacity location. Mechanisms of cataractogenesis remain incompletely understood. While cortical and nuclear cataracts are largely attributed to crystallin aggregation, such protein‐centric mechanisms fail to explain the early onset and axial location of PSC. Morphologically, PSC resembles posterior capsule opacification (PCO), a secondary cataract driven by epithelial–mesenchymal transition (EMT) of lens epithelial cells (LECs), suggesting LEC‐EMT may also contribute to PSC. Using clinically stratified human lens samples, we confirmed EMT marker expression across PSC subtypes. Transcriptomic profiling revealed that LECs, the lens's sole metabolically active cells, in age‐related PSC (ARC‐PSC), compared with age‐related nuclear cataract (ANC) and clear lenses, exhibit elevated EMT signatures tightly linked to senescence‐associated inflammatory signaling. Aqueous humor (AqH) profiling demonstrated a pro‐inflammatory milieu across PSC subtypes, with IL‐17A uniquely elevated in ARC‐PSC, consistent with transcriptomic findings. Integrated analyses support a model in which senescence functions as an upstream driver, whereby senescent LECs release SASP factors, including IL‐17A, that activate NF‐κB signaling to amplify inflammation, reinforce senescence, and drive EMT. In vitro, senolysis and IL‐17A blockade disrupted this loop, attenuating senescence‐ and EMT‐associated phenotypes. Collectively, our study demonstrates that senescent LECs sustain an IL‐17A–NF‐κB circuit that drives EMT and accelerates ARC‐PSC progression, positioning ARC‐PSC as a unique human context to study senescence‐induced epithelial remodeling in aging tissues.

Abstract Purpose Although the Woven EndoBridge (WEB) device is increasingly used for the treatment of wide-neck intracranial aneurysms, including in the acute rupture setting, comparative evidence assessing the impact of rupture status remains limited. This study compared angiographic, safety, and clinical outcomes between ruptured and unruptured intracranial aneurysms treated with WEB. Methods We conducted a retrospective analysis of prospectively collected data from the multicenter cohort registry WorldWideWEB, including consecutive adult patients with intracranial aneurysms treated with the WEB. Patients were stratified into groups of ruptured and unruptured aneurysms. Propensity score matching was used to balance baseline characteristics between both groups. Retreatment rate was the primary outcome. Secondary outcomes included mRS, safety events (thromboembolic complications) and angiographic outcomes (periprocedurally and last follow-up). Results Among 1,220 patients, 342 (28.0%) presented with ruptured aneurysms. There was no significant difference in the rate of thromboembolic complications between groups (11.8% vs 5.9%, p = 0.056). At follow-up, adequate occlusion was lower (82.2% vs 93.3%, p < 0.002) and functional outcomes were worse (mRS ≥2 in 34.1% vs 21.9%, p = 0.012) among patients with ruptured aneurysms. Periprocedural adequate occlusion (53.3% vs 53.8%, p>0.9) and retreatment rates (11.8% vs 7.1%, p = 0.14) did not differ between groups after matching. Conclusion Ruptured aneurysms demonstrated expected inferior follow-up functional and angiographic outcomes when compared with unruptured aneurysms, but no difference in retreatment rate and procedural safety. These findings support WEB as a safe and effective treatment option for appropriately selected ruptured intracranial aneurysms in routine clinical practice.

ABSTRACT Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti‐apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B‐cell lymphoma (BCL)‐X L /BCL‐2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi‐naïve patients with myelofibrosis. JAKi‐naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate‐2 and high‐risk myelofibrosis, and ECOG 0–2) and platelet count > 100 × 10 9 /L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 10 9 /L or > 150 × 10 9 /L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR 35 ) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS 50 ) at week 24, change in grade of BMF, anemia response, and safety. Thirty‐two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow‐up was 44 months (5–58). 63% (20/32) of patients achieved SVR 35 at week 24; median (range) time to first SVR 35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS 50 at week 24; median (range) time to first TSS 50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion‐independent and 100% (2/2) for transfusion‐dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi‐naïve patients with myelofibrosis. Trial Registration NCT03222609.