Citations

Abstract Background and Aims Upadacitinib (UPA)—an oral, reversible selective Janus kinase inhibitor—has a favorable benefit–risk profile for patients with Crohn’s disease (CD) and ulcerative colitis (UC). We evaluated the benefit–risk of UPA in select subgroups with CD or UC. Methods Patients were randomized to UPA 45 mg (UPA45) once daily (QD) or placebo (PBO) induction for 12 (CD: U-EXCEED, U-EXCEL) or 8 weeks (UC: U-ACHIEVE, U-ACCOMPLISH). Clinical responders were re-randomized to QD UPA 15 mg (UPA15), UPA 30 mg (UPA30), or PBO for 52-week maintenance (CD: U-ENDURE; UC: U-ACHIEVE). This exploratory post hoc analysis assessed efficacy and safety outcomes (adverse events of special interest [AESIs]: serious infections, major adverse cardiovascular [CV] events, malignancies, and venous thromboembolic events) by CV risk, prior treatment failure, and age. Results This analysis included 1021 patients with CD and 1097 with UC during induction, and 673 with CD and 746 with UC during maintenance. Improved efficacy outcomes comparable to the overall study populations were observed with UPA versus PBO across subgroups. Patients receiving UPA30 generally showed numerically higher rates of improvements versus UPA15. AESI rates were generally comparable between UPA and PBO across subgroups except for numerically higher rates of herpes zoster and serious infections in CD with UPA. Conclusions UPA resulted in consistent benefit versus placebo across CV risk, prior treatment failure, and age subgroups. No treatment differences were seen in AESIs across subgroups except herpes zoster and serious infections, reinforcing the favorable benefit–risk profile for UPA in CD and UC seen in the overall study populations. Clinical trial numbers NCT02819635, NCT03653026, NCT03345836, NCT03345849, NCT03345823

Abstract Glioma stem cells (GSCs) are key drivers of glioblastoma (GBM) progression, therapy resistance, and recurrence, making them critical therapeutic targets. While the lineage-defining transcription factor OLIG2 is critical for GSC maintenance, the molecular co-regulators and downstream pathways it engages remain poorly defined. Here, we identify a previously unrecognized, functionally significant interaction between OLIG2 and STAT5B, uncovering a novel regulatory axis in GSCs. Using proximity ligation assay (PLA), we demonstrate that OLIG2 interacts with STAT5 in human and mouse GSC models, particularly in EGFRvIII-mutant cells. We find that OLIG2 preferentially partners with STAT5B and not STAT5A. Knockdown studies in GSCs reveal that OLIG2 and STAT5B co-regulate critical oncogenes BIRC5 and NUSAP1, both of which are required for sphere formation and migration capacity of EGFRvIII positive GSCs. In orthotopic xenograft models, knockdown of either STAT5B or OLIG2 significantly prolongs survival reduces expression of stemness and invasion markers, SOX2, VIMENTIN, and NUSAP1. In contrast, STAT5A knockdown fails to recapitulate these phenotypes, underscoring the role of OLIG2-STAT5B signaling in GSCs. These findings reveal a novel OLIG2-STAT5B transcriptional circuit that plays a role in GSC stemness maintenance, invasion, and tumor growth, particularly in EGFRvIII-driven gliomas. Targeting this axis may offer a new avenue for GBM treatment.

Abstract IDH-wildtype glioblastoma (GBM) is the most malignant primary adult brain tumor, with a five-year survival rate below 5%. Despite maximal treatment, including surgical resection, radiotherapy, and temozolomide (TMZ), recurrence is universal, driven by profound intratumoral heterogeneity, diffuse invasion, and therapy resistance. A hallmark of IDH-wildtype GBM is frequent alteration of epidermal growth factor receptor (EGFR), including amplification (50%), the EGFRvIII deletion variant (25%), and extracellular missense mutations such as G598V and A289V (10–15%). These missense mutations increase ligand affinity and receptor activity, yet their downstream signaling consequences and role in shaping the tumor phenotypes remain poorly defined. Recent pathway-based subclassifications identified four subtypes in IDH-wildtype GBM. Notably, neuronal (NEU) and glycolytic/plurimetabolic (GPM) subtypes predominate the invasive tumor margins. NEU programs are enriched in synaptic and neurodifferentiation signals, while GPM programs are associated with metabolic adaptation, angiogenesis, and immune evasion. Here, we show EGFR-G598V and EGFR-A289V mutations differentially regulate these invasive subtypes identities. Transcriptional analysis reveals EGFR G598V upregulates metabolic and inflammatory pathways consistent with the GPM phenotype, while EGFR A289V activates genes involved in neuronal differentiation and synaptic function, aligning with the NEU subtype. Phosphoproteomics and kinase-substrate analysis further uncovered distinct kinases to be functionally activated/inhibited in EGFR A289V-expressing cells and G598V cells. Mechanistic studies revealed EGFR A289V induces sustained EGFR phosphorylation at Y992, activating PLCγ2 via the SRC-family kinase LCK. This cascade drives calcium release, CAMK1 activation, and STAT5 phosphorylation, defining a novel EGFR A289V–LCK/PLCγ2/CAMK1/STAT5 axis. In addition, Y1068 phosphorylation is also constitutively active in EGFR A289V, resulting in increased BRAF activation. In contrast, EGFR G598V activates MAPK6 and CAMK2 inducing AKT2 activation, reinforcing GPM-associated signaling. These findings uncover mutation-specific signaling networks that drive subtype fate in invasive GBM and highlight unique pathway(s) as tractable targets for subtype-directed therapy in EGFR-mutant GBM.

Abstract Importance and Objective Upadacitinib, an oral, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe Crohn’s disease (CD). Limiting corticosteroid exposure is an important goal in treating CD. This posthoc analysis evaluated the corticosteroid-sparing effects of upadacitinib in patients with CD. Design and Setting This study included pooled data from two phase 3, multicenter, double-blind induction trials and one maintenance trial. Randomization was stratified by corticosteroid use at induction baseline, with a mandatory corticosteroid taper starting at induction week 4. Efficacy was evaluated by baseline corticosteroid use and by achieving corticosteroid-free outcomes through year 2 of maintenance therapy. Safety was also assessed. Results At baseline, 34.7% (234/674) and 35.7% (124/347) of upadacitinib 45 mg and placebo-treated patients were taking corticosteroids, respectively. At induction week 12 and maintenance week 52, higher rates of upadacitinib-treated patients were corticosteroid-free among all patients and among patients with baseline corticosteroid use compared with placebo; upadacitinib-treated patients achieved higher rates of corticosteroid-free outcomes, compared with placebo, including corticosteroid-free clinical remission (stool frequency/abdominal pain score [SF/APS]: 42.7% vs 16.1%; CD activity index [CDAI]: 41.2% vs 23.4%) and corticosteroid-free endoscopic response (37.0% vs 8.1%), with similar results observed among responders to upadacitinib induction therapy at maintenance week 52. Corticosteroid-free outcomes were sustained through year 2 of maintenance therapy. The safety profile was similar to the overall population, with no new safety risks identified. Conclusions and Relevance The results from pivotal studies demonstrated that upadacitinib effectively induced early and sustainable corticosteroid-free clinical remission with a manageable safety profile in patients with moderate-to-severe CD. Clinical trial identifiers U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.

Abstract Background and Aims Intestinal ultrasound (IUS) is increasingly used to monitor treatment efficacy in inflammatory bowel disease (IBD) trials. However, standardized definitions for response, remission, and optimal assessment timing remain undefined. An international expert consensus meeting was held to establish IUS endpoints for clinical trials. Methods A panel of 35 international gastroenterologists and radiologists participated in a modified Delphi process, reviewing the literature and developing consensus statements. Agreement was defined as at least 75% consensus. Results Consensus was reached on 150 statements across four domains: general IBD (30 statements), luminal Crohn’s disease (CD) (43), perianal CD (51), and ulcerative colitis (UC) (26). For luminal CD and UC, ultrasound response was defined by: (1) a ≥25% reduction in bowel wall thickness (BWT) from baseline, or (2) multifactorial improvement, combining BWT reduction with ≥1 grade decrease in color Doppler signal (CDS) or another IUS parameter. Assessments were set at weeks 4-8 for the colon and week 12 for the terminal ileum. Ultrasound remission in luminal CD was defined as: (1) BWT normalization (≤3 mm) or (2) normalization of multiple parameters, including BWT, CDS, and all other IUS parameters. Similar remission criteria were proposed for UC, but the sigmoid BWT normal range (3-4 mm) remained uncertain. The bowel ultrasound score (BUSS) for CD and the Milan ultrasound criteria (MUC) for UC were supported as standardized scoring systems for trials. Conclusion This consensus provides standardized IUS definitions to enhance consistency in IBD trials, supporting the integration of IUS in future research.

Abstract Background and Aims The long-term efficacy and safety of upadacitinib in patients with moderate to severe Crohn’s disease (CD) were evaluated in the U-ENDURE Long-Term Extension (LTE) study. Here we report the results after 2 years of total maintenance treatment. Methods U-ENDURE is an ongoing 240-week LTE study conducted at 243 sites across 43 countries (first patient enrolled in LTE 21 March 2019). Patients who completed the 52-week maintenance study continued their previously assigned treatment, once-daily upadacitinib 15 mg or upadacitinib 30 mg. Efficacy was analyzed at week 48 of the LTE; safety was analyzed in the cumulative study population (combined 52 week maintenance and 48 week LTE) and the LTE study population only (cutoff date: 19 December 2023). Results From LTE week 0 to week 48, as-observed efficacy rates for clinical remission (per stool frequency/abdominal pain score, upadacitinib 15 mg: 78.3% to 82.9%; upadacitinib 30 mg: 84.7% to 76.6%; per CD Activity Index, upadacitinib 15 mg: 81.3% to 83.1%; upadacitinib 30 mg: 86.1% to 86.8%), endoscopic response (upadacitinib 15 mg: 59.6% to 67.1%; upadacitinib 30 mg: 71.2% to 69.6%), inflammatory biomarkers, and quality-of-life outcomes remained stable. The safety profile of the cumulative maintenance population observed through LTE week 48 was consistent with previous trials in the upadacitinib CD program. Treatment-emergent adverse event rates for the cumulative maintenance population were 283.1 and 273.4 events/100 patient-years for upadacitinib 15 mg and upadacitinib 30 mg, respectively. Event rates of serious treatment-­emergent adverse events were 16.0 events/100 patient-years for upadacitinib 15 mg and 14.6 events/100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest (≥ 5.0 events/100 patient-years) were hepatic disorder, lymphopenia, creatine phosphokinase elevation, herpes zoster, and anemia. There was 1 treatment-emergent adverse event of suicide leading to death. Conclusion Sustained clinical, endoscopic, quality-of-life, and biomarker outcomes were observed in patients who were initial responders to upadacitinib and completed 2 years of maintenance therapy, with no new safety signals identified. Clinical trial identifier U-ENDURE; ClinicalTrials.gov number, NCT03345823.