Citations

Abstract Objectives Type B aortic dissection (TBAD) is rare in patients aged ≤30 years, and data on this population remain limited. This study aimed to characterize the underlying aetiology, and outcomes of invasively treated young patients with TBAD, with a focus on the impact of heritable thoracic aortic disease (HTAD). Methods A retrospective multicentre analysis was conducted across 19 international aortic centres, including 139 patients aged ≤30 years with TBAD. Patients with chronic TBAD (n = 42) were excluded for the final analysis. The cohort was classified as uncomplicated (n = 86) or complicated (n = 53) TBAD. Clinical, radiologic, intraoperative, and postoperative data were collected using standardized forms. Outcomes were compared between subgroups defined by TBAD complexity, HTAD status, and surgical strategy. Kaplan-Meier and Andersen-Gill analyses were used for survival and recurrent aortic intervention, respectively. Results Mean follow-up time was 6.5 years. HTAD was identified in 57% of patients. Most presented with uncomplicated TBAD (62%), while high-risk uncomplicated cases were uncommon. Endovascular repair was predominant in complicated TBAD, while open repair was more frequent in uncomplicated cases. Early mortality was low (n = 3), and mid-term survival was excellent across all subgroups. HTAD was a significant predictor of recurrent aortic interventions (HR = 3.3, P = .004). No significant differences were observed in survival or reintervention rates between uncomplicated and complicated TBAD or between operative strategies. Conclusions In young patients, TBAD predominantly occurs in the context of HTAD. Both open and endovascular repair are associated with excellent early outcomes and mid-term survival. However, HTAD remains a significant predictor of recurrent aortic interventions.

We report that moderate hyperoxia during a critical window of mucociliary differentiation disrupts terminal maturation in neonatal airway epithelial cells cultured in a three-dimensional model. Hyperoxia induces mitochondrial bioenergetic dysfunction and metabolic reprogramming, with proteomic analysis identifying complex I disruption as a key driver of impaired differentiation. Overall, these findings reveal a previously underrecognized link between mitochondrial bioenergetics and airway epithelial development, positioning metabolic dysfunction as an early trigger of hyperoxia-induced neonatal airway injury.

Abstract Introduction:A comprehensive integration of significantly mutated genes and pathways with molecular subgroups is lacking in adult B-ALL. Furthermore, the genomic drivers underlying each subgroup remain to be identified.We aimed to perform genomic analysis on a large cohort of patients with adult B-ALL, and to correlate genomic markers with achievement of MRD negativity enabling blinatumomab randomization, and with subsequent response to blinatumomab. Methods:For genomic analysis, we studied 569 adults with newly diagnosed B-ALL registered for initial screening on the ECOG-ACRIN-led E1910 trial (NCT02003222), which evaluated the addition of blinatumomab to standard consolidation chemotherapy. The median age was 52 yrs (range 30 to 71 yrs), with 52% males. Analysis was performed on tumor and matched-normal samples using whole transcriptome sequencing (RNA-seq; tumor only; n=569), whole exome sequencing (n=490), whole genome sequencing (n=131), and single nucleotide polymorphism array (n=445). B-ALL cases were classified into 22 molecular groups. Outcome analysis was limited to patients enrolled and treated on E1910 (n=319). Results: Driver genes (n=268) were identified by the mutation-significance detection tool dNdScv or by the presence of pathogenic variants in known cancer genes, with NUP188 identified as a novel driver gene. Recurrently mutated pathways included: B-cell development (46%), cell cycle (44%), epigenetic regulation (30%), other transcriptional regulation (27%), Ras signaling (25%), RNA machinery (17%) and JAK-STAT signaling (8%). A high frequency of high-risk subtypes was observed including BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A (12%). Using tSNE analysis, we identified a new cluster of cases (n=20, 3.5%) lacking a known subgroup driver, with overexpression of CEBPA (n=13) or CEBPB (n=7), distinct from CEBPE/ZEB2, termed “CEBP-altered” ALL (CEBPalt). Five of 13 cases with high CEBPA expression harbored an IGH::CEBPA rearrangement and one harbored a RXRA::CEBPA enhancer hijacking alteration. Of the 7 cases with high CEBPB expression, 5 harbored IGH::CEBPB, and two of these had concomitant clonal BCR::ABL1 fusions. To identify additional mechanisms of CEBP deregulation, in situ Hi-C coupled to H3K27 acetylation immunoprecipitation (HiChIP) was performed on 5 cases. Four cases showed evidence of de novo CEBPA enhancer activity. In two cases, we identified novel insertions (12 and 34nt) ~2kb downstream of CEBPA. A novel translocation and enhancer hijacking event between LINC00426 and the 5' UTR of CEBPB was identified in the remaining case. Overall, we confirmed genomic alterations of CEBPA or CEBPB in 16 of 20 cases with available material. Thus, we have identified a new molecular subgroup of adult B-ALL characterized by genomic alterations that drive enhancer hijacking and oncogenic deregulation of CEBPA/CEBPB. Several subgroups were enriched in patients that failed induction chemotherapy (n=62) or were MRD-positive (n=63) compared to those that achieved MRD-negative status (n=194): BCR::ABL1-like (30 vs 14%, p<0.001), KMT2A (18 vs 9%, p=0.03) and BCL2/MYC (5 vs 1%, p=0.06). Conversely, the following subgroups were enriched in patients that achieved MRD-negativity: PAX5alt (6 vs 18%, p=0.002), TCF3::PBX1 (0 vs 5%, p=0.01) and ZNF384 (2 vs 6%, p=0.08) Within each molecular subgroup we compared the survival of patients who achieved MRD-negative status after induction and were randomized to receive blinatumomab plus chemotherapy (n=93) or chemotherapy only (n=91). Although numbers were low, blinatumomab improved relapse-free survival for patients with hyperdiploid, PAX5alt, BCR::ABL1-like and KMT2A ALL compared to chemotherapy alone. Clonal hematopoiesis of indeterminate potential (CHIP)-related gene mutations were identified in 121 of 417 cases analyzed (29% total: somatic 74%, remission 31%, both 5%). TP53 mutations were most frequent (n=65 patients), with the majority identified in patients with low hypodiploid (n=52). Interestingly, patients with CRLF2 rearrangements collectively harbored the highest number of other CHIP gene mutations (n=13), including DNMT3A (n=4), TET2 (n=3) and ASXL1 (n=3). Conclusions:We provide a comprehensive landscape of genomic alterations in adult B-ALL and identify a new group characterized by deregulation of CEBPA/CEBPB (CEBPalt). We also provide insights into the efficacy of blinatumomab in different molecular subgroups of adult B-ALL.

Abstract Menin, encoded by the MEN1 gene, is a chromatin adaptor critical in AML through its role in the MLL complex. Inhibiting the Menin–MLL interaction promotes differentiation and reduces leukemia burden in MLL-rearranged and NPM1c AMLs, leading to the approval of Menin inhibitors by FDA. However, acquired resistance remains a challenge, highlighting the need to understand long-term effects. To understand the Menin inhibitors' effect in the long-term treatment, we firstly treated the MLL-r and NPM1c AML cell lines for long term and then withdraw the inhibitors to observe the potential recovery of cells. We found the cell growth inhibition and viability decrease were not sustained and proliferation resumed after the withdrawal of 18-30 days treatment of Menin inhibitor both in MLL-r and NPM1c cell lines and NPM1c primary AML cells. In parallel, differentiation cannot be maintained after Menin inhibitor withdrawal. Differentiation marker CD11b expression also gradually lost after 10-day of withdrawal. To determine whether these regrown cells develop resistance, we compared the regrown cells to untreated cells and found that there was no significant difference in IC50 of Menin inhibitors between the regrown and untreated cells, showing the cells regrown due to the reversibility of Menin inhibitors but not resistance. Furthermore, due to the heterogeneous differentiation induced by Menin inhibitors, we compare the effect of differentiation on the cell growth. After 24 days of treatment, CD11bhi and CD11blo cells were sorted after inhibitor removal, we could observe a significant slower cell growth in CD11bhi than CD11blo cells. We also found a CD11bhi group gradually lost the differentiation marker and revert the grow rate as CD11blo. This indicates that these cells underwent dedifferentiation, suggesting that Menin inhibitors alone induce only reversible differentiation. Interestingly, we found the regrown cells silenced HOX/MEIS1 genes permanently showing the HOXA/MEIS1 genes are not playing a role in the long-term treatment of Menin inhibitors. To enhance and stabilize differentiation, we conducted a CRISPR screen targeting chromatin regulators in MOLM13 and OCI-AML3 cells treated with Menin inhibitor or DMSO for 2 weeks. CD11bhi and CD11blo cells were sorted by FACS. Hits included members of the SAGA, LSD1/CoREST, MBD2 NuRD complex, ING5, non-canonical BAF, and MLL/Menin complexes. Knockdown of RCOR1, LSD1, MBD2, MEAF6, KAT6A, and KAT2A enhanced Menin inhibitor–induced differentiation and stabilized it after withdrawal for up to 20 days. We futher screened pharmacological inhibitors of these targets and found that LSD1, KAT6A, and MBD2 inhibitors enhanced differentiation. In particular, combining the experimental MBD2 inhibitor KCC07 with the Menin inhibitor Revumenib accelerated differentiation as early as day 3 (vs. day 7 with Revumenib alone). Long-term co-treatment stabilized differentiation, induced cell death, and suppressed proliferation, indicating chromatin modulation can lock in terminal differentiation, lead to cell death, and potentiate Menin inhibitor effects. RNA-seq of OCI-AML3 cells treated with DMSO, Reumenib, KCC07, or their combination showed that the MBD2/Menin combination inhibition significantly upregulated differentiated monocytes and neutrophils signatures while reducing immature neutrophil signature. GO analysis revealed strong activation of monocyte differentiation and repression of PI3K-AKT signaling. HOXA and MEIS1 expression were only modestly changed, showing the combination mostly enhanced diffrentiation gene programs but not self-renewal maintaining HOX/MEIS1 axis. ATAC-seq revealed globally increased chromatin accessibility in the MBD2/Menin combination inhibition group in comparison with Revumenib only treatment group, with enhanced peaks located predominantly in myeloid differentiation genes, suggesting the MBD2 inhibition also leads to derepression of differentiation related genes repressed by MBD2-NuRD complexes. Our study is the first to demonstrate the reversibility of Menin inhibitor–induced growth inhibition and differentiation. More importantly, we identified differentiation associated chromatin complex targeting (such as MBD2 inhibition) as a low-toxicity strategy that enhances and stabilizes Menin inhibitor–induced differentiation, offering a promising approach to overcome durability limitations in AML therapy.

Abstract Background: Intravenous (IV) isatuximab plus pomalidomide and dexamethasone (Isa-Pd) is approved for treatment in patients with relapsed/refractory multiple myeloma (RRMM) based on the ICARIA-MM study. Subcutaneous (SC) administration of Isa offers potential advantages such as shorter administration duration and greater patient comfort compared with IV routes. Isa SC via an on-body injector (OBI), an investigational wearable bolus injector, demonstrated safety and efficacy in a Phase 1b study in patients with RRMM. The IRAKLIA trial (NCT05405166) was the first Phase 3 trial evaluating the non-inferiority of Isa-Pd SC via an OBI vs Isa-Pd IV in patients with RRMM. Here, we report the findings of the IRAKLIA trial in the East Asian subgroup with RRMM. Methods: This global, multicenter, open-label study enrolledpatients aged ≥18 years with RRMM who had received ≥1 prior line of therapy (LOT) including lenalidomide and a proteasome inhibitor (PI). Patients were randomized 1:1 to Isa SC (1400 mg) or Isa IV (10 mg/kg) weekly in Cycle (C)1, then every 2 weeks in addition to P (4 mg orally daily, Day [D]1-21) and d (40 mg orally [20 mg if age ≥75 years] weekly). Treatment was administered in 4-week cycles and continued until disease progression, unacceptable toxicity, or patient withdrawal. Co-primary endpoints included overall response rate (ORR) and observed Isa concentration before dosing (Ctrough) at steady state (predose at C6D1). Key secondary endpoints included rate of very good partial response or better (≥VGPR), Ctroughlevel Cycle 2 Day 1 (C2D1), infusion reaction incidence, and patient satisfaction rate based on the patient experience and satisfaction questionnaire (PESQ) at C5D15. Results: The East Asian subgroup consisted of 105 patients from China (Mainland, n=82 and Taiwan, n=1) and Japan(n=22) (SC, n=50; IV, n=55). Baseline characteristics of the East Asian subgroup were generally balanced between the two arms and generally comparable to the overall global population (median age 62 years; median 2 prior LOT; 29.5% high-risk cytogenetics; 82.9% refractory to lenalidomide; 7.6% prior exposure to daratumumab). After a median of 13.0 months follow-up, ORR in the SC and IV arm was 74.0% and 70.9%, respectively (relative risk [95% CI] = 1.044 [0.815 – 1.335]). The mean (SD) of Ctroughat C6D1 was 502 (232) µg/mL for SC arm and 282 (123) µg/mL for IV arm. The geometric mean ratio (90% CI) comparing SC to IV for Ctrough at steady state was 1.756 (1.346 – 2.290). The ≥VGPR rates were 58.0% for SC and 50.9% for IV (relative risk [95% CI] = 1.139 [0.798 – 1.631]). The mean(SD) of C2D1 Ctroughlevel was 420 (161) µg/mL for the SC arm and 262 (111) µg/mL for IV arm. The geometric mean ratio (90% CI) comparing SC to IV for Ctrough at C2D1 was 1.673 (1.321 to 2.120). The infusion reaction incidence was 0% and 21.8% for SC and IV, respectively. Grade ≥3treatment-emergent adverse events were observed in 82.0% and 87.3% of patients in the SC and IV arms, respectively. Treatment discontinuation rates were 6% for the SC arm and 12.7% for the IV arm. Injection site reactions (ISRs) occurred in 4% (2/50) of patients in the SC arm and in 0.21% (2/964) of SC injections (all Grade 1), with 99.3% of SC injections completed successfully. Isa SC patients expressed higher satisfaction with their injection method, with 64.0% of patients reporting “satisfied” or “very satisfied” vs 52.7% of Isa IV patients (odds ratio [95% CI] = 1.594 [0.728 – 3.489]). Conclusions: The efficacy, safety and pharmacokinetic results between Isa SC vs IV + Pd in the East Asian population from the IRAKLIA study were consistent with the results of the overall global population, in which non-inferiority of ORR, Ctrough at C6D1, ≥VGPR and Ctrough at C2D1 was demonstrated and statistically significantly fewer infusion reactions and higher patient satisfaction were also noted for SC vs IV. These results support the potential use of Isa SC delivered via OBI in East Asian patients and demonstrate the potential of this delivery method to improve patient experience and practice efficiency.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and glioblastoma (GBM). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent GBM and NSCLC. After determining the maximum tolerated dose, adults with recurrent GBM were treated in two expansion cohorts: (a) non-surgical cohort (6/12 patients thus far): EGFRvIII mutation, first recurrence; food-effect study included (b) surgical cohort (6/6 patients), any EGFR mutation, any recurrence; window-of-opportunity study (WOO) included. Among these 12 patients, median age = 60 years; 50% female; 58% ECOG 0). All patients received prior radiation and temozolomide. After the WOO or food-effect study, patients were dosed at 120 mg BID (5 days on, 2 days off), and escalated to 160 mg BID (5 days on, 2 days off) based on tolerability. Common adverse events (>40%) are comparable to other EGFR inhibitors (acneiform rash, diarrhea, fatigue, xerosis, pruritis). Treatment-related grade 3+ adverse events were limited to lymphopenia (n = 1). WSD0922-Fu exposure in the fed state exceeded the fasted state (median plasma Cmax and AUC0-24h are 1.6x and 1.3x, respectively) with a delayed Tmax (6.0 vs 1.8 hours). For the WOO, time between last dose administered to tumor collection ranged between 4 - 13.5 hours. Median tumor WSD0922-Fu concentration was 0.76 µg/g; estimated median unbound tumor concentration was 24.9 ng/g and within expectations for pharmacodynamic effect. Median brain/plasma ratio = 0.59; median unbound brain/unbound plasma = 0.88. Enrollment to the non-surgical cohort is ongoing, so formal efficacy data remain immature. However, examples of clinical efficacy will be shown along with data on recurrence patterns. Phase 2 clinical trial development is in progress.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Abstract Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. “Steady,” marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. “Proliferative” shows high proliferation markers, TP53 mutations, and gene fusions. “Chaotic,” with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. Significance: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423

Abstract Failure to repair radiation (RT)-induced DNA damage results in cell lethality, and combined treatment with DNA repair inhibitors can markedly enhance tumor control achieved with radiation. These inhibitors also can potentiate acute RT toxicities by suppressing DNA repair. Capitalizing on this normal tissue radiosensitizing effect, we determined effective radiosensitizing dosing regimens in mice for the ATM inhibitor WSD0628 and the DNAPK inhibitor WNC0901 in mice. Drugs were administered via oral gavage prior to each RT dose, and RT was delivered using an anterior/posterior 225 kVp beam. In an initial iteration of this model, various combinations of WSD0628 and RT were administered to cohorts of mice (n=5/group) and body weight was followed for 2 weeks. The resulting data were modeled to define the total dose of radiation estimated to cause 50% of mice to lose >20% body weight (D50). There was an inverse relationship between the WSD0628 and D50 doses: 0 mg/kg WSD0628/24.0 Gy (95% confidence interval (CI) 24.5–24.7); 0.25 mg/kg/19.2 Gy (95% CI 16.7–21.8); 1 mg/kg/13.7 Gy (95% CI 13.2–14.2); 2.5 mg/kg/11.0 Gy (95% CI 10.5–11.5); 5 mg/kg/11.3 Gy (95% CI 6.7–15.9) and 7.5 mg/kg/7.8 Gy (95% CI 7.8–7.9). Histological review of tongues from animals treated with 15 Gy RT (5Gy x 3) + 7.5 mg/kg WSD0628 demonstrated epithelial denudation and acute inflammation consistent with oral mucositis, while these features were not seen with the same dose as RT alone. Similar WSD0628 doses were evaluated in combination with 8 Gy supratentorial RT (via lateral beams) in orthotopic GBM43 PDX tumors. By treatment arm, the median time to a moribund state was: sham (29 days (d)), RT (39d), 1 mg/kg (42d), 2.5 mg/kg (49d), 5 mg/kg (65d), and 10 mg/kg (123d, overall p<0.0001). A second mucositis model was used for evaluation of WNC0901. Cohorts of 5 mice/group were treated with a set dose of RT (4Gy x 3) to the oral cavity alone and in combination with various doses of WNC0901, and the fraction of mice with >20% weight loss within 2 weeks was determined. The results of this study are as follows: placebo (0 of 5 mice with >20% weight loss); 15 mg/kg (3 of 5 mice); 25, 50, or 100 mg/kg (5 of 5 mice). Based on these data, we defined 25 mg/kg WNC0901 as the minimally effective dose and predicted that 50 mg/kg would provide robust radiosensitization. Consistent with this prediction, co-treatment of B16 melanoma flank tumor xenografts with RT (8Gy x 1) and WNC0901 (50 mg/kg) more than doubled the median tumor control duration (median 42 [range 24-45] days; time from implantation for tumor to exceed 1500 mm3) as compared to RT alone (24 [13-30] days) or sham treatment (17 [13-17] days; overall p<0.0001). This study describes how a radiation-induced oral mucositis model can be used to identify effective radiosensitizing regimens faster and with fewer resources than relying on tumor control studies alone. Citation Format: Danielle Burgenske, Darwin Garcia, Jiayan Le, Wenjuan Zhang, Sneha Rathi, Katrina K. Bakken, Lauren L. Ott, Zeng Hu, Brett L. Carlson, Ann Mladek, Jessica L. Abraham, Paul A. Decker, Matthew L . Kosel, Jeanette E. Eckel-Passow, William F. Elmquist, Wei Zhong, Jann N. Sarkaria. Radiation-induced oral mucositis to rapidly determine effective radiosensitizing dosing regimens for ATM and DNAPK inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B090.

Metastatic castration-resistant prostate cancer (mCRPC) progresses aggressively and resists existing therapies. Although poly(ADP-ribose) polymerase inhibitors (PARPis) benefit a subset of patients with mCRPC and BRCA1/2 deficiencies, therapeutic options remain limited for those without such mutations. Here, we uncover a critical role for the ATM-TRMT10A-BRCA1 signaling axis in regulating homologous recombination (HR) repair and PARPi sensitivity. We demonstrate that ATM phosphorylates TRMT10A at serine-28 after DNA damage, promoting BRCA1 recruitment and efficient HR repair. TRMT10A deletion disrupts HR repair, sensitizing cells to PARPis. Moreover, TRMT10A is up-regulated in mCRPC through stabilization by USP10. Targeting USP10 with spautin-1 induces TRMT10A degradation and enhances tumor sensitivity to PARPis in cell-derived xenografts and patient-derived xenograft models. These findings identify TRMT10A as a therapeutic vulnerability in mCRPC and demonstrate that combined inhibition of PARP and USP10 offers a promising synthetic lethal strategy for a broader group of patients lacking classical BRCA mutations.