Citations

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

Abstract Background Oligodendrogliomas were previously defined by histology, but since 2016, the WHO has integrated molecular signatures to create the entity of IDH-mutant 1p/19q-codeleted oligodendroglioma. These tumors harbor recurrent genetic alterations—including IDH mutations, CIC and FUBP1 loss-of-function mutations, and PI3K-activating mutations—that collectively define a genetic profile distinct from IDH-mutant astrocytoma and IDH wild-type glioblastoma. The paucity of faithful model systems has impeded progress in advancing mechanistic insights and therapeutic development for oligodendroglioma. Results To test whether recurrent mutations found in oligodendroglioma patients would drive tumor formation in mice, we utilized in utero electroporation to introduce combinations of gain- and loss-of-function mutations into the developing cortex. Initial tests that included expression of IDH-and PIK3CA-mutants with Cic and Fubp1 loss (termed Oligo) were non-tumorigenic but biased cells towards glial lineages. Introducing Cdkn2a-loss, which is normally suppressed by IDH-associated epigenetic changes in human tumors, to the Oligo combination (termed Oligo-Cdkn2a) resulted in fully penetrant tumor formation. Histopathological review showed the Oligo Cdkn2a-loss mouse model resembled grade II/III oligodendroglioma with rounded nuclei and open chromatin. If Trp53-loss is used (termed Oligo-Trp53) in place of Cdkn2a-loss, tumor histology shifts to a more astrocytic phenotype with angulated nuclei with denser chromatin, demonstrating a direct impact of Trp53-loss on histological features. Bulk RNA-sequencing verifies metabolic alterations driven by the presence of IDH-mutations in Oligo-Cdkn2a mouse models compared to an IDH wild-type GBM model. Single-cell transcriptional profiling shows that Oligo-Cdkn2a tumors contain an increased population of tumor cells that resemble more differentiated oligodendrocytes. Examination of the tumor immune microenvironment within Oligo-Cdkn2a and IDHWT GBM mouse models is being performed to determine changes in immune cell infiltration and transcriptional programs. Conclusion We have created, to our knowledge, the first murine model of IDH-mutant 1p/19q-codeleted oligodendroglioma that incorporates Cic loss. This immune-competent mouse model of IDH-mutant 1p/19q-codeleted oligodendroglioma offers a powerful new tool for interrogating tumor biology and evaluating preclinical therapeutic strategies.

Abstract Pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine glioma (DIPG), are among the most aggressive childhood brain tumors, with five-year survival rates below 10%. Current treatment options are limited to radiation, highlighting the urgent need for novel therapies. Telomere maintenance via telomerase activation is a hallmark of cancer, enabling replicative immortality. Our prior studies demonstrate telomerase activity in 73% of HGGs and 47% of DIPG, implicating telomere biology as a critical therapeutic target. 6-thio-dG (THIO) is a first-in-class telomere-targeting agent that incorporates into telomeres of telomerase-positive cells, inducing telomere uncapping, genomic instability, and apoptosis. THIO crosses the blood–brain barrier and exhibits synergy with radiation in preclinical DIPG models. Telomere dysfunction is confirmed by telomere dysfunction-induced foci (TIFs), marked by colocalization of DNA damage response proteins (ATM S1981-P, γH2AX, 53BP1) at telomeres. Historical pediatric leukemia trials established THIO’s safety profile, and recent adult studies in non-small cell lung cancer demonstrated efficacy at lower doses. As part of the biologically-guided umbrella trial CONNECT TarGeT [NCT05839379], we are developing TarGeT-H, a phase 1/2 and surgical study to evaluate THIO combined with focal radiation in pediatric, adolescent, and young adult patients with newly diagnosed HGG or DIPG harboring telomerase activation, confirmed by hTERT mRNA expression—assessed via tumor submission, profiling, and rapid central screening through TarGeT-SCR. Specific aims include: (1) determining pharmacokinetics and safety to establish the recommended Phase 2 dose (RP2D); (2) estimating efficacy by progression-free survival (HGG) and overall survival (DIPG) compared to historical controls; and (3) assessing telomere dysfunction in resected HGG tumors via TIF analysis. Up to 90 patients will receive THIO intravenously during radiation and maintenance cycles for up to two years. By leveraging a selective telomere-targeting mechanism distinct from current therapies and demonstrating synergy with radiation, THIO represents a promising strategy to improve outcomes in devastating pediatric cancers.

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance.

Abstract Background and Objectives Cholangiocarcinoma (CCA) is an aggressive, highly lethal cancer of the biliary tract epithelium for which tumor resection is the only curative treatment. However, approximately half of patients present with nonresectable disease and median survival of these patients is just 8-12 months. A significant need exists for tumor-targeted therapeutics for patients with advanced disease who currently have limited treatment options. We aimed to address this need by developing an aptamer-targeted therapy for delivery of siRNAs inhibiting undruggable components of the Hippo pathway, a key driver of cholangiocarcinoma. Method We applied cell-SELEX against human CCA model cell line HuCCTl with negative selection against normal hepatocytes and cholangiocytes to identify an aptamer that selectively bound tumor cells. This aptamer, termed MC7122, was chemically modified to include fluorescent labels that enabled whole-animal biodistribution studies to assess in vivo selectivity. MC7122 was then deployed onto the surface of siRNA-loaded nanovesicles to drive tumor-targeted nucleic acid delivery. Tumor-bearing mice were treated with siRNAs three times per week for two weeks alone or in combination with standard of care chemotherapy. Results Combined treatment with siRNAs and standard of care chemotherapy reduced tumor burden in mice versus vehicle controls and slowed the spread of metastasis. Importantly, we found tumor-specific target gene knockdown without corresponding off-target knockdown in healthy surrounding liver tissue. Further, we demonstrated that sites in the lung, the primary location of metastasis in this model, were reduced not because of global target knockdown in lung but due to tumor-specific knockdown at the site of liver implantation. Conclusions Aptamer-guided vesicles represent a promising platform for targeted therapy delivery for previously undruggable targets. With this platform, tumor-selective therapies can be designed to exhibit exceptionally potent cytotoxicity, as healthy tissues remain unaffected by off-target effects. Future work will focus on refinement of therapeutic siRNA target selection and modification of nanovesicle components for enhanced levels of tumor specificity.

Abstract Rationale Seralutinib is an investigational, first-in-class tyrosine kinase inhibitor designed for inhalation and selective for PDGFRα, PDGFRβ, CSF1R, and cKIT, targeting proliferation, inflammation, and fibrosis ─ three core drivers of pulmonary vascular remodeling in PAH. The phase 2 TORREY trial of seralutinib added to standard-of-care treatment in adults with PAH WHO FC II or III met its primary endpoint of a statistically significant reduction in pulmonary vascular resistance (PVR) vs. placebo at 24 weeks. Methods PROSERA (NCT05934526), a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluated the efficacy and safety of inhaled seralutinib in PAH patients treated for up to 48 weeks. Eligible patients (WHO Group 1 PH, FC II or III; REVEAL Lite 2 Risk Score ≥5 or NT-proBNP ≥300 ng/L or PVR ≥800 dyne•s/cm5) on standard background therapy were randomized 1:1 to seralutinib 90 mg or placebo delivered by dry powder inhaler twice daily. The primary endpoint was change in six-minute walk distance (6MWD) from baseline to week 24 in the seralutinib treatment group vs. placebo. Key secondary endpoints included: time to clinical worsening (TTCW), proportion of patients with clinical improvement at week 24, change in NT-proBNP from baseline to week 24, and proportion of patients with ≥1-point decrease from baseline in REVEAL Lite 2 Risk Score at week 24. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs). Patients who completed blinded treatment could be eligible to participate in an open-label extension study. Preliminary Blinded Results 390 patients were randomized at 132 sites worldwide. At baseline, mean age was 50.0 years. PAH etiologies included 61.0% idiopathic, 9.7% heritable, and 22.3% associated with connective tissue disease. 25.6% of patients were WHO FC II and 74.4% FC III. Mean time from diagnosis was TBD years. Most patients were receiving 2 (39.2%) or ≥ 3 (54.6%) PAH medications, 29.2% were receiving parenteral prostacyclin. Baseline PVR was 798.4 dyne•s/cm5, 6MWD was 373.7 m, and NT-proBNP was 986.8 ng/L. The difference in 6MWD from baseline to week 24 between seralutinib and placebo was TBD [SD] m (p=TBD). Secondary endpoints of TTCW, clinical improvement, NT-proBNP, and REVEAL Lite 2 Risk Score will be reported. The most common AEs were TBD (x%) and TBD (y%). SAEs and discontinuations related to AE will be reported. Conclusions The PROSERA study demonstrates⋯ [to be updated following unblinding of the data]. Funding Gossamer Bio, Inc. This abstract is funded by: Gossamer Bio, Inc.

Abstract The Tau Global Conference 2025, hosted by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation, convened international experts from academia, industry, government, and philanthropy to explore advances and challenges in tauopathy research. The meeting highlighted progress across tau biology, including emerging models of tau regulation, degradation, and propagation; advances in biomarker development for the diagnosis and staging of tauopathies; and evolving therapeutic strategies targeting diverse aspects of tau pathophysiology. Discussions also emphasized the importance of cross‐sector collaboration, and global initiatives to address disparities in tau research. This report synthesizes key insights from the conference and underscores the critical role of interdisciplinary, biomarker‐driven, and globally inclusive approaches in accelerating the translation of tau research into effective clinical applications.

ABSTRACT Background Men with castration‐resistant prostate cancer (CRPC) who have a pre‐existing history of cardiovascular disease (CVD) or other comorbidities are often excluded from clinical trials involving oral androgen receptor pathway inhibitors (ARPi). In this study, we compared all‐cause and prostate cancer‐specific mortality among CRPC patients, with and without a pre‐existing history of CVD, receiving ARPi compared to chemotherapy. Methods Men with CRPC were identified using the Surveillance, Epidemiology, and End Results‐Medicare Linked Database from 2004 to 2015. Patients were grouped into two analytical cohorts by drug use. Inverse probability treatment weights (IPTW)‐adjusted Cox models and Fine‐Gray subdistribution hazards models were used to evaluate associations between ARPi and chemotherapy, and between ENZ and AA for all‐cause mortality and cancer‐specific mortality separately. Results The study cohort included 1438 men with CRPC. Nearly 54.4% of patients had a pre‐existing history of CVD. Patients with a pre‐existing history of CVD had a higher incidence of all‐cause and prostate cancer‐specific mortality compared to patients without a history of CVD (all‐cause mortality: 69.7% vs. 59.3%, prostate cancer‐specific mortality: 56.0% vs. 49.5%, respectively). In the pre‐existing history of CVD cohort, the IPTW‐adjusted Cox model showed a significantly lower all‐cause mortality in patients who received APRi, enzalutamide, and abiraterone, versus chemotherapy (IPTW‐adjusted hazard ratio [AHR], 0.56; 95% Confidence Interval [CI], 0.48–0.64; p ‐value < 0.001). Further, the IPTW‐adjusted competing risk model showed significantly lower prostate cancer‐specific mortality in patients who received ARPi compared with those who received chemotherapy (IPTW‐AHR, 0.48; 95% CI, 0.41 to 0.57; p ‐value < 0.001). In the without pre‐existing history of CVD cohort, the adjusted Cox model showed significantly lower all‐cause mortality in patients who received APRi than those who received chemotherapy (IPTW‐AHR, 0.49; 95% CI, 0.41–0.60; p ‐value < 0.001). Whereas the IPTW‐adjusted competing risk model showed significantly lower prostate cancer‐specific mortality in patients who received ARPi compared with those who received chemotherapy (IPTW‐AHR, 0.52; 95% CI, 0.42–0.64; p ‐value < 0.001). Conclusion In this population‐based cohort of older men with castration‐resistant prostate cancer, treatment with oral androgen receptor pathway inhibitors was associated with lower estimated risks of all‐cause and prostate cancer–specific mortality compared with chemotherapy in patients with and without pre‐existing CVD. These findings add real‐world comparative effectiveness evidence for patient populations not well represented in randomized clinical trials; however, given the observational design and limitations of administrative data, residual confounding and unmeasured clinical differences may have influenced the results.

Background: Pediatric tibial fractures are common long-bone injuries, yet uncertainty remains in the optimal immobilization strategy. The comparative effectiveness and safety of short leg versus long leg casts in achieving stable healing and functional recovery have not been clearly established. Methods: A literature search was conducted across Medline, CINAHL, Embase, and Cochrane Library, from inception to August 2025, following PRISMA guidelines and registered with the International Prospective Register of Systematic Reviews (PROSPERO). Statistical analyses were performed using a random-effects model. Results: The initial search yielded 1236 studies; 6 studies with 413 pediatric patients met the inclusion criteria. A total of 163 underwent short leg casting (SLC) and 250 long leg casting (LLC). No differences were observed between SLC and LLC for coronal angulation (MD=0.12 degrees, 95% CI=−0.89 to 1.12, I 2 =58%) or sagittal angulation (MD=0.18 degrees, 95% CI=−0.71 to 1.07, I 2 =56%). Subgroup analyses showed no differences for tibial shaft fractures or Salter-Harris distal tibial fractures. Cast duration was similar between groups (MD=−0.74 wk, 95% CI=−1.49 to 0.01, I 2 =92%). Overall complication rates did not differ (OR=0.76, 95% CI=0.25 to 2.34, I 2 =0%), with no differences in Salter-Harris subgroup analysis (OR=0.67, 95% CI=0.05 to 9.91; I 2 =54%). SLC was associated with shorter time to weight-bearing (MD=−2.29, 95% CI=−4.49 to −0.08, I 2 =68%) and faster time to union (MD=−1.21, 95% CI=−2.16 to −0.25, I 2 =30%). Conclusion: SLCs may be considered as an alternative to LLCs in pediatric tibial shaft and distal tibial physeal fractures based on currently available retrospective comparative evidence. However, the evidence is limited by the retrospective design, clinical heterogeneity, and risk of confounding. Further prospective comparative studies are needed to define optimal indications for SLC use in this population. Level of Evidence: Level III, systematic review and meta-analysis of retrospective comparative studies.

Abstract Multiple myeloma (MM) is a heterogenous cancer that remains mostly incurable. A unifying feature of MM cells is a highly interconnected network of transcription factors and co-factors that coordinate the activity of super-enhancers to enforce myeloma cell identity. Targeting this network offers a promising avenue for therapeutic intervention across genetically diverse myeloma sub-types. Using integrated molecular and functional genomic approaches we identified Menin as a key driver of oncogenic gene expression in MM cells. Menin and its co-factor KMT2A bind at super-enhancers and maintain expression of essential myeloma genes, including IRF4. We demonstrate that Menin inhibitors, which have recently been approved for treatment of acute myeloid leukaemia, are highly active in myeloma cell lines and in vivo models. Combining Menin inhibitors with other super-enhancer targeting therapies such EP300/CREBBP inhibitors or immunomodulatory drugs (IMiDs) overcomes epigenetic plasticity in cells resistant to single agent treatment.