Lazow, Margot

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.

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors. Our understanding of the clinical course, prognostic factors, and optimal treatment strategies remains limited. Histologic, molecular, and clinical data were collected and analyzed for 25 patients with DLGNT reviewed at St. Jude Children’s Research Hospital. The median age at diagnosis was 6 years (11 months-20 years). Nineteen (72%) patients were male. The disease was localized at diagnosis in 12 (48.0%) patients, with most tumors localized in the spinal cord. BRAF fusion was present in 22 (95.6%) of 23 patients who had material for testing. Of 18 patients who had tissue for DNA methylation profiling, 3 (16.7%) matched to DLGNT MC-1, 3 (16.7%) to DLGNT MC-2, and 12 (66.7%) did not match to a DLGNT subclass. Median follow-up was 63 months. Twenty-four (96.0%) patients received adjuvant therapy after initial diagnosis or at progression. Thirty-five cytotoxic chemotherapy and 24 single-agent targeted therapy regimens were used in 22 and 13 patients, respectively. With targeted therapy, 3 (12%) patients had partial responses. Eleven (44.0%) received radiotherapy. Median progression-free survival (PFS) after a patient’s first chemotherapy, targeted therapy, or radiotherapy regimen was 44 months (1-77), 11 months (4-39), and 16.5 months (9-23), respectively. The 5-year PFS was 18.7%±9.2, while the 5-year overall survival (OS) was 82.4%±9.2. The 5-year OS was lower in patients older than 9 years at diagnosis (60.0%±21.9 vs 91.7%±8.0, p = 0.02). Ki67 >4% was associated with worse PFS (0%±0 vs 24.6%±11.9 at 5 years, p = 0.03). Initial disease dissemination (localized vs. disseminated) and 1q gain status do not influence PFS or OS. PFS for DLGNT remains poor across all treatment modalities, including targeted therapies, despite the high frequency of BRAF fusions. Due to its rarity, establishing optimal therapeutic strategies for DLGNT requires additional treatment and outcome data and prospective multi-institutional trials.