Abstract
Somatostatin type-2A receptors (SST2A) regulate cell growth through downstream modulation of proliferation and apoptosis signaling, representing a potential therapeutic target. Membranous SST2A protein expression has been identified immunohistochemically in certain pediatric CNS tumors, but little is known about functional expression by DOTATATE PET. CONNECT2007 (NCT05278208, currently accruing) is a multicenter phase I/II study investigating safety and efficacy of Lutathera ((177)Lu-DOTATATE), SST2A-targeted radionuclide therapy, in children and adults with recurrent/progressive SST2A-expressing CNS tumors. Eligibility screening consists of (68)Ga-DOTATATE PET imaging for functional confirmation of adequate SST2A expression (Krenning score [KS] ≥2 out of 4) by central review. As of 05/2025, 22 patients (progressive meningioma [n=7], relapsed medulloblastoma [n=10], rarer high-grade glioneuronal tumors [n=5]) have undergone screening. Strong DOTATATE uptake was observed across all meningiomas, with mean KS=2.7 (range: 2-4), including two patients with germline predisposition syndromes (CHEK2, BAP1). DOTATATE uptake in medulloblastoma was variable (KS range: 0-3), potentially reflecting molecular heterogeneity: uptake was greater in two group 3 cases (KS=2, 3) and two children with SHH, TP53-mutant disease (KS=2, 3); uptake was less in three adolescent/young adult patients with SHH, TP53-wildtype disease (KS=0-1) and one young adult with WNT medulloblastoma (KS=0). Two patients with group 4 medulloblastoma had KS of 1 and 3. Among rarer entities, strong uptake (KS=3) was observed in high-grade diffuse leptomeningeal glioneuronal tumor and neuroepithelial tumor with suspected BCOR ITD, whereas cases of pineoblastoma, PFA ependymoma, and BCOR-fused high-grade neuro-epithelial tumor had KS of zero. Preliminary CONNECT2007 screening results provide insight into the prevalence and heterogeneity of targetable SST2A expression across high-risk pediatric and young adult CNS tumors. Strong DOTATATE uptake was identified in all patients with progressive meningiomas, some patients with medulloblastoma (particularly group 3 and SHH, TP53-mutant), and rarer high-grade glioneuronal tumors, suggesting a potential role for SST2A-targeted theranostics in these entities.