JZP3507

DU145 and PC3 AIPC cells were treated with ONC201 (parent compound), ONC206, or ONC212...Imipridones induced a time-dependent cell-cycle redistribution with increased sub-G1 accumulation and modulated mitochondrial membrane potential and mass in a context-dependent manner. Collectively, these findings position ONC212 as a leading imipridone candidate in AIPC models, combining potent inhibition of tumor and stem-like cell functions with a coherent stress-response signature that supports further translational evaluation.

These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.

P2, N=30, Not yet recruiting, Jazz Pharmaceuticals

Our results highlight ONC206 as a novel therapeutic option for patients with high-risk medulloblastoma and provide strong rationale for testing the efficacy of ONC206 in the treatment of these patients.

P2, N=90, Recruiting, Jazz Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=20, Not yet recruiting, Prinses Maxima Centrum voor Kinderoncologie B.V.

B7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models.

P1, N=102, Recruiting, Jazz Pharmaceuticals | Trial primary completion date: Dec 2025 --> Jul 2026

P2, N=90, Not yet recruiting, Jazz Pharmaceuticals

Dordaviprone (ONC201) and its chemical derivative with nanomolar potency, ONC206, induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). We also saw that ONC206 very significantly prolonged survival of medulloblastoma-bearing mice, both in genetically engineered mouse models and patient-derived xenografts. Our study provides a strong rationale for testing the efficacy of ONC206 in the treatment of patients with medulloblastoma and has set the stage for a clinical trial with this agent in pediatric patients with recurrent malignant brain tumors, including medulloblastoma ( NCT04732065 ).

This work offers a biologically-informed, clinically translatable strategy integrating small molecule therapeutics with CAR T cell therapy and support the development of multi-agent immunotherapy trials for children with DIPG and other high-grade brain and spinal cord tumors. B7-H3 CAR T cells are cytotoxic against preclinical DMG models.ONC206 causes metabolic apoptosis in preclinical DMG models.B7-H3 CAR T cells and ONC206 have combinatorial efficacy against DMG.

sNK cell-mediated cytotoxicity against K27M was significantly increased when sNK cells were combined with ONC201 and ONC206. This study suggests the potential use of sNK cells alone or in combination with ONC201 or ONC206 as therapeutic strategies in treating and preventing the recurrence of aggressive pediatric brain tumors.