P1, N=20, Completed, University of Nebraska | Active, not recruiting --> Completed | Trial completion date: Aug 2027 --> Mar 2025 | Trial primary completion date: Oct 2026 --> Mar 2025

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 ).

Inhibiting IDH mutations with vorasidenib lowers D-2HG and is beneficial to patients. Other drugs like ONC201 and metformin can metabolically suppress oncogenic chromatin states in pediatric gliomas. This dynamic cross talk between metabolism and epigenetics not only underpins tumor biology but also presents opportunities for innovative therapeutic strategies.

Although ravoxertinib alone showed limited antitumor activity, its combination with BRAFi/MEKi yielded substantial benefits, especially in chronic settings. These findings suggest that combinatorial regimens incorporating ERK inhibitors represent a promising therapeutic strategy for BRAF-mutant melanoma.

The ferroptosis activator RSL3 further attenuated tumor progression in both the knockdown and overexpression models, and combined treatment with the ERK inhibitor SCH772984 synergistically suppressed tumor growth in MIR4435-2HG-overexpressing xenografts. Notably, RSL3 diminished IQGAP3, Ras, ERK, CREB, and GPX4 levels across the experimental conditions. These findings indicate that MIR4435-2HG is a pivotal regulator of bladder cancer progression and ferroptosis via the IQGAP3/Ras/ERK/CREB axis, suggesting that MIR4435-2HG is a potential therapeutic target for intervention.

The ERK inhibitor GDC-0994 exhibited significant synergistic effects with the AR inhibitor bicalutamide. Specifically, the combination therapy inhibits FOXC2-driven EMT and induces ferroptosis via the FOXC2-Hippo signaling axis, suppressing tumor proliferation, migration, and invasion. In summary, this study uncovers the value of AR/ERK co-targeting in TNBC, which might potentiate the development of novel targeted therapeutic strategies in TNBC.

The interaction mechanism between circNFIB and IGF2BP3, which enhances L1CAM mRNA stability, was explored using RNA pulldown, mass spectrometry, RNA Immunoprecipitation (RIP), and actinomycin D assays...Finally, we verified circNFIB as a potential therapeutic target that can mitigate the anti-tumor effects of SCH772984 in vivo. RBMS1-mediated circNFIB interacts with IGF2BP3 to stabilize L1CAM mRNA, thereby activating the ERK/MAPK signaling pathway and promoting PNI in PDAC. This study provides a novel perspective on the molecular mechanisms underlying PNI in PDAC and lays the theoretical foundation for circNFIB as a potential therapeutic target for PDAC.

P1, N=36, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | N=24 --> 36

Despite its minimal renal clearance, dordaviprone geometric mean AUC was increased by ~50% in severe RI participants, suggesting CYP3A4 activity may have been suppressed in these participants. The results of this study will be used to inform dordaviprone dosing in patients with RI.

P2, N=73, Terminated, Chimerix | Active, not recruiting --> Terminated; The Sponsor terminated the study to prioritize enrollment in a randomized Phase 3 trial of ONC201 in an earlier setting. This decision was unrelated to any safety concerns with dordaviprone (ONC201).

P2, N=4, Terminated, Neurological Associates of West Los Angeles | The participant's caregiver requested for the participant to be withdrawn from the study. The investigator has decided to close out.

P2, N=360, Recruiting, University of California, San Francisco | Trial primary completion date: Dec 2025 --> Dec 2027