We identified polyprenoic acid (PA, peretinoin) as the first ligand capable of directly binding HNF4A...Importantly, hepatocyte-specific Hnf4a knockdown or lipid-nanoparticle-mediated Hnf4a siRNA abrogated the protective effects of PA. These findings establish HNF4A as a pharmacologically controllable tumor suppressor and highlight PA-like compounds as promising agents for preventing liver carcinogenesis.

P3, N=39, Not yet recruiting, Polaryx Therapeutics, Inc. | Trial completion date: Mar 2026 --> Dec 2026 | Trial primary completion date: Mar 2026 --> Dec 2026

P4, N=16, Completed, Bausch Health Americas, Inc. | Recruiting --> Completed | N=45 --> 16 | Trial completion date: Mar 2027 --> Feb 2026 | Trial primary completion date: Feb 2027 --> Feb 2026

The study by Moyer and colleagues demonstrated that RXR agonists, particularly IRX4204, delay tumor onset in BRCA1-deficient and triple-negative mouse models, suggesting a potential preventive role through immunomodulation...A rational next step may be to carefully design window-of-opportunity trials in BRCA1 carriers undergoing risk-reducing bilateral mastectomy to assess biomarker modulation and tolerability. See related article by Moyer et al., p. 161.

P2, N=20, Suspended, Io Therapeutics | Not yet recruiting --> Suspended

In this study, we tested whether nuclear retinoid X receptor (RXR) ago-nists, IRX4204 and 9cUAB30, which have been evaluated in clinical trials, could prevent the de-velopment of ER-negative and triple-negative breast cancers (TNBCs). Biomarker analysis revealed that delayed tumors arising after IRX4204 treatment had decreased Ki-67 expression and increased infiltration of cytotoxic T-cells. Our pre-clinical study data support the further evaluation of use of RXR agonists for the prevention of TNBC.

P3, N=15, Terminated, Icahn School of Medicine at Mount Sinai | N=30 --> 15 | Active, not recruiting --> Terminated; Interim analysis did not show any significant differences between groups

P4, N=45, Recruiting, Bausch Health Americas, Inc. | Trial completion date: Jun 2024 --> Mar 2027 | Trial primary completion date: Jun 2024 --> Feb 2027

This review suggests that HP/TAZ is a valuable option for the topical treatment of severe hyperkeratotic plaques through its additive mechanisms targeting inflammation and keratinocyte regulation.

While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities. These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance.

P3, N=39, Not yet recruiting, Polaryx Therapeutics, Inc. | Trial completion date: Dec 2025 --> Mar 2026 | Trial primary completion date: Dec 2025 --> Mar 2026