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Intravitreal HDAC Inhibitor Belinostat Effectively Eradicates Vitreous Seeds Without Retinal Toxicity In Vivo in a
Jessica V Kaczmarek1, Carley M Bogan1, Janene M Pierce1
1Division of Ocular Oncology and Pathology, Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Purpose:
Current melphalan-based regimens for intravitreal chemotherapy for retinoblastoma vitreous seeds are effective but toxic to the retina. Thus, alternative agents are needed. Based on the known biology of histone deacetylases (HDACs) in the retinoblastoma pathway, we systematically studied whether the HDAC inhibitor belinostat is a viable, molecularly targeted alternative agent for intravitreal delivery that might provide comparable efficacy, without toxicity.
Methods:
In vivo pharmacokinetic experiments in rabbits and in vitro cytotoxicity experiments were performed to determine the 90% inhibitory concentration (IC90). Functional toxicity by electroretinography and structural toxicity by optical coherence tomography (OCT), OCT angiography, and histopathology were evaluated in rabbits following three injections of belinostat 350 µg (2× IC90) or 700 µg (4× IC90), compared with melphalan 12.5 µg (rabbit equivalent of the human dose). The relative efficacy of intravitreal belinostat versus melphalan to treat WERI-Rb1 human cell xenografts in rabbit eyes was directly quantified. RNA sequencing was used to assess belinostat-induced changes in RB cell gene expression.
Results:
The maximum nontoxic dose of belinostat was 350 µg, which caused no reductions in electroretinography parameters, retinal microvascular loss on OCT angiography, or retinal degeneration. Melphalan caused severe retinal structural and functional toxicity. Belinostat 350 µg (equivalent to 700 µg in the larger human eye) was equally effective at eradicating vitreous seeds in the rabbit xenograft model compared with melphalan (95.5% reduction for belinostat, P < 0.001; 89.4% reduction for melphalan, P < 0.001; belinostat vs. melphalan, P = 0.10). Even 700 µg belinostat (equivalent to 1400 µg in humans) caused only minimal toxicity. Widespread changes in gene expression resulted.
Conclusions:
Molecularly targeted inhibition of HDACs with intravitreal belinostat was equally effective as standard-of-care melphalan but without retinal toxicity. Belinostat may therefore be an attractive agent to pursue clinically for intravitreal treatment of retinoblastoma.
Insights
Belinostat, an HDAC inhibitor, shows equal efficacy to melphalan for treating retinoblastoma vitreous seeds but without retinal toxicity. This molecularly targeted agent offers a safer alternative for intravitreal chemotherapy.
Area of Science:
- Ophthalmology
- Oncology
- Molecular Biology
Background:
- Current intravitreal chemotherapy for retinoblastoma vitreous seeds relies on melphalan, which is effective but causes retinal toxicity.
- Histone deacetylase (HDAC) inhibitors are implicated in retinoblastoma pathways, suggesting potential for targeted therapy.
Purpose of the Study:
- To investigate belinostat, an HDAC inhibitor, as a potential intravitreal agent for retinoblastoma vitreous seeds.
- To evaluate belinostat's efficacy and retinal toxicity compared to melphalan in a preclinical model.
Main Methods:
- In vivo and in vitro studies were conducted in rabbits and cell cultures.
- Toxicity was assessed using electroretinography, OCT, OCT angiography, and histopathology.
- Efficacy was quantified by measuring the reduction of WERI-Rb1 human cell xenografts.
Main Results:
- The maximum non-toxic dose of belinostat (350 µg) demonstrated no significant retinal toxicity.
- Belinostat (350 µg) was equally effective as melphalan in eradicating vitreous seeds (95.5% vs. 89.4% reduction).
- Higher doses of belinostat also showed minimal toxicity, with widespread gene expression changes observed.
Conclusions:
- Intravitreal belinostat offers a molecularly targeted approach for retinoblastoma vitreous seeds.
- Belinostat demonstrated comparable efficacy to melphalan with significantly reduced retinal toxicity.
- Belinostat presents a promising alternative for clinical development in retinoblastoma treatment.
