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Updated: Nov 30, 2025
Reconstruct Human Retinoblastoma In Vitro
Published on: October 11, 2022
A decision process for drug discovery in retinoblastoma
María Belen Cancela1,2, Santiago Zugbi1,2, Ursula Winter3
1Precision Medicine, Hospital de Pediatría JP Garrahan, 1245, Buenos Aires, Argentina.
Abstract:
Intraocular retinoblastoma treatment has changed radically over the last decade, leading to a notable improvement in ocular survival. However, eyes that relapse remain difficult to treat, as few alternative active drugs are available. More challenging is the scenario of central nervous system (CNS) metastasis, in which almost no advancements have been made. Both clinical scenarios represent an urgent need for new drugs. Using an integrated multidisciplinary approach, we developed a decision process for prioritizing drug selection for local (intravitreal [IVi], intrathecal/intraventricular [IT/IVt]), systemic, or intra-arterial chemotherapy (IAC) treatment by means of high-throughput pharmacological screening of primary cells from two patients with intraocular tumor and CNS metastasis and a thorough database search to identify clinical and biopharmaceutical data. This process identified 169 compounds to be cytotoxic; only 8 are FDA-approved, lack serious toxicities and available for IVi administration. Four of these agents could also be delivered by IT/IVt. Twelve FDA-approved drugs were identified for systemic delivery as they are able to cross the blood-brain barrier and lack serious adverse events; four drugs are of oral usage and six compounds that lack vesicant or neurotoxicity could be delivered by IAC. We also identified promising compounds in preliminary phases of drug development including inhibitors of survivin, antiapoptotic Bcl-2 family proteins, methyltransferase, and kinesin proteins. This systematic approach may be applied more broadly to prioritize drugs to be repurposed or to identify novel hits for use in retinoblastoma treatment.
Insights
New drug discovery for retinoblastoma, especially for relapsed intraocular tumors and central nervous system metastasis, is crucial. This study presents a systematic approach to identify viable drug candidates for various treatment routes.
Area of Science:
- Oncology
- Pharmacology
- Ophthalmology
Background:
- Intraocular retinoblastoma treatment has improved, but relapsed cases and central nervous system (CNS) metastasis remain challenging.
- There is an urgent need for novel therapeutic agents to address these difficult-to-treat retinoblastoma scenarios.
- Current treatment options for advanced retinoblastoma, particularly CNS metastasis, are limited.
Purpose of the Study:
- To develop a systematic decision process for prioritizing drug selection for retinoblastoma treatment.
- To identify existing and novel drug candidates for local (intravitreal, intrathecal/intraventricular), systemic, and intra-arterial chemotherapy (IAC) administration.
- To repurpose FDA-approved drugs and discover new therapeutic agents for retinoblastoma.
Main Methods:
- Integrated multidisciplinary approach combining high-throughput pharmacological screening of patient-derived cells.
- Database search for clinical and biopharmaceutical data to identify drug properties and administration routes.
- Prioritization of compounds based on cytotoxicity, safety profiles, and route-specific delivery feasibility.
Main Results:
- Identified 169 cytotoxic compounds; 8 FDA-approved drugs suitable for intravitreal (IVi) administration with low toxicity.
- Identified 12 FDA-approved drugs for systemic delivery crossing the blood-brain barrier and 6 for IAC.
- Discovered promising investigational drugs targeting survivin, Bcl-2 family proteins, methyltransferase, and kinesin proteins.
Conclusions:
- A systematic drug prioritization framework can effectively identify viable treatment options for retinoblastoma.
- Repurposing FDA-approved drugs and exploring novel agents offers new hope for relapsed and metastatic retinoblastoma.
- This approach can accelerate the development of new therapies for challenging retinoblastoma cases.
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