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A decision process for drug discovery in retinoblastoma

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Summary

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.

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Acknowledgments

The authors would like to thank Maximiliano Distefano, Hospital de Pediatria JP Garrahan (Argentina) for technical support.

Availability of data and materials

All data generated or analyzed during this study are included in this article.

Funding

This work was supported by Fund for Ophthalmic Knowledge, NY, USA; Fundación Natalie Dafne Flexer de Ayuda al Niño con Cancer, Argentina; Fundación Bunge y Born, Argentina; Fondation Nelia et Amadeo Barletta; National Agency for Science and Technology Promotion (PIDC 2014–0043; PICT 2016–1505), Argentina; and by NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center.

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Authors and Affiliations

  1. Precision Medicine, Hospital de Pediatría JP Garrahan, 1245, Buenos Aires, Argentina

    María Belen Cancela, Santiago Zugbi, Ana Laura Martinez, Guillermo Chantada & Paula Schaiquevich

  2. National Scientific and Technical Research Council, CONICET, 1425, Buenos Aires, Argentina

    María Belen Cancela, Santiago Zugbi, Guillermo Chantada & Paula Schaiquevich

  3. Pathology Service, Hospital de Pediatría JP Garrahan, 1245, Buenos Aires, Argentina

    Ursula Winter

  4. Hematology-Oncology Service, Hospital de Pediatría JP Garrahan, 1245, Buenos Aires, Argentina

    Claudia Sampor

  5. Ophthalmology Service, Hospital de Pediatría JP Garrahan, 1245, Buenos Aires, Argentina

    Mariana Sgroi

  6. Ophthalmic Oncology Service, Memorial Sloan-Kettering Institute and Cancer Center, New York, NY, 10065, USA

    Jasmine H. Francis & David H. Abramson

  7. Gene Editing And Screening Core facility, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Institute and Cancer Center, New York, NY, 10065, USA

    Ralph Garippa

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  1. María Belen Cancela
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Contributions

conceptualization: DA, JF, RG, GCH, PS; classification process: BC, CS, MS, GCH, PS; cell culture: BC, SZ, UW, LM, RA; high-throughput screening: RG, SZ; patient treatment and clinical assessments: CS, MS, GCH, JF, DA; data analysis: BC, UW, SZ, RG, PS.

All authors significantly contributed to the design of the study, to the interpretation of the data and to the writing and editing.

Corresponding author

Correspondence to Paula Schaiquevich.

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Cancela, M.B., Zugbi, S., Winter, U. et al. A decision process for drug discovery in retinoblastoma. Invest New Drugs 39, 426–441 (2021). https://doi.org/10.1007/s10637-020-01030-0

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