A decision process for drug discovery in retinoblastoma
- PDF / 615,727 Bytes
- 16 Pages / 595.276 x 790.866 pts Page_size
- 108 Downloads / 206 Views
PRECLINICAL STUDIES
A decision process for drug discovery in retinoblastoma María Belen Cancela 1,2 & Santiago Zugbi 1,2 & Ursula Winter 3 & Ana Laura Martinez 1 & Claudia Sampor 4 & Mariana Sgroi 5 & Jasmine H. Francis 6 & Ralph Garippa 7 & David H. Abramson 6 & Guillermo Chantada 1,2 & Paula Schaiquevich 1,2 Received: 17 August 2020 / Accepted: 28 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Retinoblastoma . Intraocular . Metastasis . Decision process . High-throughput drug screening
Introduction Retinoblastoma is the most common primary neoplasm of the eye in childhood [1]. The current use of novel routes to more selectively deliver chemotherapy to the eye, such as intraarterial chemotherapy (IAC) or intravitreal administration (IVi), has resulted in major improvements in eye preservation
* Paula Schaiquevich [email protected] 1
Precision Medicine, Hospital de Pediatría JP Garrahan, 1245 Buenos Aires, Argentina
2
National Scientific and Technical Research Council, CONICET, 1425 Buenos Aires, Argentina
3
Pathology Service, Hospital de Pediatría JP Garrahan, 1245 Buenos Aires, Argentina
while reducing systemic drug exposure [1–4]. However, for eyes that relapse after conventional therapy or have refractory tumors, treatment options are few, and many eyes must be enucleated. Even less progress has
Data Loading...
