Emerging New Therapeutics for Retinoblastoma

Abstract

Background: Over the last few decades, chemotherapy has become the main treatment of retinoblastoma, delivered through various routes: intravenous, intra-arterial, and intravitreal. Despite its efficacy, chemotherapy-related toxicity (ocular and systemic) and recurrences due to resistant tumor clones are common, highlighting the need for novel therapeutic agents. Summary: Recent advances in our understanding of the molecular drivers of Rb1 tumorigenesis and mechanisms of tumor resistance have afforded opportunities to explore novel targets such as the MDMX-p53 pathway (nutlin-3), histone deacetylase inhibitors, spleen tyrosine kinase inhibitors, and genetic and immune modulatory drugs. In this review, we discuss the limitations of current therapeutic strategies, candidate cellular pathways, current evidence for newer targeted drugs, and offer a look toward the future. Key Messages: Advances in the understanding of the molecular drivers of the RB pathway have provided opportunities to explore novel drugs with targeted effects, improved bioavailability, and reduced chemotoxicity.

Keywords: Pharmacology; Retinoblastoma; Target drugs.

Fig. 1.

The RB-E2F and p53 pathways and the novel therapeutic targets. The major components of RB pathway include pRB, E2F, D-cyclins, CDK4/6, p16, p21, and their functional interactions. Various potential therapeutic agents targeting different stages of RB cell cycle are shown in this diagram. RB, retinoblastoma; E2F, E2 factor; CDK, cyclin-dependent kinase; MDM2/K, mouse double minute 2 homolog; CHKN1, cyclin-dependent kinase inhibitor 1; CHKN2, cyclin-dependent kinase inhibitor 2; P53, tumor suppressor P53; OTX2, orthodenticle homeobox 2; ATRA, all-transretinoic acid; MYCN, N-myc proto-oncogene.