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      Emerging New Therapeutics for Retinoblastoma

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          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.

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          Most cited references46

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          Cyclin D-CDK4/6 functions in cancer.

          The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.
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            Dinutuximab Synergistically Enhances the Cytotoxicity of Natural Killer Cells to Retinoblastoma Through the Perforin-Granzyme B Pathway

            Purpose Conventional chemotherapy and enucleation usually fail to cure advanced retinoblastoma. We investigated the retinoblastoma immune microenvironment and the efficacy of the combination of dinutuximab and CD16-expressing NK-92MI (NK-92MIhCD16-GFP) cells on retinoblastoma cells in this study. Patients and Methods Immunohistochemistry and flow cytometry (FC) were performed to assess the expression level of GD2 in retinoblastoma tissues and cells. Gene set enrichment analysis (GSEA), immunohistochemisrztry and immunocytochemistry were conducted to assess the retinoblastoma immune microenvironment and the integrity of the blood-retinal barrier (BRB). After overexpressing CD16 in NK-92MI cells, fluorescence-activated cell sorting (FACS) was applied to select the positive subpopulation. LDH assays and FC were used to detect LDH release and apoptosis in retinoblastoma cells subjected to a combination of dinutuximab and NK-92MIhCD16-GFP cells. Finally, the release of perforin-granzyme B and the expression of CD107a in NK-92MIhCD16-GFP stimulated by retinoblastoma cells were assessed via enzyme-linked immunosorbent assays (ELISAs) and FC in the presence of dinutuximab or an isotype control. Results GD2 was heterogeneously expressed in retinoblastoma tissues and cell lines and positively correlated with proliferation and staging. GSEA revealed the immunosuppressive status of retinoblastoma microenvironment. The immune cell profile of retinoblastoma tissues and vitreous bodies suggested BRB destruction. LDH release and apoptosis in retinoblastoma cells caused by NK-92MIhCD16-GFP cells were significantly enhanced by dinutuximab. Finally, the release of perforin-granzyme B and the expression of CD107a in NK-92MIhCD16-GFP cells stimulated by retinoblastoma cells were obviously increased by dinutuximab. Conclusion This study indicates that retinoblastoma impairs the integrity of the BRB and contributes to dysregulated immune cell infiltrates. GD2 is a specific target for natural killer (NK) cell-based immunotherapy and that the combination of dinutuximab and NK-92MIhCD16-GFP cells exerts potent antitumor effects through antibody-dependent cell-mediated cytotoxicity.
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              Intravitreal HDAC Inhibitor Belinostat Effectively Eradicates Vitreous Seeds Without Retinal Toxicity In Vivo in a Rabbit Retinoblastoma Model

              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 (IC 90 ). 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× IC 90 ) or 700 µg (4× IC 90 ), 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.
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                Author and article information

                Journal
                OOP
                OOP
                10.1159/issn.2296-4657
                Ocular Oncology and Pathology
                S. Karger AG
                2296-4681
                2296-4657
                2022
                November 2022
                09 May 2022
                : 8
                : 3
                : 149-155
                Affiliations
                [_a] aThe Operation Eyesight Universal Institute for Eye Cancer, L V Prasad Eye Institute, Hyderabad, India
                [_b] bConsultant Ophthalmologist, Birmingham Children’s Hospital, Birmingham, UK
                [_c] cDepartment of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
                Article
                524919 Ocul Oncol Pathol 2022;8:149–155
                10.1159/000524919
                c13442d3-1e4d-49f1-9f19-4b638e4ce405
                © 2022 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.

                History
                : 28 January 2022
                : 27 April 2022
                Page count
                Figures: 1, Tables: 1, Pages: 7
                Funding
                This work was supported in part by an unrestricted grant from Research to Prevent Blindness to the Cole Eye Institute. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Categories
                Review Article

                Vision sciences,Ophthalmology & Optometry,Pathology
                Retinoblastoma,Pharmacology,Target drugs
                Vision sciences, Ophthalmology & Optometry, Pathology
                Retinoblastoma, Pharmacology, Target drugs

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