Molecular Vision 2022; 28:130-146 <>
Received 12 August 2021 | Accepted 09 July 2022 | Published 11 July 2022

Review: New horizons in retinoblastoma treatment: an updated review article

Fatemeh Azimi,1 Reza Mirshahi,2 Masood Naseripour1,2

1Eye Research Center, the Five Senses Institute, Iran University of Medical Sciences, Tehran, Iran; 2Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran

Correspondence to: Masood Naseripour, Department of Ophthalmology, Iran University of Medical Sciences (IUMS), Rassoul Akram Hospital, Niayesh Ave., 14455-364, Iran; Phone: 021 6655 8811; FAX: +98 21 66509162; email:


Retinoblastoma (Rb) is a rare childhood intraocular malignancy with an incidence rate of approximately 9000 children per year worldwide. The management of Rb is inherently complex and depends on several factors. The orders of priorities in the treatment of Rb are saving life, globe salvage and vision salvage. Rarity and the young age at diagnosis impede conducting randomized clinical trials (RCTs) for new therapeutic options, and therefore pre-RCTs studies are needed.

This review provides an overview of advances in Rb treatment options, focusing on the emergence of new small molecules to treat Rb. Articles related to the management and treatments of Rb were searched in different databases.

Several studies and animal models discussing recent advances in the treatment of Rb were included to have a better grasp of the biological mechanisms of Rb. Over the years, the principles of management and treatment of Rb have changed significantly. Innovations in targeted therapies and molecular biology have led to improved patient and ocular survival. However, there is still a need for further evaluation of the long-term effects of these new treatments.


Retinoblastoma (Rb) is a primary neuroectodermal tumor caused by immature retinoblasts, and accounts for 3% of all childhood cancers. It is the most common childhood intraocular malignancy [1]. The disease usually manifests as unifocal or multifocal tumors involving one or both eyes [2]. There are currently many effective modalities for Rb treatment, including focal treatments (laser therapy, cryotherapy, and radiotherapy), systemic chemotherapy, innovative new drug delivery methods (intravitreal and intra-ophthalmic chemotherapy), and enucleation to prevent extraocular extension and metastases and subsequent fatality [3]. The treatment of recurrent tumors depends on the extent of the disease, the laterality and number of tumor foci (unifocal, unilateral, multifocal), the size and location of the tumor, the presence of vitreous and subretinal seeding, the age and general health condition of the child, and the previous treatments. Both the International Intraocular Retinoblastoma Classification and Intraocular Classification of Retinoblastoma classification systems are used worldwide as the main intraocular Rb classification methods [4] (Table 1). Due to intra-tumoral heterogeneity, chemical-resistant phenotypes, and obstacles in drug delivery to the eye, Rb is still a major public health problem despite the continuous progress in its treatment, screening, and care [5].

In Rb, the tumor might initially be chemosensitive, but cross-resistance may ensue in the course of the treatment. The cross-resistance mechanisms are complex in nature and may differ from individual drug resistance. Drug resistance, especially in metastatic tumors, directly leads to treatment failure [6]. The main target of the traditional anti-tumor chemotherapeutic agents is cell division affecting the dynamics of the microtubules responsible for the mitotic spindle and DNA replication [7].

It is better to conduct clinical studies on the optimization of combination therapies (a treatment modality that combines two or more therapeutic agents) with a cytotoxic chemotherapeutic agent, another molecular targeting agent, or epigenetic-based or immune therapy [8]. The integration of anti-cancer drugs increases the effectiveness of the treatment compared to monotherapy due to critical pathways that basically decrease drug resistance. Moreover, tumor cells are often unable to adapt to the simultaneous toxic effects of two therapeutic agents combined [9].

However, combination therapies have limitations that should be considered in clinical trials. The design of combination trials may require pharmacodynamics studies and the collaboration of more than one pharmaceutical company to measure more than one biochemical or physiologic effect [10].

Advances in the development of targeted therapy and biomolecular tumor pathways have improved the survival rates in developed countries [11]. Despite the fact that developing countries have lower Rb survival rates, the horizon in such countries is promising, and the results are encouraging [12].

Advances in biomedical research have led to a better understanding of the biology of tumors through the study of genomics, proteomics, epigenetics, and the microenvironment. New research is thus constantly being sought to obtain newer targeted treatment options with minimal complications and maximum effectiveness against Rb. The US Food and Drug Administration (FDA) has recently approved the clinical use of targeted therapeutic agents for various types of cancer [13].

Targeted therapeutic agents exert their anti-cancer effects through a variety of mechanisms, including inhibition of proliferation, induction of apoptosis, suppression of metastasis, regulation of immune function, and reversal of multi-drug resistance [14]. Considering the young ages of Rb patients and the rarity of the disease, the behaviors of isolated cell cultures need to be studied to understand the biology of tumor cells in the body. Cell cultures are used to create new diagnostic tests and new treatments for Rb. The most important Rb cell lines primarily used in Rb research include Y79 (the first Rb cell line), Weri, Rb355, Rb116, SNUOT-Rb1, and HXO-Rb44 [1520]. In this article, the successes and challenges of incorporating molecularly targeted therapies, tubulin-modifying molecules, immunotherapy, high-mobility group A (HMGA) protein, vitamin D analogs, angiogenesis inhabitation, neurotransmitter pathway disruption, arsenic trioxide, EDL-155, gene therapy, local drug delivery systems, new hydrogel implant, ncRNAs, aqueous humor markers, exosomes, and MLN4924 (pevonedistat) in the management of Rb are highlighted (Table 2).

Searches for relevant articles were conducted at the PubMed, Scopus, Embase, and Google Scholar electronic databases. The searches were limited to English articles. The mesh term keywords that were used for the electronic-database searches were “advances OR treatment OR targeted therapies” AND “Retinoblastoma.” The included articles reported original studies and new Rb treatments.


Molecularly targeted therapy

Molecularly targeted therapies are relatively new, and many questions about how and when to combine them in the first-line Rb treatment remain unanswered [21]. The first tumor suppressor gene to be identified and cloned was RB1, but there is currently no effective molecularly targeted treatment for Rb [22]. However, there has been significant progress in the understanding of tumor biology, leading to the discovery and development of small molecules for the treatment of Rb, including new targeted therapies such as MDMX-p53 response inhibitors (nutlin-3a), spleen tyrosine kinase (SYK) inhibitors, histone deacetylase (HDAC) inhibitors [3], and CEP1347 (small-molecule kinase inhibitor) [23].

MDMX-P53 response inhibitors-- Nutlin-3A was discovered by Vassilev et al. [24] in 2003 to inhibit p53-murine double minute (MDM2/MDM4) interaction when they screened a chemical library. It is a cis-imidazole analog involved in the activation of p53, a tumor-inhibiting protein, and attenuates tumor cell viability both in vivo and in vitro [25]. Nutlin-3A is currently being studied in a phase 1 clinical trial for Rb treatment [25,26]. Subconjunctival nutlin-3A in a mouse model of Rb has a reduced tumor burden especially in combination with topotecan (TPT) [25]. However, it should be noted that due to the blood-retinal barrier in Rb, the effective entry of many drugs, such as nutlin-3A, is hindered [25,27].

Epigenetic mechanisms: SYK and HDAC inhibition-- The proto-oncogene tyrosine-protein kinase (also known as spleen tyrosine kinase [SYK]), although not normally expressed in the human retina, is upregulated in 100% of Rb tumor specimens and leads to tumor cell survival [28]. Inhibition of SYK by BAY-61–3606 and R406 could result in tumor cell death in Rb, and an in vivo study of subconjunctival BAY-61–3606 injection with systemic TPT in orthotopic xenograft mice has shown its effectiveness in inhibiting Rb cell proliferation [28]. In addition, recent studies have demonstrated that the mediators of SYK are the B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) protein families [29].

Bcl-2 is a protein known to prevent apoptosis and to help in cell viability. Bcl-2 inhibitors (especially MCL-1 inhibitors) can be a novel therapeutic candidate due to their upregulation in Rb, and are also being developed as a treatment for other cancers [30]. HDAC inhibitors are another class of targeted anti-cancer therapies currently being investigated in phase 1 clinical trials that may be effective as a targeted treatment for Rb [31]. Several properties of HDAC inhibitors make them potential candidates for the treatment of Rb. First, the epigenetic profile of Rb exhibits dysregulation compared to normal retinoblasts [28]. Second, HDAC inhibitors have selective cytotoxic effects on tumor cells, and tumor cells with dysregulated E2F1activity are sensitive to HDAC inhibition [32]. Finally, numerous studies have shown that HDAC inhibitors have synergistic effects with other agents in the treatment of Rb [28]. Cells with higher E2F1activity and with overexpression of pro-apoptotic agents are highly sensitive to HDAC inhibitors. Rb cells have high E2F1 activity, and Rb-derived cell lines are particularly sensitive to HDAC-induced apoptosis. Recent studies have suggested that HDAC inhibitors may specifically inhibit Rb tumor cell proliferation and therefore have less systemic toxicity than other chemotherapeutic agents [33].

Small-molecule kinase inhibitor

CEP1347 is a promising candidate for cancer stem cell-targeted therapy [34]. It is a semi-synthetic compound that protects various nerve cells against various insults leading to apoptosis, and subsequently improves the survival of dopamine neurons [35].

CEP1347 is a safe drug that inhibits mixed-lineage kinases and activates apoptotic pathways in the pathogenesis of Parkinson’s disease [34]. It selectively inhibits MDM4 expression and activates the p53 pathway, leading to anti-proliferative effects on the Rb cells [23]. Currently, none of the drugs acting on Rb by activating p53, including nutlin-3A, have a strong clinical potential. However, as CEP1347 may be able to pass through the blood-retinal barrier, it is a potential candidate for the treatment of Rb and other cancers in which the P53 gene is intact [23].

Tubulin-modifying molecules

Vincristine (VCR), also known as leurocristine and Oncovin [36], is a first-line chemoreduction agent for Rb that was first isolated in 1961 [37]. Its mechanism of action is inhibition of microtubule assembly [38]. Therefore, Rb tumor cells may show similar sensitivity to other tubulin-modifying compounds. Some studies have revealed that VCR in combination with TPT [39] and carboplatin (CBP) [40] is effective for the treatment of advanced intraocular Rb. Chemotherapy is the standard treatment for Rb, but chemotherapy agents such as VCR, etoposide (ETP), and CBP may lead to drug resistance and treatment failure [41].

Paclitaxel (PTX) was first obtained from the Taxus brevifolia (Pacific yew) in 1971 and was approved for medical use in 1993 [42]. It is a taxane that causes marked apoptosis in tumor cells by affecting the tubulin dynamics [43].

Paclitaxel is used to treat breast cancer, ovarian cancer, and small cell lung cancer. Recent studies have demonstrated its potential therapeutic effects in Rb [44]. Its mechanism of action is inactivation of the intracellular proteins necessary for cell survival and function, which results in cell death [45]. Subconjunctival injection of paclitaxel effectively inhibits intraocular tumor burden in the human luteinizing hormone (β subunit; LH beta) Tag Rb model. The main barriers to the use of paclitaxel as an Rb chemotherapy regime are its toxicity [46] and its formulation [47].


CAR T-cell therapy-- Chimeric antigen receptor T cells (CAR T cells) are T cells that have been genetically engineered to produce chimeric or fusion proteins through recombinant DNA technology on the T cells for use in immunotherapy. In CAR T immunotherapy, the T cells are modified to identify and more effectively target and destroy tumor cells. CD171 (neural cell adhesion molecule L1), also known as L1CAM, was first identified in 1984 by Rathjen and Schenker in post-mitotic mice neurons cells [48]. L1CAM is expressed in Rb cells and plays an important role in the adhesion-mediated proliferation and chemoresistance of tumor cells [49]. GD2 (a b-series ganglioside disialoganglioside) is expressed in tumors of neuroectodermal origin, including human melanoma, neuroblastoma, and Rb [50,51], with a limited expression in natural tissues [52]. CD171- and GD2-specific CAR T cells are highly activated by Rb cell collision and are highly efficient against Rb cells in vitro depending on the expression of the target antigen. CAR T-cell therapy can improve the treatment strategies for metastatic Rb.

The antigens on the targeted tumor cells are destroyed upon treatment with CAR T cells, but sequential antigen modification in CAR T-cell therapy increases its ability to kill Rb cells. This approach provides the basis for in vivo studies to select the most useful regimens and target compounds for the development of CAR T-cell therapy for Rb [53].

Signal transducer CD24-- Cluster of differentiation 24 (CD24) or heat-stable antigen CD24 (HSA) is a highly glycosylated protein that binds to membrane lipid raft microdomains through a glycosylphosphatidylinositol anchor [54]. Recent studies have shown that CD24 positivity is associated with poor prognosis in many types of tumors, including glioma [55], hepatocellular carcinoma [56], and breast cancer [57]. CD24 is highly expressed in Rb and is thus a potential indicator or predictor of the severity and prognosis of the disease. A positive association between CD24 and the chemotherapeutic response of Rb cells to VCR-based chemotherapy has recently been found [58]. However, the cellular mechanisms involved in CD24 activity in Rb are still unclear. CD24 inhibition can reduce autophagy activation via the PTEN/Akt/mTORC1 pathway, thus increasing VCR sensitivity. It facilitates a new therapeutic target for Rb chemotherapy [59].

Nucleolin protein

The nucleolin (NCL) protein is a small nucleolar RNA termed U20 that is expressed differently on the surfaces of tumor cells, connects ligands, and regulates carcinogenesis and angiogenesis [60]. NCL is expressed in Rb tumor tissues and cell lines more than in the normal retina. Cell proliferation using aptamers (oligonucleotide or peptide molecules) is significantly inhibited in Rb cell lines (Y79 and WERI-Rb1) [61]. Nucleolin aptamer (NCL-APT) treatment downregulates the apoptosis protein inhibitors and alters the serum cytokine, tumor miRNA-18a, and serum miRNA-18a levels. The effect of NCL-APT and locked nucleic acid-modified NCL-APT on the Rb tumor was successfully tested using Y79 xenografts of nude mice [61,62].

A powerful method of accurately measuring the metabolites in tissues and examining the lipid changes between normal and cancerous tissues is lipid imaging using desorption electrospray ionization mass spectrometry (DESI-MS) [63]. It is potentially helpful for studying the biology of retinal diseases. DESI-MS can also potently grade cancer stages, identify the margin of the surgical tumor, and examine tumor lipogenesis [63,64]. DESI-MS is used in NCL-APT therapy to observe the changes in the phosphatidylcholine levels in Rb cell lines and tumor tissues. Therefore, NCL-APT-based targeting is a useful treatment strategy in Rb especially in conjunction with DESI-MS for monitoring the therapeutic responses [61].

HMGA protein

The HMGA protein is overexpressed in Rb and is associated with the invasion and metastasis of the disease [65]. Aptamers, siRNAs, or DNA minor groove binders such as natropsin can optionally target HMGA proteins and mRNA transcripts [66]. siRNA causes apoptosis in cancer cells by targeting HMGA2 [67]. Another approach is HMGA aptamer therapy in Rb, which reduces cell proliferation by activating the TGFb-SMAD4-mediated apoptotic pathway. In addition, combining the HGMA2 aptamer with ETP has a synergistic effect [68]. The third option for targeting HMGA in Rb cells is NCL antibody-mediated delivery of HMGA aptamer (NCLAb–HMGAap) [69]. Recent studies have demonstrated that conjugate NCLAb–HMGAap has unbeatable features, such as easier synthesis, superior conjugation, higher rate of cellular internalization in WERI-Rb1 cells through receptor-mediated internalization, and increased cytotoxicity (more than 50-fold) in WERI-Rb1 compared to free HMGA aptamer and NCLAp–HMGA2si conjugate [69].

Vitamin D analogs

There is ample evidence of the role of vitamin D in cancer growth and development. The mechanism of the anti-cancer activity of vitamin D is regulation of apoptosis, angiogenesis, cell differentiation, proliferation, and migration [70]. However, the applicability of vitamin D therapy to Rb has not been established due to the lack of preclinical models and the possibility of vitamin D toxicity [71]. In 1966, due to the observation of calcification in regressed tumors, Verhoeff proposed the use of vitamin D for the treatment of Rb [72]. Since then, several studies have assessed the effects of vitamin D analogs on Rb [7375].

Vitamin D appears to act as a protective agent in the eye through ubiquitously expressed receptors, where its local production and activation is possible due to the presence of the required enzymes [76]. Vitamin D analogs may produce anti-tumor effects on Rb by targeting the hedgehog signaling pathway [77].

However, the mechanism of vitamin D analogs in the treatment of Rb is still unknown and needs further investigation. The upregulation of p53and p21, though, was observed in the Y79 cell line following vitamin D analog therapy [71], which is related to an increased Bax protein concentration and a decreased Bcl-2content [78]. Both in vitro and in vivo models have been used to investigate the anti-tumor effect of vitamin D analogs, including calcitriol.

Calcitriol (1, 25-dihydroxyvitamin D3), which is normally produced in the kidney, is the active form of vitamin D. It inhibits the growth of Y79 cells in vitro [79] and minimized the tumor burden in both xenograft and transgenic mouse Rb models [71,79,80]. Despite the efficacy of calcitriol in both these models of Rb, its use as a treatment for Rb is limited due to its systemic toxicity (hypercalcemia and renal toxicity) [71,81].

Angiogenesis inhibition

Angiogenesis is known to be a major driving force in various tumors [82]. As Rb is an angiogenesis-dependent tumor, anti-angiogenic therapy is expected to have a positive effect on it [83]. Tigecycline, niclosamide, and quercetin have recently been investigated and have been determined to be potential candidates for the treatment of Rb by suppressing Rb cell proliferation through the modulation of angiogenesis pathways [84]. Anti-angiogenic compounds play an important role in Rb treatment. First, Rb is a completely vascularized tumor that depends on its vascular supply, and second, vascular endothelial growth factor (VEGF) is overexpressed in Rb cells and Rb patients [83].

Bevacizumab (Avastin) obtained FDA approval for use in certain types of cancer [85]. Bevacizumab reduces the tumor microvascular density twofold, which reduces Rb growth by 75% without significant systemic toxicity [83]. Angiogenesis inhibitors are safe for the adult retina, but there are concerns regarding their use in children with Rb due to their potential impact on the ocular development [86].

Celastrol nanomicelles

Celastrol nanomicelles (CNMs, 27.2 mg/kg/2 days) [87] are traditional Chinese medicine components with strong anti-tumor [88], anti-inflammatory, and anti-angiogenic activities [89]. Celastrol nanoparticles (NPs) inhibit the growth of retinoblastoma SO-Rb50 cells in humans by inducing apoptosis. In recent studies, CNMs were able to inhibit the growth of Rb in a mouse model by preventing neovascularization, which may be relevant to the inhibition of the VEGF pathway and of hypoxia-induced HIF-1α. CNMs may be a potent alternative for Rb treatment [87].


One of the potentially eukaryotic translation initiation factors (eIF) that plays a key role in the development and transformation of various cancers is eIF4E [90]. However, few studies have investigated its potential role in Rb treatment [20]. Angiogenesis is one of the key pathways in Rb tumor survival and metastasis. Bevacizumab and pigment epithelium-derived factor result in angiogenesis inhibition in Rb, with negligible systemic toxicity [83,91]. Ribavirin is a pharmacologic eIF4E function inhibitor [92] that targets angiogenesis and potentially suppresses VEGF-induced migration by disrupting capillary network formation. Mechanistically, ribavirin decreases the protein but not the mRNA levels of c-Myc, cyclin D1, and VEGF and inhibits the eIF4E function in Rb cells. The combined use of ribavirin and CBP leads to an efficacious treatment with a greater potential for inhibiting Rb than the use of single drugs separately [20].

Neurotransmitter pathway disruption

The growth of Rb by disrupting the pathways of neurotransmitter receptors, transporters, and biosynthetic enzymes, which are expressed in human Rb, can be reduced both in vivo and in vitro [93]. Mixtures of genes commonly found in the cells of retinal progenitors and differentiated retinal neurons (photoreceptors and amacrine cells) are also expressed in human Rb. Amacrine cells are interneurons that form synapses with ganglion or bipolar cells, which are distributed in the innermost part of the inner nuclear layer of the retina and play a critical role in processing visual signals [84]. Thirteen well-defined drug agents targeting major neurotransmitter pathways were tested in vitro, and it was found that monoaminergic amacrine cell transporter inhibitors, along with fluphenazine and chlorpromazine injections for 3 consecutive weeks, prevent the proliferation of Rb cell lines (Weri, Y79, and Rb355) [93].

Activator protein-2 (AP-2, a family of transcription factors, with AP-2α, AP-2β, AP-2δ, AP-2ε, and AP-2γ) has a regulatory role in biologic functions, including differentiation, cell proliferation, apoptosis, and carcinogenesis [94,95]. In the amacrine cells in fetal chickens, mice, and humans, the AP-2 family is expressed in the early stages of the development of the retina [95,96]. Co-expression of AP-2α/AP-2β is observed in a high percentage of amacrine cells [95]. The AP-2 expression scheme in the Rb cell lines mimics the amacrine cell differentiation patterns [97]. Transfection of AP-2α and AP-2β expression into Rb cells induces apoptosis and inhibits proliferation [98].

Arsenic trioxide

Arsenic trioxide (white arsenic or As2O3; ATO) was approved for medical use by FDA in 2000 for relapsed/refractory acute promyelocytic leukemia [99,100]. ATO is thought to function through mechanisms distinct from those of traditional chemotherapeutic agents (e.g., the reactive oxygen species due to oxidative damage leading to apoptosis) and is not prone to drug resistance [101].

ATO inhibits the growth of Rb cell lines (both Y79 and SNUOT-Rb1) at high and low levels of concentration through apoptosis and differentiation, respectively. Weekly intravitreal injection of 0.1 μM or 5 μM ATO minimized the tumorigenesis in the SNUOT-Rb1 cells in orthotopic xenograft mice and showed no change in retinal thickness despite a more pronounced decrease at higher doses. Moreover, inflammatory cells were not observed in ATO treatment in the choroid, retina, or vitreous [18].


EDL-155, an isoquinoline derivative, was found to have high concentrations and to be effective in vivo, but it was found to have relatively weak potency in cultured Y79 cells [102]. In a Y79-Luc Rb xenograft mouse model, the tumor burden was significantly reduced with the periocular administration of EDL-155 (20 mg/kg/day in 0.1% dimethyl sulfoxide in saline) within 4 consecutive days, without any toxic side effect. EDL-155 disrupts the mitochondrial function and causes autophagy, thereby killing Rb cells [102].

Gene therapy

Gene therapy is the therapeutic transfer of nucleic acid polymers into diseased cells for the treatment of an underlying disease [103]. Suicide gene therapy includes the process of transferring the gene materials of a virus or of bacteria into tumor cells to convert a non-toxic compound to a lethal drug. A phase 1 study showed that intravitreal injections of adenovirus vectors including herpes simplex virus-tyrosine kinase (HSV-TK), along with ganciclovir (GCV), is safe and effective in vitreous seeding [104]. Also, HSV-TK/GCV can lead to the significant destruction of retinal tumor cell lines [19]. Despite these promising results, the use of this approach in gene therapy as a first-line treatment for Rb is unlikely, and it may be useful as a complement to the standard therapy for refractory vitreous seeding [104].

VCN-01 is a clinically oncolytic adenovirus that is genetically engineered from type 5 (Ad5) modified adenovirus and is used to inhibit the proliferation of cancer cells with a high content of free E2F1, following the dysfunctional Rb1 pathway [105]. It successfully annihilated chemoresistant specimens in vitro and effectively killed cancer cells derived from mouse Rb xenograft models. A recent study has shown that VCN-01 is safe in mice and juvenile rabbits [106]. According to the preliminary phase 1 results from Rb patients treated with intravitreal VCN-01, there was evidence of viral replication in the tumor cells, which led to anti-tumor activity in vitreous seeds of Rb. This treatment causes localized vitreous inflammation without any systemic inflammation.

The intravitreal injection of VCN-01 in xenograft models of Rb improved the ocular survival rate compared to the conventional chemotherapy, and inhibited micrometastatic spread to the brain. These promising results suggest that the development of oncolytic adenoviruses targeting Rb1 may provide selective and independent treatment options for Rb [106].

Local drug delivery systems

Over the past decade, nanotechnology-based drug delivery systems for cancer therapy have made significant progress by providing site-specific delivery options and increasing bioavailability [107]. Various materials have been widely used as intraocular drug carriers, such as dendrimers, liposomes, biodegradable polyesters, mesoporous silica, and gold NPs [107]. These modified particles can target specific cells. In addition, they can be designed to increase the therapeutic efficacy of the drug molecules and ensure the continuous release of the drug contained in them [108].

The use of NP-based systems enhances drug delivery to the posterior part of the eye. It also expands the intravitreal half-life of chemotherapeutic agents [109]. The rapid development of nanotechnology has allowed the use of intelligent nanosystems for cancer imaging, targeted drug delivery, and cancer regression monitoring in post-treatment oncology. In personalized nanomedicine (at least pre-clinically), drug delivery systems including NPs are used [110].

NPs as alternative drug delivery systems for systemic administration provide an essential substrate for improving the ocular transmission of therapeutic agents such as melphalan (MEL) by maintaining the stability of the drug, decreasing the need for frequent prescribing, targeting only cancerous tissues, having a long-term curative effect, minimizing complications, and reducing the number of invasive procedures and the need for the systemic administration of MEL [111]. Surface-modified NP formulations, when used in vivo, may improve Rb treatment. Surface-modified NPs with ligands such as MPG or TET1 pave the way for overcoming in vivo delivery challenges and increase the effectiveness of MEL [111].

Polylactic-co-glycolic acid

Polylactic-co-glycolic acid (PLGA) is especially used in ocular therapy due to its biocompatibility, favorable degradation, and approved clinical applications [112]. Previously, PLGA NPs were used as vectors for the intraocular delivery of active agents such as flurbiprofen [113].

Flurbiprofen-rich NPs showed a greater anti-inflammatory effect than the available eye drops in animal models of ocular inflammation, indicating that NPs increase the bioavailability of flurbiprofen. Surface-modified NPs and MPGs have a greater effect on Rb cells than unmodified NPs [111].

Other available drugs are anthracyclines (doxorubicin, idarubicin), which destroy cancer cells through DNA intercalation and inhibition of topoisomerase, and also have the ability to inhibit metastatic Rb [114]. The intravitreal injection of doxorubicin encapsulated in poly-β-hydroxybutyrate-based microspheres in rabbit ocular tissue showed reduced toxicity to the surrounding natural structures [115]. In addition, encapsulation reduces the peak doxorubicin level compared to free doxorubicin in ocular tissues. The ex vivo transscleral release of doxorubicin encapsulated in PLGA polymer NPs or liposomes (Doxil®, Tibotec Therapy) demonstrated that doxorubicin is easily released in the sclera isolated from humans, but its encapsulation (both in PLGA and liposomes) reduces the rate of transmission [116]. PLGA NPs were studied on Y79 Rb cell lines for the delivery of doxorubicin [117] and ETP [118] and may be prominent candidates for continuous drug delivery models.

Gold NPs

Gold NPs are highly absorptive of near-infrared light and can kill cancer cells due to their unique physical properties [118]. Moreover, light-activated drug secretion can be achieved by using gold NPs that bind to chemotherapeutic agents [119]. Gold nanocages are surrounded by a smart polymer; the nanocages absorb light and change in response to heat, causing the polymer to break down and release doxorubicin [120]. Gold NPs can also easily cross the blood-retinal barrier and do not cause significant cytotoxicity [121]. Gold liposomes and virus-like NPs containing TPT have been administered intravitreally in rabbit models of vitreous seeds [122].

Fibrin glue

Fibrin glue, a biodegradable carrier, is another injectable that is currently being tested as a delivery system for chemotherapy agents [123]. CBP [124] and TPT [125] secreted from fibrin stocks have both been shown to maintain their biologic activity against cultured Rb cells and to reduce the tumor volume in a transgenic mouse model of Rb [126]. In another study, fibrin sealants allowed the continuous transfer of CBP to the ocular tissues and were rapidly cleared in vivo [127]. Clinical studies have also shown promising results for TPT conjugated with fibrin [128].


Dendrimer macromolecules (synthetic polymers) are spherical macromolecules 1–100 nm in size, with three different domains [129]. They have controllable shapes, sizes, surface properties, and voids and can be considered suitable candidates for drug delivery systems because they control the physical and chemical environment during their synthesis [130] and because of their appropriate design parameters, reproducibility and optimization, and ability to overcome drugs’ physicochemical limitations (e.g., solubility, specificity, stability, biologic distribution, and therapeutic efficacy). Dendrimers are also capable of eliminating biologic barriers such as the first pass effect, immune cleaning, cell infiltration, and off-target interactions [131].

The effect of dendrimers as drug delivery systems in ophthalmology has also been studied. They play an effective role in the transmission of drugs to the intraocular tissues [132]. A recent study reported the successful injection of the subconjunctival polyamidoamine dendrimer G3.5 into transgenic Rb mice without toxicity. Also, higher doses of NPs can even lead to reduced tumor burden in the untreated contralateral eye. Another study showed that dendrimer NP-based CBP significantly minimized the tumor load compared to free CBP in a mouse model of Rb [133].

New hydrogel implant

The new hydrogel implant can deliver low-molecular-weight hydrophilic anti-tumor drugs such as TPT and VCR in therapeutic doses. It can prevent the strong complications of systemic or intravitreal/intra-arterial chemotherapy by facilitating lower exposition, long-term medicinal action, and transscleral drug delivery (bypassing the bloodstream) and by reducing the cytotoxicity/necrosis risks (with controlled drug release at the site of drug use) [134]. The purpose of the new hydrogel implant is the direct delivery of anti-tumor drugs to the globe. This implant has two components: an inner hydrophilic layer of 2-hydroxyethyl methacrylate (HEMA) filled with the drug and an outer hydrophobic layer of 2-ethoxyethyl methacrylate to protect the healthy tissue from in vivo exposure to the chemotherapy agent [134].

A recent study assessed the stability of VCR and TPT, their transmitting properties, and the properties of HEMA-based hydrogels. The study showed that VCR is generally more stable while the drug concentration, medium type, and temperature affected the stability of TPT. The best results were obtained in water with a higher concentration at 4 °C and in the RPMI 1640 culture medium [134]. On the basis of the obtained results, it was recommended that the new hydrogel implant be used as a potent therapeutic tool for the delivery of topical medications in the treatment of Rb and other ocular disorders.


ncRNAs are transcripts that are not converted to proteins. They are scattered throughout the human genome and are also abnormally regulated in tumor cells. They are commonly located in fragile regions, in heterozygosity loss sites, and in breakpoint regions. They indicate a new series of genes involved in tumorigenesis [135,136]. ncRNAs are divided into two categories according to function: those with an oncogenic function and those acting as tumor suppressors [137]. They are also classified into two groups on the basis of the length of their sequence: short ncRNAs, with a maximum length of 200 nucleotides, and long ncRNAs (lncRNAs), which are transcripts with more than 200 nucleotides [138]. Recently obtained evidence has shown that lncRNAs are involved in many cellular processes, such as cell proliferation, differentiation, migration, and invasion. Multiple lncRNAs, including BANCR [139], AFAP1-AS1 [140], NEAT1 [141], XIST [142], PlncRNA-1 [143], HOTAIR [144], PANDAR [145], DANCR [146], and THOR [147], cause the progression and metastasis of Rb, but some lncRNAs, such as MEG3 [148], MT1JP [149], and H19 [150], play a tumor-suppressive role.

New evidence also suggests that some lncRNAs, such as MALAT1, H19, and BANCR [149,151,152], are beneficial in the diagnosis and prognosis of Rb. lncRNA has differential expression in Rb and normal tissues, making it a potential biomarker for the diagnosis of Rb. It may also be a potential target for Rb therapy. The most studied class of ncRNAs is the microRNAs (miRNAs), which are about 22 nucleotides long and involved in regulating the expression of more than 60% of all genes [153]. They are also a group of small ncRNAs with independent promoters posited in intergenic sites [154], but they can also be transcribed in introns with the same host gene promoter [155]. They play an important role in cellular physiology and functions and are also involved in the development of various cancers by regulating the expression of the target genes; thus, they have been suggested as attractive biomarkers of tumors for the detection of Rb [153,155]. There are several evidences that the deregulation of different miRNAs is involved in different stages of Rb [156]. Recent studies have reported that miRNAs such as miR-30, miR-let-7e, miR-21, miR-204, and miR-320 are dysregulated in Rb patients and have been recommended as diagnostic biomarkers for Rb detection [157159].

Several critical miRNAs, such as hsa-miR-373, hsa-miR-181a, hsa-miR-125b, and hsa-let-7b, cause Rb progression and metastasis. They might act as tumor suppressors by co-regulating CDK6, CDC25A, and LIN28A. Some miRNAs, such as hsa-miR-25, hsa-miR-18a, and hsa-miR-20a, might exert their function by co-regulating BCL2L1 [160]. Few studies, however, have evaluated the circulation of miRNAs as diagnostic and prognostic biomarkers in Rb [161]. Thus, further research is needed to identify miRNAs and circulating miRNAs that are suitable candidates for the treatment and diagnosis of Rb [162].

Aqueous humor markers

Unlike other cancers, Rb cannot be classified through biopsy. Thus, it does not have any genetic tumor marker [163]. Tissue biopsy is contraindicated in Rb largely because it is invasive and poses a risk of extraocular tumor spread [164]. Nonetheless, studies of tumors in enucleated eyes have provided abundant information regarding the genetics of Rb [165].

Aqueous humor (AH) as an “alternative tumor biopsy” [167] addresses the problems associated with tissue biopsy. The recently shown cell-free tumor DNA (cfDNA) in AH has a potential biomarker role [168]. AH paracentesis is now a standard protocol during administrations of intravitreal chemotherapy for Rb patients. Anterior chamber paracentesis is conducted before the intravitreal injection of the chemotherapy agent to induce transient hypotony and therefore prevent the reflux of tumor cells during injection [169]. It has been found in recent studies that the reproducible AH samples reflect the genomic status of the tumor and Rb somatic chromosomal copy number alterations (SCNAs), which are involved in Rb tumorigenesis. The recurrent SCNAs of Rb in the AH predict the tumor’s response to globe salvage therapy [170], Hence, these results show that a 6p gain in the AH is a strong prognostic biomarker for poor clinical response to treatment [170]. Thus, circulating tumor cell- and cfDNA-based fluid biopsies in the blood or other fluids can now be used clinically for the management of Rb without the need for enucleation [171,172].


A new biomarker called exosome has been introduced in fluid sampling to monitor tumor progression and drug resistance. Exosomes are NPs derived from cell membranes (30–100 nanometers in diameter) and contain RNA, miRNA, lipids, and proteins. Their microvesicles secreted by invasive tumor cells can be found in a variety of body fluids [173]. In recent years, numerous investigations have been made to show that there is a relationship between proteins’ and peptides’ levels of expression and different pathological diseases [174]. In a recent study, exosomes from Rb tumors and tumor seeding in the vitreous humor from Rb cell lines were isolated using high-resolution mass spectrometry [175]. This paves the way for the definition of exosomal markers as potential diagnostic and potential markers of prognostic and therapeutic targets in Rb.


Neddylation or adding Nedd8 modifies post-translational protein and has been linked to cancer development in 1997 [176]. MLN4924, also known as pevonedistat, is a neddylation inhibitor currently being studied on solid tumors [177] and blood malignancies [178] in phase I clinical trials.

The members of the choline family are the physiologic substrates of neddylation. The neddylation of all cullins is effectively blocked by MLN4924 and leads to the accumulation of their substrates, thus causing multiple cellular reactions, including cell cycle arrest, apoptosis, aging, and cell-type dependent-manner autophagy [179].

A recent study showed that in Rb, MLN4924 potently prevents Rb1 loss (Rb1null) and MYCN amplification. The maximum tolerable dose for intravitreal MLN4924 is 10–30 μg [180].

In addition, S-phase kinase-associated protein 2 (SKP2) has been identified as a potential therapeutic target [181]. A recent study demonstrated that the loss of SKP2 destroys Rb1null cells. Thus, intravitreal MLN4924 is an excellent new therapy for Rb, killing cancer cells by removing SKP2 complexes [180].


Despite the availability of various treatments for Rb, there is still an urgent need for new therapeutic options to prevent the delayed side effects of the current interventions and to maintain the patient’s vision to the extent possible. Rb treatment options have evolved rapidly in recent years by changing the paradigm from the standard treatment protocols to targeted chemotherapy agents.

Targeted therapy is a promising treatment for various kinds of cancer. New Rb treatments and modalities have been explored, such as the use of new transporters and pathways for the local delivery of therapeutic agents and targeted molecular therapies. According to the available literature, anti-tumor drugs with molecular targeting are effective in treating Rb. Recent studies have predicted that future combinations of new targeted chemotherapeutic agents with local delivery, including CBP, TPT, and MEL, will increasingly play an important role in the management of Rb by creating safe and effective treatments that can help better control tumors while maintaining the patients’ vision.

Despite the advances in the management of Rb in recent years, there are still some fundamental limitations in the clinical use of the new targeted therapies and delivery pathways. The long-term effects of these new treatment options also need to be further evaluated. It is hoped that with the benefit of better insight into the relationship between Rb cell biology and the future development of targeted and less toxic therapies, non-responder Rb cases will be a thing of the past.


Author contributions: F.A. performed the bibliography research and prepared the initial draft; R.M. commented on and revised the manuscript; M.N. contributed to the study design and participated in the review process. Declarations of Funding: No external funding was provided for the preparation of this article. Conflicts of interest: The authors declare that they have no conflicts of interest.


  1. Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004; 24:828-48. [PMID: 15579980]
  2. Tien H-F, Chuang S-M, Chen M-S, Lee F-Y, Hou P-K. Cytogenetic evidence of multifocal origin of a unilateral retinoblastoma: A help in genetic counseling. Cancer Genet Cytogenet. 1989; 42:203-8. [PMID: 2790755]
  3. M Pritchard EM. A Dyer M, Kiplin Guy R. Progress in small molecule therapeutics for the treatment of retinoblastoma. Mini Rev Med Chem. 2016; 16:430-54. [PMID: 26202204]
  4. Fabian ID, Reddy A, Sagoo MS. Classification and staging of retinoblastoma. Community Eye Health. 2018; 31:11-13.
  5. Kim J, Do H, Egbert P. Enucleated eyes after failed intra-arterial infusion of chemotherapy for unilateral retinoblastoma: histopathologic evaluation of vitreous seeding. Clin Ophthalmol. 2011; 5:1655 [PMID: 22174572]
  6. Nishida S, Tsubaki M. Exploration of Molecular Targets in the Development of New Therapeutics Aimed at Overcoming Multidrug Resistance. Yakugaku Zasshi. 2017; 137:145-9. [PMID: 28154323]
  7. Jackson JR, Patrick DR, Dar MM, Huang PS. Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer. 2007; 7:107-17. [PMID: 17251917]
  8. Lebaron S, Zeltzer LK, Lebaron C, Scott SE, Zeltzer PM. Chemotherapy side effects in pediatric oncology patients: drugs, age, and sex as risk factors. Med Pediatr Oncol. 1988; 16:263-8.
  9. Yap TA, Omlin A, De Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013; 31:1592-605. [PMID: 23509311]
  10. Riechelmann RP, Tannock IF, Wang L, Saad ED, Taback NA, Krzyzanowska MK. Potential drug interactions and duplicate prescriptions among cancer patients. J Natl Cancer Inst. 2007; 99:592-600. [PMID: 17440160]
  11. Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the USA: 1975–2004. Br J Ophthalmol. 2009; 93:24-7. [PMID: 18718969]
  12. Naseripour M. “Retinoblastoma survival disparity”: The expanding horizon in developing countries. Saudi J Ophthalmol. 2012; 26:157-61. [PMID: 23960987]
  13. Dholaria B, Hammond W, Shreders A, Lou Y. Emerging therapeutic agents for lung cancer. J Hematol Oncol. 2016; 9:138 [PMID: 27938382]
  14. González-Cao M, Karachaliou N, Viteri S, Morales-Espinosa D, Teixidó C, Ruiz JS, Molina-Vila MÁ, Santarpia M, Rosell R. Targeting PD-1/PD-L1 in lung cancer: current perspectives. Lung Cancer. 2015; 6:55 [PMID: 28210151]
  15. Reid TW, Albert DM, Rabson AS, Russell P, Craft J, Chu EW, Tralka TS, Wilcox JL. Characteristics of an established cell line of retinoblastoma. J Natl Cancer Inst. 1974; 53:347-60. [PMID: 4135597]
  16. McFall RC, Sery TW, Makadon M. Characterization of a new continuous cell line derived from a human retinoblastoma. Cancer Res. 1977; 37:1003-10. [PMID: 844036]
  17. Griegel S, Hong C, Frötschl R, Hülser DF, Greger V, Horsthemke B, Rajewsky MF. Newly established human retinoblastoma cell lines exhibit an “immortalized” but not an invasive phenotype in vitro. Int J Cancer. 1990; 46:125-32. [PMID: 2365495]
  18. Kim JH, Kim JH, Yu YS, Kim DH, Kim CJ, Kim K-W. Antitumor activity of arsenic trioxide on retinoblastoma: cell differentiation and apoptosis depending on arsenic trioxide concentration. Invest Ophthalmol Vis Sci. 2009; 50:1819-23. [PMID: 19060284]
  19. Yi QY, Bai ZS, Cai B, Chen N, Chen LS, Yuan T, Mao JH. HSV-TK/GCV can induce cytotoxicity of retinoblastoma cells through autophagy inhibition by activating MAPK/ERK. Oncol Rep. 2018; 40:682-92. [PMID: 29845211]
  20. Wang G, Li Z, Li Z, Huang Y, Mao X, Xu C, Cui S. Targeting eIF4E inhibits growth, survival and angiogenesis in retinoblastoma and enhances efficacy of chemotherapy. Biomed Pharmacother. 2017; 96:750-6. [PMID: 29049978]
  21. Kapatai G, Brundler M-A, Jenkinson H, Kearns P, Parulekar M, Peet A, McConville CM. Gene expression profiling identifies different sub-types of retinoblastoma. Br J Cancer. 2013; 109:512-25. [PMID: 23756868]
  22. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986; 323:643-6. [PMID: 2877398]
  23. Togashi K, Okada M, Suzuki S, Sanomachi T, Seino S, Yamamoto M, Yamashita H, Kitanaka C. Inhibition of Retinoblastoma Cell Growth by CEP1347 Through Activation of the P53 Pathway. Anticancer Res. 2020; 40:4961-8. [PMID: 32878784]
  24. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004; 303:844-8. [PMID: 14704432]
  25. Brennan RC, Federico S, Bradley C, Zhang J, Flores-Otero J, Wilson M, Stewart C, Zhu F, Guy K, Dyer MA. Targeting the p53 pathway in retinoblastoma with subconjunctival Nutlin-3a. Cancer Res. 2011; 71:4205-13. [PMID: 21515735]
  26. Laurie NA, Donovan SL, Shih C-S, Zhang J, Mills N, Fuller C, Teunisse A, Lam S, Ramos Y, Mohan A, Johnson D. Inactivation of the p53 pathway in retinoblastoma. Nature. 2006; 444:61-6. [PMID: 17080083]
  27. Zhang F, Tagen M, Throm S, Mallari J, Miller L, Guy RK, Dyer MA, Williams RT, Roussel MF, Nemeth K, Zhu F. Whole-body physiologically based pharmacokinetic model for nutlin-3a in mice after intravenous and oral administration. Drug Metab Dispos. 2011; 39:15-21. [PMID: 20947617]
  28. Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 2012; 481:329-34. [PMID: 22237022]
  29. Gobessi S, Laurenti L, Longo P, Carsetti L, Berno V, Sica S, Leone G, Efremov DG. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia. 2009; 23:686-97. [PMID: 19092849]
  30. Bodur C, Basaga H. Bcl-2 inhibitors: emerging drugs in cancer therapy. Curr Med Chem. 2012; 19:1804-20. [PMID: 22414090]
  31. Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014; 13:673-91. [PMID: 25131830]
  32. Zhao Y, Tan J, Zhuang L, Jiang X, Liu ET, Yu Q. Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci USA. 2005; 102:16090-5. [PMID: 16243973]
  33. Dalgard CL, Van Quill KR, O’Brien JM. Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma. Clin Cancer Res. 2008; 14:3113-23. [PMID: 18483379]
  34. Okada M, Takeda H, Sakaki H, Kuramoto K, Suzuki S, Sanomachi T, Togashi K, Seino S, Kitanaka C. Repositioning CEP-1347, a chemical agent originally developed for the treatment of Parkinson’s disease, as an anti-cancer stem cell drug. Oncotarget. 2017; 8:94872 [PMID: 29212273]
  35. Togashi K, Okada M, Yamamoto M, Suzuki S, Sanomachi T, Seino S, Yamashita H, Kitanaka C. A small-molecule kinase inhibitor, CEP-1347, inhibits survivin expression and sensitizes ovarian cancer stem cells to paclitaxel. Anticancer Res. 2018; 38:4535-42. [PMID: 30061219]
  36. Moncrief JW, Lipscomb WN. Structure of leurocristine methiodide dihydrate by anomalous scattering methods: relation to leurocristine (vincristine) and vincaleukoblastine (vinblastine). Acta Crystallogr. 1966; 21:322-31. [PMID: 5953637]
  37. Ravina E. The evolution of drug discovery: from traditional medicines to modern drugs: John Wiley & Sons; 2011.
  38. Pellegrini F, Budman DR. Tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest. 2005; 23:264-73. [PMID: 15948296]
  39. Qaddoumi I, Billups CA, Tagen M, Stewart CF, Wu J, Helton K, McCarville MB, Merchant TE, Brennan R, Free TM, Given V. Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity. Cancer. 2012; 118:5663-70. [PMID: 22516936]
  40. Rodriguez-Galindo C, Wilson MW, Haik BG, Merchant TE, Billups CA, Shah N, Cain A, Langston J, Lipson M, Kun LE, Pratt CB. Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol. 2003; 21:2019-25. [PMID: 12743157]
  41. Murphree AL, Villablanca JG, Deegan WF, Sato JK, Malogolowkin M, Fisher A, Parker R, Reed E, Gomer CJ. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol. 1996; 114:1348-56. [PMID: 8906025]
  42. Fischer J, Ganellin CR, Ganesan A, Proudfoot J. Analogue-based drug discovery: Wiley-VCH Hoboken, NJ; 2010.
  43. Yared JA, Tkaczuk KH. Update on taxane development: new analogs and new formulations. Drug Des Devel Ther. 2012; 6:371-84..
  44. Di Fiore R, Drago-Ferrante R, D’Anneo A, Augello G, Carlisi D, De Blasio A, Giuliano M, Tesoriere G, Vento R. In human retinoblastoma Y79 cells okadaic acid–parthenolide co-treatment induces synergistic apoptotic effects, with PTEN as a key player. Cancer Biol Ther. 2013; 14:922-31. [PMID: 23938948]
  45. Wang TH, Wang HS, Soong YK. Paclitaxel‐induced cell death: where the cell cycle and apoptosis come together. Cancer. 2000; 88:2619-28. [PMID: 10861441]
  46. Suárez F, Jockovich M-E, Hernandez E, Feuer W, Parel J-M, Murray TG. Paclitaxel in the treatment of retinal tumors of LH beta-Tag murine transgenic model of retinoblastoma. Invest Ophthalmol Vis Sci. 2007; 48:3437-40. [PMID: 17652710]
  47. Rowinsky EK, Eisenhauer E, Chaudhry V, Arbuck S, Donehower RC. Clinical toxicities encountered with paclitaxel (Taxol®). Semin Oncol. 1993; 20:1-15. [PMID: 8102012]
  48. Rathjen FG, Schachner M. Immunocytological and biochemical characterization of a new neuronal cell surface component (L1 antigen) which is involved in cell adhesion. EMBO J. 1984; 3:1-10. [PMID: 6368220]
  49. Jo DH. Lee K, Kim JH, Jun HO, Kim Y, Cho YL, Yu YS, Min JK, Kim JH. L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. Oncotarget. 2017; 8:15441 [PMID: 28061460]
  50. Doronin II, Vishnyakova PA, Kholodenko IV, Ponomarev ED, Ryazantsev DY, Molotkovskaya IM, Kholodenko RV. Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. BMC Cancer. 2014; 14:295-317. [PMID: 24773917]
  51. Chantada GL, Rossi J, Casco F, Fandiño A, Scopinaro M, de Dávila MT, Abramson DH. An aggressive bone marrow evaluation including immunocytology with GD2 for advanced retinoblastoma. J Pediatr Hematol Oncol. 2006; 28:369-73. [PMID: 16794505]
  52. Suzuki M, Cheung N-KV. Disialoganglioside GD2 as a therapeutic target for human diseases. Expert Opin Ther Targets. 2015; 19:349-62. [PMID: 25604432]
  53. Andersch L, Radke J, Klaus A, Schwiebert S, Winkler A, Schumann E, Grunewald L, Zirngibl F, Flemmig C, Jensen MC, Rossig C. CD171-and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing. BMC Cancer. 2019; 19:895 [PMID: 31500597]
  54. Gilliam DT, Menon V, Bretz NP, Pruszak J. The CD24 surface antigen in neural development and disease. Neurobiol Dis. 2017; 99:133-44. [PMID: 27993646]
  55. Deng J, Gao G, Wang L, Wang T, Yu J, Zhao Z. CD24 expression as a marker for predicting clinical outcome in human gliomas. BioMed Res Intel. 2012;2012.
  56. Wan X, Cheng C, Shao Q, Lin Z, Lu S, Chen Y. CD24 promotes HCC progression via triggering Notch-related EMT and modulation of tumor microenvironment. Tumour Biol. 2016; 37:6073-84. [PMID: 26608371]
  57. Jing X, Cui X, Liang H, Hao C, Yang Z, Li X, Yang X, Han C. CD24 is a potential biomarker for prognosis in human breast carcinoma. Cell Physiol Biochem. 2018; 48:111-9. [PMID: 30001552]
  58. Sun J, Feng D, Xi H, Luo J, Zhou Z, Liu Q, Chen Y, Shao Q. CD24 blunts the sensitivity of retinoblastoma to vincristine by modulating autophagy. Mol Oncol. 2020; 14:1740-59. [PMID: 32394616]
  59. Li J, Li C, Yuan H, Gong F. Clinical value of CD24 expression in retinoblastoma. J Biomed Biotechnol. 2012; 2012:158084-89.
  60. Daniely Y, Borowiec JA. Formation of a complex between nucleolin and replication protein A after cell stress prevents initiation of DNA replication. J Cell Biol. 2000; 149:799-810. [PMID: 10811822]
  61. Subramanian N, Srimany A, Kanwar JR, Kanwar RK, Akilandeswari B, Rishi P, Khetan V, Vasudevan M, Pradeep T, Krishnakumar S. Nucleolin-aptamer therapy in retinoblastoma: molecular changes and mass spectrometry–based imaging. Mol Ther Nucleic Acids. 2016; 5:e358 [PMID: 27574784]
  62. Chévez-Barrios P, Hurwitz MY, Louie K, Marcus KT, Holcombe VN, Schafer P, Aguilar-Cordova CE, Hurwitz RL. Metastatic and nonmetastatic models of retinoblastoma. Am J Pathol. 2000; 157:1405-12. [PMID: 11021842]
  63. Eberlin LS. DESI-MS imaging of lipids and metabolites from biological samples. Mass Spectrom Metabolom: Springer; 2014. p. 299–311.
  64. Calligaris D, Caragacianu D, Liu X, Norton I, Thompson CJ, Richardson AL, Golshan M, Easterling ML, Santagata S, Dillon DA, Jolesz FA. Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis. Proc Natl Acad Sci USA. 2014; 111:15184-9. [PMID: 25246570]
  65. Pallante P, Sepe R, Puca F, Fusco A. High mobility group a proteins as tumor markers. Front Med. 2015; 2:15 [PMID: 25859543]
  66. Miao Y, Cui T, Leng F, Wilson WD. Inhibition of high-mobility-group A2 protein binding to DNA by netropsin: a biosensor-surface plasmon resonance assay. Anal Biochem. 2008; 374:7-15. [PMID: 18023407]
  67. Esmailzadeh S, Mansoori B, Mohammadi A, Shanehbandi D, Baradaran B. siRNA-mediated silencing of HMGA2 induces apoptosis and cell cycle arrest in human colorectal carcinoma. J Gastrointest Cancer. 2017; 48:156-63. [PMID: 27629422]
  68. Nalini V, Deepa PR, Raguraman R, Khetan V, Reddy MA, Krishnakumar S. Targeting HMGA2 in retinoblastoma cells in vitro using the aptamer strategy. Ocul Oncol Pathol.. 2016; 2:262-9.
  69. Balachandran A, Zambre A, Kainth JS, Selvan LDN, Parameswaran S, Afrasiabi Z, Krishnakumar S, Kannan R. Targeting HMGA protein inhibits retinoblastoma cell proliferation. RSC Adv.. 2018; 8:31510-4.
  70. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016; 96:365-408. [PMID: 26681795]
  71. Audo I, Darjatmoko SR, Schlamp CL, Lokken JM, Lindstrom MJ, Albert DM, Nickells RW. Vitamin D analogues increase p53, p21, and apoptosis in a xenograft model of human retinoblastoma. Invest Ophthalmol Vis Sci. 2003; 44:4192-9. [PMID: 14507860]
  72. Verhoeff FH. Retinoblastoma undergoing spontaneous regression. Calcifying agent suggested in treatment of retinoblastoma. Am J Ophthalmol. 1966; 62:573 [PMID: 5922000]
  73. Shternfeld IS, Lasudry JG, Chappell RJ, Darjatmoko SR, Albert DM. Antineoplastic effect of 1, 25-dihydroxy-16-ene-23-yne-vitamin D3 analogue in transgenic mice with retinoblastoma. Arch Ophthalmol. 1996; 114:1396-401. [PMID: 8906031]
  74. Sabet SJ, Darjatmoko SR, Lindstrom MJ, Albert DM. Antineoplastic effect and toxicity of 1, 25-dihydroxy-16-ene-23-yne-vitamin D3 in athymic mice with Y-79 human retinoblastoma tumors. Arch Ophthalmol. 1999; 117:365-70. [PMID: 10088815]
  75. Albert DM, Marcus DM, Gallo JP, O’Brien JM. The antineoplastic effect of vitamin D in transgenic mice with retinoblastoma. Invest Ophthalmol Vis Sci. 1992; 33:2354-64. [PMID: 1634333]
  76. Skowron K, Pawlicka I, Gil K. The role of vitamin D in the pathogenesis of ocular diseases. Folia Med Cracov. 2018; 58:103-18. [PMID: 30467438]
  77. Dormoy V, Béraud C, Lindner V, Coquard C, Barthelmebs M, Brasse D, Jacqmin D, Lang H, Massfelder T. Vitamin D3 triggers antitumor activity through targeting hedgehog signaling in human renal cell carcinoma. Carcinogenesis. 2012; 33:2084-93. [PMID: 22843547]
  78. Wagner N, Wagner K-D, Schley G, Badiali L, Theres H, Scholz H. 1, 25-dihydroxyvitamin D3-induced apoptosis of retinoblastoma cells is associated with reciprocal changes of Bcl-2 and bax. Experiment Eye Res.. 2003; 77:1-9.
  79. Albert DM, Nickells RW, Gamm DM, Zimbric ML, Schlamp CL, Lindstrom MJ, Audo I. Vitamin D analogs, a new treatment for retinoblastoma: the first Ellsworth Lecture. Ophthalmic Genet. 2002; 23:137-56. [PMID: 12324873]
  80. Kulkarni AD, Van Ginkel PR, Darjatmoko SR, Lindstrom MJ, Albert DM. Use of combination therapy with cisplatin and calcitriol in the treatment of Y-79 human retinoblastoma xenograft model. Br J Ophthalmol. 2009; 93:1105-8. [PMID: 19336429]
  81. Drago-Ferrante R, Santulli A, Di Fiore R, Giuliano M, Calvaruso G, Tesoriere G, Vento R. Low doses of paclitaxel potently induce apoptosis in human retinoblastoma Y79 cells by up-regulating E2F1. Int J Oncol. 2008; 33:677-87. [PMID: 18813780]
  82. Scholz D, Cai W-j Schaper W. Arteriogenesis, a new concept of vascular adaptation in occlusive disease. Angiogenesis. 2001; 4:247-57. [PMID: 12197469]
  83. Lee SY, Kim D-K, Cho JH, Koh J-Y, Yoon YH. Inhibitory effect of bevacizumab on the angiogenesis and growth of retinoblastoma. Arch Ophthalmol. 2008; 126:953-8. [PMID: 18625942]
  84. Huang L, Zhang Z, Zhang S, Ren J, Zhang R, Zeng H, Li Q, Wu G. Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1α pathway. Int J Mol Med. 2011; 27:407-15. [PMID: 21249310]
  85. Al‐Husein B, Abdalla M, Trepte M, DeRemer DL, Somanath PR. Antiangiogenic therapy for cancer: an update. Pharmacotherapy. 2012; 32:1095-111. [PMID: 23208836]
  86. Miguel NC, Matsuda M, Portes ALF, Allodi S, Mendez-Otero R, Puntar T, Sholl-Franco A, Krempel PG, Monteiro ML. In vitro effects of bevacizumab treatment on newborn rat retinal cell proliferation, death, and differentiation. Invest Ophthalmol Vis Sci. 2012; 53:7904-11. [PMID: 23139275]
  87. Li Z, Guo Z, Chu D, Feng H, Zhang J, Zhu L, Li J. Effectively suppressed angiogenesis-mediated retinoblastoma growth using celastrol nanomicelles. Drug Deliv. 2020; 27:358-66. [PMID: 32091275]
  88. Nanjundaiah SM, Venkatesha SH, Yu H, Tong L, Stains JP, Moudgil KD. Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis by modulating osteoimmune cross-talk. J Biol Chem. 2012; 287:22216-26. [PMID: 22549786]
  89. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-74.
  90. Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I. Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015; 14:261-78. [PMID: 25743081]
  91. Yang H, Cheng R, Liu G, Zhong Q, Li C, Cai W, Yang Z, Ma J, Yang X, Gao G. PEDF inhibits growth of retinoblastoma by anti‐angiogenic activity. Cancer Sci. 2009; 100:2419-25. [PMID: 19832843]
  92. Shi F, Len Y, Gong Y, Shi R, Yang X, Naren D, Yan T. Ribavirin inhibits the activity of mTOR/eIF4E, ERK/Mnk1/eIF4E signaling pathway and synergizes with tyrosine kinase inhibitor imatinib to impair Bcr-Abl mediated proliferation and apoptosis in Ph+ leukemia. PLoS One. 2015; 10:e0136746 [PMID: 26317515]
  93. McEvoy J, Flores-Otero J, Zhang J, Nemeth K, Brennan R, Bradley C, Krafcik F, Rodriguez-Galindo C, Wilson M, Xiong S, Lozano G. Coexpression of normally incompatible developmental pathways in retinoblastoma genesis. Cancer Cell. 2011; 20:260-75. [PMID: 21840489]
  94. Li Q, Löhr CV, Dashwood RH. Activator protein 2α suppresses intestinal tumorigenesis in the Apcmin mouse. Cancer Lett. 2009; 283:36-42. [PMID: 19376641]
  95. Bassett EA, Pontoriero GF, Feng W, Marquardt T, Fini ME, Williams T, West-Mays JA. Conditional deletion of activating protein 2α (AP-2α) in the developing retina demonstrates non-cell-autonomous roles for AP-2α in optic cup development. Mol Cell Biol. 2007; 27:7497-510. [PMID: 17724084]
  96. Bassett EA, Korol A, Deschamps PA, Buettner R, Wallace VA, Williams T, West-Mays JA. Overlapping expression patterns and redundant roles for AP‐2 transcription factors in the developing mammalian retina. Dev Dyn. 2012; 241:814-29. [PMID: 22411557]
  97. Jain S, Glubrecht DD, Germain DR, Moser M, Godbout R. AP-2ε expression in developing retina: contributing to the molecular diversity of amacrine cells. Sci Rep. 2018; 8:1-13. [PMID: 29311619]
  98. Li X, Glubrecht DD, Godbout R. AP2 transcription factor induces apoptosis in retinoblastoma cells. Genes Chromosomes Cancer. 2010; 49:819-30. [PMID: 20607706]
  99. Waxman S, Anderson KC. History of the development of arsenic derivatives in cancer therapy. Oncologist. 2001; 6:3-10.
  100. Grimwade D, Mistry AR, Solomon E, Guidez F. Acute promyelocytic leukemia: a paradigm for differentiation therapy. Acute Myelogenous Leukemia: Springer; 2009. p. 219–35.
  101. Miller WH. Molecular targets of arsenic trioxide in malignant cells. Oncologist. 2002; 7:14-9.
  102. Nassr M, Wang X, Mitra S, Freeman-Anderson NE, Patil R, Yates CR, Miller DD, Geisert EE. Treating retinoblastoma in tissue culture and in a rat model with a novel isoquinoline derivative. Invest Ophthalmol Vis Sci. 2010; 51:3813-9. [PMID: 20570997]
  103. Kaji EH, Leiden JM. Gene and stem cell therapies. JAMA. 2001; 285:545-50. [PMID: 11176856]
  104. Chévez-Barrios P, Chintagumpala M, Mieler W, Paysse E, Boniuk M, Kozinetz C, Hurwitz MY, Hurwitz RL. Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol. 2005; 23:7927-35. [PMID: 16258092]
  105. Rodríguez-García A, Giménez-Alejandre M, Rojas JJ, Moreno R, Bazan-Peregrino M, Cascalló M, Alemany R. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res. 2015; 21:1406-18. [PMID: 25391696]
  106. Pascual-Pasto G, Bazan-Peregrino M, Olaciregui NG, Restrepo-Perdomo CA, Mato-Berciano A, Ottaviani D, Weber K, Correa G, Paco S, Vila-Ubach M, Cuadrado-Vilanova M. Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01. Sci Transl Med. 2019; 11eaat9321 [PMID: 30674657]
  107. Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014; 66:2-25. [PMID: 24270007]
  108. Salmaso S, Caliceti P. Stealth properties to improve therapeutic efficacy of drug nanocarriers. J Drug Deliv. 2013; 2013:374252-70.
  109. Bhavsar D, Subramanian K, Sethuraman S, Krishnan UM. Management of retinoblastoma: opportunities and challenges. Drug Deliv. 2016; 23:2488-96. [PMID: 25758593]
  110. Jaque D, Maestro LM, Del Rosal B, Haro-Gonzalez P, Benayas A, Plaza J, Rodríguez EM, Solé JG. Nanoparticles for photothermal therapies. Nanoscale. 2014; 6:9494-530.
  111. Sims LB, Tyo KM, Stocke S, Mahmoud MY, Ramasubramanian A, Steinbach-Rankins JM. Surface-Modified Melphalan Nanoparticles for Intravitreal Chemotherapy of Retinoblastoma. Invest Ophthalmol Vis Sci. 2019; 60:1696-705. [PMID: 31009525]
  112. You S, Luo J, Grossniklaus HE, Gou M-L, Meng K, Zhang Q. Nanomedicine in the application of uveal melanoma. Int J Ophthalmol. 2016; 9:1215 [PMID: 27588278]
  113. Weng Y, Liu J, Jin S, Guo W, Liang X, Hu Z. Nanotechnology-based strategies for treatment of ocular disease. Acta Pharm Sin B. 2017; 7:281-91. [PMID: 28540165]
  114. Subramanian N, Raghunathan V, Kanwar JR, Kanwar RK, Elchuri SV, Khetan V, Krishnakumar S. Target-specific delivery of doxorubicin to retinoblastoma using epithelial cell adhesion molecule aptamer. Mol Vis. 2012; 18:2783 [PMID: 23213278]
  115. Hu T, Le Q, Wu Z, Wu W. Determination of doxorubicin in rabbit ocular tissues and pharmacokinetics after intravitreal injection of a single dose of doxorubicin-loaded poly-β-hydroxybutyrate microspheres. J Pharm Biomed Anal. 2007; 43:263-9.
  116. Kim ES, Durairaj C, Kadam RS, Lee SJ, Mo Y, Geroski DH, Kompella UB, Edelhauser HF. Human scleral diffusion of anticancer drugs from solution and nanoparticle formulation. Pharm Res. 2009; 26:1155-61. [PMID: 19194787]
  117. Xu Q, Kambhampati SP, Kannan RM. Nanotechnology approaches for ocular drug delivery. Middle East Afr J Ophthalmol. 2013; 20:26 [PMID: 23580849]
  118. Mitra M, Dilnawaz F, Misra R, Harilal A, Verma RS, Sahoo SK, Krishnakumar S. Toxicogenomics of nanoparticulate delivery of etoposide: potential impact on nanotechnology in retinoblastoma therapy. Cancer Nanotechnol. 2011; 2:21-36. [PMID: 26069482]
  119. Menon JU, Jadeja P, Tambe P, Vu K, Yuan B, Nguyen KT. Nanomaterials for photo-based diagnostic and therapeutic applications. Theranostics. 2013; 3:152 [PMID: 23471164]
  120. Yavuz MS, Cheng Y, Chen J, Cobley CM, Zhang Q, Rycenga M, Xie J, Kim C, Song KH, Schwartz AG, Wang LV. Gold nanocages covered by smart polymers for controlled release with near-infrared light. Nat Mater. 2009; 8:935-9. [PMID: 19881498]
  121. Kim JH, Kim JH, Kim K-W, Kim MH, Yu YS. Intravenously administered gold nanoparticles pass through the blood–retinal barrier depending on the particle size, and induce no retinal toxicity. Nanotechnology. 2009; 20:505101 [PMID: 19923650]
  122. Kang SJ, Grossniklaus HE. Rabbit model of retinoblastoma. J Biomed Biotechnol. 2010; 2010:394730-36.
  123. Martin NE, Kim JW, Abramson DH. Fibrin sealant for retinoblastoma: where are we? J Ocul Pharmacol Ther. 2008; 24:433-8. [PMID: 18788992]
  124. Gorodetsky R, Peylan-Ramu N, Reshef A, Gaberman E, Levdansky L, Marx G. Interactions of carboplatin with fibrin (ogen), implications for local slow release chemotherapy. J Control Release. 2005; 102:235-45. [PMID: 15653148]
  125. Tsui JY, Dalgard C, Van Quill KR, Lee L, Grossniklaus HE, Edelhauser HF, O’Brien JM. Subconjunctival topotecan in fibrin sealant in the treatment of transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci. 2008; 49:490-6. [PMID: 18234990]
  126. Van Quill KR, Dioguardi PK, Tong CT, Gilbert JA, Aaberg TM, , Jr Grossniklaus HE, Edelhauser HF, O’Brien JM. Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. Ophthalmology. 2005; 112:1151-8. [PMID: 15885791]
  127. Simpson AE, Gilbert JA, Rudnick DE, Geroski DH, Aaberg TM, Edelhauser HF. Transscleral diffusion of carboplatin: an in vitro and in vivo study. Arch Ophthalmol. 2002; 120:1069-74. [PMID: 12149061]
  128. Yousef YA, Halliday W, Chan HS, Héon E, Gallie BL, Dimaras H. No ocular motility complications after subtenon topotecan with fibrin sealant for retinoblastoma. Can J Ophthalmol. 2013; 48:524-8. [PMID: 24314416]
  129. Gillies ER, Frechet JM. Dendrimers and dendritic polymers in drug delivery. Drug Discov Today. 2005; 10:35-43.
  130. Tomalia DA. Birth of a new macromolecular architecture: dendrimers as quantized building blocks for nanoscale synthetic polymer chemistry. Prog Polym Sci. 2005; 30:294-324.
  131. Mignani S, El Brahmi N, Eloy L, Poupon J, Nicolas V, Steinmetz A, El Kazzouli S, Bousmina MM, Blanchard-Desce M, Caminade AM, Majoral JP. Anticancer copper (II) phosphorus dendrimers are potent proapoptotic Bax activators. Eur J Med Chem. 2017; 132:142-56. [PMID: 28350998]
  132. Franiak-Pietryga I, Ziemba B, Messmer B, Skowronska-Krawczyk D. Dendrimers as Drug Nanocarriers: The future of gene therapy and targeted therapies in cancer. Dendrimers.. 2018; 25:7
  133. Kang SJ, Durairaj C, Kompella UB, O’Brien JM, Grossniklaus HE. Subconjunctival nanoparticle carboplatin in the treatment of murine retinoblastoma. Arch Ophthalmol. 2009; 127:1043-7. [PMID: 19667343]
  134. Cocarta A-I, Hobzova R, Sirc J, Cerna T, Hrabeta J, Svojgr K, Pochop P, Kodetova M, Jedelska J, Bakowsky U, Uhlik J. Hydrogel implants for transscleral drug delivery for retinoblastoma treatment. Mater Sci Eng C. 2019; 103:109799 [PMID: 31349439]
  135. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acadm Sci.. 2004; 101:2999-3004. [PMID: 14973191]
  136. Calin GA, Liu C-g Ferracin M, Hyslop T, Spizzo R, Sevignani C, Fabbri M, Cimmino A, Lee EJ, Wojcik SE, Shimizu M. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell. 2007; 12:215-29. [PMID: 17785203]
  137. Vannini I, Fanini F, Fabbri M. Emerging roles of microRNAs in cancer. Curr Opin Genet Dev. 2018; 48:128-33. [PMID: 29429825]
  138. Yang M, Wei W. Long non-coding RNAs in retinoblastoma. Pathol Res Pract. 2019; 215:152435 [PMID: 31202519]
  139. Su S, Gao J, Wang T, Wang J, Li H, Wang Z. Long non-coding RNA BANCR regulates growth and metastasis and is associated with poor prognosis in retinoblastoma. Tumour Biol. 2015; 36:7205-11. [PMID: 25894373]
  140. Hao F, Mou Y, Zhang L, Wang S, Yang Y. LncRNA AFAP1–AS1 is a prognostic biomarker and serves as oncogenic role in retinoblastoma. Biosci Rep. 2018; 38:BSR20180384 [PMID: 29654169]
  141. Zhong W, Yang J, Li M, Li L, Li A. Long noncoding RNA NEAT1 promotes the growth of human retinoblastoma cells via regulation of miR‐204/CXCR4 axis. J Cell Physiol. 2019; 234:11567-76. [PMID: 30479013]
  142. Hu C, Liu S, Han M, Wang Y, Xu C. Knockdown of lncRNA XIST inhibits retinoblastoma progression by modulating the miR-124/STAT3 axis. Biomed Pharmacother. 2018; 107:547-54. [PMID: 30114638]
  143. Yang Y, Peng X-W. The silencing of long non-coding RNA ANRIL suppresses invasion, and promotes apoptosis of retinoblastoma cells through the ATM-E2F1 signaling pathway. Biosci Rep. 2018; 38 [PMID: 30355646]
  144. Wang S, Liu J, Yang Y, Hao F, Zhang L. PlncRNA‐1 is overexpressed in retinoblastoma and regulates retinoblastoma cell proliferation and motility through modulating CBR3. IUBMB Life. 2018; 70:969-75. [PMID: 30096220]
  145. Dong C, Liu S, Lv Y, Zhang C, Gao H, Tan L, Wang H. Long non-coding RNA HOTAIR regulates proliferation and invasion via activating Notch signalling pathway in retinoblastoma. J Biosci. 2016; 41:677-87. [PMID: 27966488]
  146. Sheng L, Wu J, Gong X, Dong D, Sun X. SP1-induced upregulation of lncRNA PANDAR predicts adverse phenotypes in retinoblastoma and regulates cell growth and apoptosis in vitro and in vivo. Gene. 2018; 668:140-5. [PMID: 29778422]
  147. Wang JX, Yang Y, Li K. Long noncoding RNA DANCR aggravates retinoblastoma through miR‐34c and miR‐613 by targeting MMP‐9. J Cell Physiol. 2018; 233:6986-95. [PMID: 29744877]
  148. Shang Y. LncRNA THOR acts as a retinoblastoma promoter through enhancing the combination of c-myc mRNA and IGF2BP1 protein. Biomed Pharmacother. 2018; 106:1243-9. [PMID: 30119193]
  149. Gao Y, Xiaohe L. LncRNA-MEG3 mediated apoptosis of retinoblastoma by regulating P53 pathway. Rec Adv Ophthalmol.. 2017; 37:301-4.
  150. Bi L, Han F, Zhang X, Li Y. LncRNA MT1JP acts as a tumor inhibitor via reciprocally regulating Wnt/beta‐catenin pathway in retinoblastoma. Eur Rev Med Pharmacol Sci. 2018; 22:4204-14. [PMID: 30024609]
  151. Qi D, Wang M, Yu F. Knockdown of lncRNA-H19 inhibits cell viability, migration and invasion while promotes apoptosis via microRNA-143/RUNX2 axis in retinoblastoma. Biomed Pharmacother. 2019; 109:798-805. [PMID: 30551533]
  152. Tian X, Xu G. Clinical value of lncRNA MALAT1 as a prognostic marker in human cancer: systematic review and meta-analysis. BMJ Open. 2015; 5:e008653 [PMID: 26423854]
  153. Zhang H, Zhong J, Bian Z, Fang X, Peng Y, Hu Y. Long non-coding RNA CCAT1 promotes human retinoblastoma SO-RB50 and Y79 cells through negative regulation of miR-218–5p. Biomed Pharmacother. 2017; 87:683-91. [PMID: 28088735]
  154. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007; 318:1931-4. [PMID: 18048652]
  155. Carvalho IN, Reis AH, dos Santos AC, Vargas FR. A polymorphism in mir-34b/c as a potential biomarker for early onset of hereditary retinoblastoma. Cancer Biomark. 2017; 18:313-7. [PMID: 28106538]
  156. Singh U, Malik MA, Goswami S, Shukla S, Kaur J. Epigenetic regulation of human retinoblastoma. Tumour Biol. 2016; 37:14427-41. [PMID: 27639385]
  157. Beta M, Venkatesan N, Vasudevan M, Vetrivel U, Khetan V, Krishnakumar S. Identification and insilico analysis of retinoblastoma serum microRNA profile and gene targets towards prediction of novel serum biomarkers. Bioinform Biol Insights. 2013; 7:S10501
  158. Wu X, Zeng Y, Wu S, Zhong J, Wang Y, Xu J. MiR-204, down-regulated in retinoblastoma, regulates proliferation and invasion of human retinoblastoma cells by targeting CyclinD2 and MMP-9. FEBS Lett. 2015; 589:645-50. [PMID: 25647033]
  159. Liu SS, Wang YS, Sun YF, Miao LX, Wang J, Li YS, Liu HY, Liu QL. Plasma microRNA-320, microRNA-let-7e and microRNA-21 as novel potential biomarkers for the detection of retinoblastoma. Biomed Rep. 2014; 2:424-8. [PMID: 24748987]
  160. Zhao J-J, Yang J, Lin J, Yao N, Zhu Y, Zheng J, Xu J, Cheng JQ, Lin JY, Ma X. Identification of miRNAs associated with tumorigenesis of retinoblastoma by miRNA microarray analysis. Childs Nerv Syst. 2009; 25:13-20. [PMID: 18818933]
  161. Yang Y, Mei Q. miRNA signature identification of retinoblastoma and the correlations between differentially expressed miRNAs during retinoblastoma progression. Mol Vis. 2015; 21:1307 [PMID: 26730174]
  162. Mirakholi M, Mahmoudi T, Heidari M. MicroRNAs horizon in retinoblastoma. Acta Med Iran. 2013; 51:823-9. [PMID: 24442535]
  163. Golabchi K, Soleimani‐Jelodar R, Aghadoost N, Momeni F, Moridikia A, Nahand JS, Masoudifar A, Razmjoo H, Mirzaei H. MicroRNAs in retinoblastoma: Potential diagnostic and therapeutic biomarkers. J Cell Physiol. 2018; 233:3016-23. [PMID: 28657205]
  164. Mallipatna A, Gallie B, Chévez-Barrios P, Lumbroso-Le Rouic L, Chantada G, Doz F. AJCC Cancer Staging Manual Vol. Springer; 2017.
  165. Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology. 1985; 92:1763-7. [PMID: 4088631]
  166. Thériault BL, Dimaras H, Gallie BL, Corson TW. The genomic landscape of retinoblastoma: a review. Clin Experiment Ophthalmol. 2014; 42:33-52.
  167. Xu L, Berry JL, Kooi I, Murphree AL, Prabakar RK, Reid MW, Stachelek K, Le BH, Welter L, Jubran R, Lee TC. Genomic cfDNA analysis of aqueous humor in retinoblastoma (RB) predicts eye salvage. Cancer Res. 2019; 79:2877
  168. Francis JH, Abramson DH, Ji X, Shields CL, Teixeira LF, Schefler AC, Cassoux N, Hadjistilianou D, Berry JL, Frenkel S, Munier FL. Risk of extraocular extension in eyes with retinoblastoma receiving intravitreous chemotherapy. JAMA Ophthalmol. 2017; 135:1426-9. [PMID: 29098285]
  169. Munier FL, Soliman S, Moulin AP, Gaillard M-C, Balmer A, Beck-Popovic M. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol. 2012; 96:1084-7. [PMID: 22368262]
  170. Berry JL, Xu L, Kooi I, Murphree AL, Prabakar RK, Reid M, Stachelek K, Le BH, Welter L, Reiser BJ, Chevez-Barrios P. Genomic cfDNA analysis of aqueous humor in retinoblastoma predicts eye salvage: the surrogate tumor biopsy for retinoblastoma. Mol Cancer Res. 2018; 16:1701-12. [PMID: 30061186]
  171. Tarazona N, Cervantes A. Liquid biopsy: another tool towards tailored therapy in colorectal cancer. Ann Oncol. 2018; 29:7-8. [PMID: 29045545]
  172. Zhang W, Xia W, Lv Z, Xin Y, Ni C, Yang L. Liquid biopsy for cancer: circulating tumor cells, circulating free DNA or exosomes? Cell Physiol Biochem. 2017; 41:755-68. [PMID: 28214887]
  173. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010; 73:1907-20. [PMID: 20601276]
  174. Ispas CR, Crivat G, Andreescu S. Recent developments in enzyme-based biosensors for biomedical analysis. Anal Lett. 2012; 45:168-86.
  175. Galardi A, Colletti M, Lavarello C, Paolo VD, Mascio P, Russo I, Cozza R, Romanzo A, Valente P, De Vito R, Pascucci L. Proteomic Profiling of Retinoblastoma-Derived Exosomes Reveals Potential Biomarkers of Vitreous Seeding. Cancers (Basel). 2020; 12:1555 [PMID: 32545553]
  176. Kamitani T, Kito K, Nguyen HP, Yeh ET. Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein. J Biol Chem. 1997; 272:28557-62. [PMID: 9353319]
  177. Sarantopoulos J, Shapiro GI, Cohen RB, Clark JW, Kauh JS, Weiss GJ, Cleary JM, Mahalingam D, Pickard MD, Faessel HM, Berger AJ. Phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with advanced solid tumors. Clin Cancer Res. 2016; 22:847-57. [PMID: 26423795]
  178. Swords RT, Erba HP, DeAngelo DJ, Bixby DL, Altman JK, Maris M, Hua Z, Blakemore SJ, Faessel H, Sedarati F, Dezube BJ. Pevonedistat (MLN 4924), a First‐in‐Class NEDD 8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br J Haematol. 2015; 169:534-43. [PMID: 25733005]
  179. Pan Y, Xu H, Liu R, Jia L. Induction of cell senescence by targeting to Cullin-RING Ligases (CRLs) for effective cancer therapy. Int J Biochem Mol Biol. 2012; 3:273 [PMID: 23097743]
  180. Aubry A, Yu T, Bremner R. Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy. Cell Death Dis. 2020; 6:2-12. [PMID: 32123578]
  181. Chen Z, Sui J, Zhang F, Zhang C. Cullin family proteins and tumorigenesis: genetic association and molecular mechanisms. J Cancer. 2015; 6:233 [PMID: 25663940]