RARE DISEASE
Hereditary retinoblastoma
Hereditary retinoblastoma
Hereditary retinoblastoma
Drug discovery
2
drugs
With orphan designations
Overview
Hereditary retinoblastoma is caused by germline RB1 mutations, predisposing patients to bilateral retinal tumors typically diagnosed by age 2. It accounts for 40% of cases [2][6][14] and confers lifelong risks of trilateral retinoblastoma (pineal tumors) [1][11] and secondary malignancies (osteosarcoma, melanoma) [7][15]. Genetic counseling and RB1 testing are critical for family risk assessment [1][11][19].
Categories: rare genetic diseases, rare neoplastic diseases, rare ophthalmic disorders
Research Papers
314 drug discovery papers about Hereditary retinoblastoma, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
314 drug discovery papers about Hereditary retinoblastoma, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2024-01-19 | Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3
Abstract Background GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. Methods The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. Results We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro , significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. Conclusion Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.
2022-05-18 | Comprehensive Analysis of the Immune Cell Infiltration Landscape and Immune-Related Methylation in Retinoblastoma
Retinoblastoma is a common pediatric intraocular cancer, originating from cone precursors. The development of immunotherapies can help eradicate the tumor without vision loss, which would largely improve the quality of life of patients with retinoblastoma. Investigation of the tumor immune microenvironment provides knowledge for developing novel immunotherapies in cancer. However, the immune cell infiltrative landscape of retinoblastoma is unknown. Here, we compared the relative expression of immune gene signatures among 59 patients with retinoblastoma. The patients were divided into two subgroups according to the 28 types of immune cell infiltration (ICI) scores. We found that a subgroup with high ICI scores had increased expression levels of late cone markers, while the other subgroup exhibited larger tumor size and metastasis propensity. Furthermore, hypermethylated genes in the high-ICI subgroup were associated with immune regulation in the tumor microenvironment, suggesting that DNA methylation may play a vital regulatory role in retinoblastoma immunity. Our study provides a comprehensive framework for the systemic analysis of the influences of epigenetic events on the tumor immune microenvironment. We anticipate that our assay can not only provide insights into tumor immune regulation but also open up the perspectives for the identification of novel immunotherapy targets for retinoblastoma.
2018-04-01 | THE RECOGNITION OF CAVITARY RETINOBLASTOMA TUMORS
Purpose: To assess the role of consolidating adjuvant therapy for cavitary retinoblastoma and to understand if there is any phenotype–genotype correlation. Methods: Patients with retinoblastomas having ophthalmoscopically visible cavities between 2004 and 2014 in whom 4 to 6 cycles of systemic chemotherapy were given. Results: Eighteen eyes of 17 patients displayed cavitary retinoblastomas. This represented 6.8% of 250 patients. Mean age at diagnosis was 13 months; 5 unilateral (29%) and 12 bilateral (71%). The mean (median, range) number of retinoblastoma tumors per eye was 2 (2; 1–6). The number of cavities per tumor was 3 (2, 1–6). Intratumoral cavities were seen in the superficial portion of the tumor in 10 eyes (55%). The cavities became visible in eight eyes (44%) and collapsed in eight eyes (44%). Two eyes required enucleation because of relapse in noncavitary tumors. Germline mutations were detected in 14 patients (82%) of whom four demonstrated mosaicism (29%); only one had a low penetrant mutation. The mean follow-up period was 40 (35, 6–120) months. Conclusion: Cavitary retinoblastomas can be detected after systemic chemotherapy with cavities becoming visible after mean two cycles of chemotherapy (secondary cavitary retinoblastoma). The etiology is uncertain. They remain stable and do not require aggressive adjuvant therapy. There was no evident phenotype–genotype correlation with mosaicism noted in 29%.
2017-03-22 | DO MRPS18-2 AND RB PROTEINS COOPERATE TO CONTROL CELL STEMNESS AND DIFFERENTIATION, PREVENTING CANCER DEVELOPMENT?
In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule. These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1-encoded protein (RB) does not control the cell cycle in embryonic stem cells. It has not been yet well understood how RB controls cell stemness and differentiation. The question arises why “inactive” RB is required for the survival and stemness of cells? Recently, we have found that overexpression of the RB-binding protein MRPS18-2 (S18-2) in primary fibroblasts leads to their immortalization, which is accompanied by the induction of embryonic stem cell markers and, eventually, malignant transformation. We suggest that cell stemness may be associated with high expression levels of both proteins, RB and S18-2. There must be a strict regulation of the expression levels of S18-2 and RB during embryogenesis. Disturbances in the expression of these proteins would lead to the abnormalities in development. We think that the S18-2 protein, together with the RB, plays a crucial role in the control on cell stemness and differentiation. We hope to uncover the new mechanisms of the cell fate determination. The S18-2 may serve as a new target for anticancer medicines, which will help to improve human health.
2017-02-22 | HER2 Overexpression in Retinoblastoma: A Potential Therapeutic Target
Retinoblastoma (RB) is the most common primary intraocular malignancy. Current therapies are associated with high morbidity in the short- and long-term. Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein detected in 15-30% of breast cancers, but it has also been described in other malignancies. Recently, it has been claimed that a truncated version of this protein is expressed in RB, responsive to directed therapies in vitro. We scored HER2 overexpression in RB tissue samples and discussed its potential clinical utility.HER2 overexpression was investigated using immunohistochemistry; the overexpression was evaluated with a score ranging from 0 to 3+ according to the membranous staining pattern in archival formalin-fixed, paraffin-embedded RBs.A total of 60 RB cases and a RB cell line (Y79) were considered. The mean age at enucleation was 31.6 ± 31.5 months. The mean time from diagnosis to enucleation was 11.8 ± 11.2 months (range 1-44). Five (8%) cases were multifocal. HER2 overexpression was negative in all RB cases (49 cases scored 0 and 11 scored 1+) and in the Y79 cell line.Overall, we were not able to demonstrate the overexpression of HER2. Further studies should clarify and better elucidate the potential role of HER2-targeted therapies in RB.
small molecules
2025-04-25 | Epigenetic Reprogramming by Decitabine in Retinoblastoma
Introduction: Retinoblastoma (Rb) is a rare cancer, yet it is the most common eye tumor in children. It can occur in either a familial or sporadic form, with the sporadic variant being more prevalent, though its downstream effects on epigenetic markers remain largely unclear. Currently, the treatment for retinoblastoma typically involves aggressive chemotherapy and surgical resection. The identification of specific epigenetic characteristics of non-hereditary (sporadic) Rb has led to the development of advanced, high-throughput methods to explore its epigenetic profile. Our previous research demonstrated that treatment with the demethylating agent 5-Aza-2′-deoxycytidine (decitabine; DAC) induced cell cycle arrest and apoptosis in a well-characterized retinoblastoma model (WERI-Rb-1). Our analysis of time-dependent gene expression in WERI-Rb-1 cells following DAC exposure has led to the development of testable hypotheses to further investigate the epigenetic impact on the initiation and progression of retinoblastoma tumors. Methods: Gene expression analysis of publicly available datasets from patients’ primary tumors and normal retina have been compared with those found in WERI-Rb-1 cells to assess the relevance of DAC-driven genes as markers of primary retinoblastoma tumors. The effect of DAC treatment has been evaluated in vivo, both in subcutaneous xenografts and in orthotopic models. qPCR analysis of gene expression and Methylation-Specific PCR (MSP) was performed. Results: Our analysis of network maps for differentially expressed genes in primary tumors compared to DAC-driven genes identified 15 hub/driver genes that may play a pivotal role in the genesis and progression of retinoblastoma. DAC treatment induced significant tumor growth arrest in vivo in both subcutaneous and orthotopic xenograft retinoblastoma models. This was associated with changes in gene expression, either through the direct switching-on of epigenetically locked genes or through the indirect regulation of linked genes, suggesting the potential use of DAC as an epigenetic anti-cancer drug for the treatment of retinoblastoma patients. Conclusion: There is a pressing need to develop innovative treatments for retinoblastoma. Our research revealed that DAC can effectively suppress the growth and progression of retinoblastoma in in vivo models, offering a potential new therapeutic approach to battle this destructive disease. This discovery highlights the impact of this epigenetic therapy in reprogramming tumor dynamics, and thus its potential to preserve both the vision and lives of affected children.
2024-12-30 | Expression of Wnt signaling proteins LEF1, β-catenin, GSK3β, DVL1, and N-myc varies across retinoblastoma subtypes and pRb phosphorylation status
Retinoblastoma, a rare childhood eye cancer, has hereditary and non-hereditary forms. While TNM classification helps in prognosis, understanding molecular mechanisms is vital for the clinical behavior of retinoblastoma prediction. Our study aimed to analyze the expression levels of key Wnt pathway proteins, GSK3β, LEF1, β-catenin, and DVL1, and associate them to non-phosphorylated active form (pRb) and the phosphorylated inactive form (ppRb) and N-myc expression, in retinoblastoma cells and healthy retinal cells, in order to elucidate their roles in retinoblastoma and identify potential targets that could help to improve diagnostic and therapy. Specimens from 22 retinoblastoma cases (unilateral, bilateral, and trilateral) were analyzed. Immunohistochemistry assessed proteins' expressions, followed by semi-quantitative analysis using the Immunoreactivity Score (IRS). Bayesian statistical methods were employed for data analysis. The study revealed various expression patterns of Wnt signaling proteins across different retinoblastoma types. The high expression levels were observed for LEF1 and DVL1. Inactive GSK3β and nuclear localization of β-catenin indicated Wnt signaling activation. The levels of inactive ppRb were significantly higher in retinoblastoma compared to healthy retina, as well as the levels of inactive GSK3β. Positive correlations between DVL1 and N-myc, GSK3β Y216 and GSK3β S9 and non-P β-catenin and LEF1 were established. Retinoblastomas without germline mutations (RB1+/+) exhibited high pRb, N-myc, and LEF1 levels, while those in genetically predisposed children (RB1+/-) showed lower expression of these proteins. Trilateral retinoblastomas demonstrated especially high N-myc and LEF1, but low pRb and ppRb levels. The findings highlight the meaningful role of the Wnt signaling pathway in retinoblastoma pathogenesis, providing insights into potential therapeutic targets. Understanding molecular features may pave the way for personalized treatments and improve outcomes for retinoblastoma patients.
2024-03-18 | Therapeutic Strategies for RB1-Deficient Cancers: Intersecting Gene Regulation and Targeted Therapy
The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.
2024-03-15 | Advancement in the treatment, genetic understanding, and diagnostic approaches for retinoblastoma
The most common intraocular tumor in children is retinoblastoma. In developed countries, there has been an impressive rise in the survival rate and visual outcome of patients with retinoblastoma. This is clarified by developments in retinoblastoma treatment and early detection of tumors. The primary therapy remedy for intraocular retinoblastoma is now chemotherapy along with adjuvant consolidative treatment, instead of external beam radiation. Likewise, prophylactic chemotherapy is now allowed to treat potential micro metastases in enucleated eyes based on the identification of high-risk histopathological factors. Extra ocular retinoblastoma still has a poor future outcome; chances of survival have been reported to be between 50% and 70%. Retinoblastoma patients' overall survival is still struggling in developing countries, mostly because of delayed presentation and greater risk of extra ocular illness while compared to with the developed world, where intraocular disease contributes to majority of cases. To enhance the survival rate for those with retinoblastoma in developing countries, greater priority must be given to early detection of tumors. We provide a summary of the latest clinical management of retinoblastoma in this article.
2024-03-01 | Characterization of Retinoblastoma Patients in a Referral Center on the Colombian North Coast
Purpose: The purpose of the following study was to describe the sociodemographic, clini-cal, and therapeutic characteristics of patients with retinoblastoma (RB), the most common intraocular tumor in children, receiving medical care in an eyecare institution in the Carib-bean region of Colombia.Methods: A case series between 2016 and 2021 was carried out. Eyes of patients with RB, receiving medical care in a single health care institution, and in compliance with the esta-blished follow-up protocol, were included. Descriptive analyzes of relevant variables were performed.99Characterization of Retinoblastoma Patients in a Referral Center on the Colombian North CoastAna María Álvarez Castillo, Cesar Atencia Niño,Diana Cifuentes Zapata, Katia Gutiérrez Brun,Jaime Moreno Chaparro, Javier Antonio Amaya Nieto, Javier Vásquez RamírezVol. 40(1), 2024, 97-108Barranquilla (Col.) Results: In this study, a totalof 21 eyes of 16 patients were examined. The average age at the time of diagnosis was 17.7 months, and 50% of children were male. Using the Interna-tional Classification for Intraocular Retinoblastoma, 42.9% of the total cases were classi-fied as group D. Out of the 21 cases, 71.4% went into total remission without the necessity for enucleation, and the most common treatment was chemotherapy, using Melphalan® via intraarterial or intravitreal administration.Conclusion: Specific findings of patients with RB in the Caribbean Coast of Colombia were identified. These findings imply that, despite the obstacles to healthcare access, an early diagnosis and a treatment plan using intraarterial chemotherapy may provide a satisfac-tory clinical outcome (remission).
oligonucleotides
2023-02-23 | Intraocular siRNA Delivery Mediated by Penetratin Derivative to Silence Orthotopic Retinoblastoma Gene
Gene therapy brings a ray of hope for inherited ocular diseases that may cause severe vision loss and even blindness. However, due to the dynamic and static absorption barriers, it is challenging to deliver genes to the posterior segment of the eye by topical instillation. To circumvent this limitation, we developed a penetratin derivative (89WP)-modified polyamidoamine polyplex to deliver small interference RNA (siRNA) via eye drops to achieve effective gene silencing in orthotopic retinoblastoma. The polyplex could be spontaneously assembled through electrostatic and hydrophobic interactions, as demonstrated by isothermal titration calorimetry, and enter cells intactly. In vitro cellular internalization revealed that the polyplex possessed higher permeability and safety than the lipoplex composed of commercial cationic liposomes. After the polyplex was instilled in the conjunctival sac of the mice, the distribution of siRNA in the fundus oculi was significantly increased, and the bioluminescence from orthotopic retinoblastoma was effectively inhibited. In this work, an evolved cell-penetrating peptide was employed to modify the siRNA vector in a simple and effective way, and the formed polyplex interfered with intraocular protein expression successfully via noninvasive administration, which showed a promising prospect for gene therapy for inherited ocular diseases.
2022-03-05 | LncRNA HOTAIR facilitates proliferation and represses apoptosis of retinoblastoma cells through the miR-20b-5p/RRM2/PI3K/AKT axis
Retinoblastoma (RB) represents an adolescent eye malignancy. Long non-coding RNA (LncRNA) HOTAIR shows aberrant expression in many malignancies. This research investigated the mechanism of HOTAIR in RB.Normal retinal cell lines (ARPE-19 and RPE-1) and RB cell lines (ORB50, Y79, HXO-RB44, and WERI-RB) were selected for detection of HOTAIR expression by qRT-PCR. sh-HOTAIR was delivered into Y79 and HXO-RB44 cells. Cell-cycle distribution, proliferation, and apoptosis were detected by CCK-8 assay and flow cytometry. Binding relationships among HOTAIR, miR-20b-5p, and RRM2 were confirmed using dual-luciferase assay. Roles of miR-20b-5p and RRM2 in RB cell-cycle distribution, proliferation, and apoptosis were ascertained by functional rescue experiments. Murine model of xenograft tumor was established, followed by detection of tumor growth and counting of Ki67-positive cells. Expressions of proliferation- and apoptosis-associated proteins and PI3K/AKT pathway-related proteins were determined by Western blot.HOTAIR was elevated in RB cells relative to that in normal retinal cells and showed relatively high expression in Y79 and HXO-RB44 cells. sh-HOTAIR induced RB cell-cycle arrest, restrained proliferation, and strengthened apoptosis. HOTAIR functioned as the ceRNA of miR-20b-5p and targeted RRM2. RB cells had poorly-expressed miR-20b-5p and highly-expressed RRM2. miR-20b-5p downregulation or RRM2 overexpression facilitated RB cell-cycle and proliferation, suppressed apoptosis, and reversed the protective effect of sh-HOTAIR on RB. sh-HOTAIR reduced tumor growth and Ki67-positive cells in vivo and inactivated PI3K/AKT pathway.LncRNA HOTAIR upregulated RRM2 by competitively binding to miR-20b-5p and activated PI3K/AKT pathway, thereby facilitating proliferation and repressing apoptosis of RB cells.
2021-10-14 | Identification and functional annotation of differentially expressed long noncoding RNAs in retinoblastoma
Retinoblastoma (RB), the most common intraocular malignancy, typically occurs in pediatric patients under the age of 6 years. The present study aimed to explore the long noncoding RNA (lncRNA) expression profile in RB and identify novel lncRNA biomarkers to facilitate the investigation of molecular mechanisms of RB and improve clinical therapy. Raw microarray data for the comparison of gene expression between three RB and three adjacent normal tissue samples were downloaded from Gene Expression Omnibus (dataset no. GSE111168). After identification of differentially expressed lncRNAs (DELs) and differentially expressed mRNAs (DEMs) in RB, functional enrichment analyses and a DEL-DEM weighted correlation network analysis were performed. A total of 3,915 DELs (1,774 upregulated and 2,141 downregulated) and 3,715 DEMs (1,492 upregulated and 2,223 downregulated) were identified in RB. The DEL-targeted DEMs were highly enriched by genes involved in hexose transport, muscle tissue morphogenesis, the stereocilium membrane, endothelin B receptor binding and γ-filamin/ABP-L, α-actinin and telethonin binding protein of the Z-disc binding. Furthermore, associations of the DELs and DEMs with several pathways were determined, including PI3K/AKT, Hippo and cancer signaling, as well as extracellular matrix-receptor interaction pathways. Coexpression network analysis revealed that the top three DELs, lnc-DAZ1-161, lnc-HDAC7-21 and lnc-OR52A1-55, formed coexpression modules with 181, 156 and 210 DEMs, respectively. In addition, the top three DEMs, namely EIF1AY, GSTM1 and NLRP11, formed coexpression modules with 33, 50 and 41 DELs, respectively. Validation using reverse transcription-quantitative PCR indicated that the expression of representative lncRNAs (lnc-DAZ1-161 and lnc-HDAC7-21) in RB cells in vitro was consistent with that in RB tissues in the database, while the expression of lnc-OR52A1-55 was not consistent with the database. These results suggested that the aberrant lncRNA expression profile in RB is related to the differential regulation of numerous physiological and pathological processes. The lncRNA and mRNA profiles in RB identified may provide novel targets for the investigation of its molecular mechanisms and thus lead to improvements in clinical therapy for RB.
2020-11-01 | <p>Effect of miR-515-5p on Proliferation and Drug Sensitivity of Retinoblastoma Cells</p>
Retinoblastoma (RB) is a common malignancy in children eyes. Aberrant microRNA (miR) expression is observed in many cancer cases. miR-515-5p is reported to be concerned with the course of many cancers. This study explores the role of miR-515-5p in proliferation and drug sensitivity of RB cells.Human RB cell lines (WERI-RB1, SO-RB50 and Y79) and human retinal pigment epithelial cell line ARPE-19 were utilized in this study. Drug-resistant cells SO-RB50/VCR and SO-RB50/CBP were constructed for the following experiments. The expressions of miR-515-5p and Notch1 in RB cells were detected. Notch1 was significantly upregulated in RB cells while miR-515-5p was notably downregulated. Then, the binding relationship between miR-515-5p and Notch1 was predicted and verified.miR-515-5p negatively regulated Notch1 expression. In vitro and in vivo experiments revealed that overexpressed miR-515-5p inhibited RB cell proliferation and enhanced drug sensitivity. Functional rescue experiment suggested that miR-515-5p regulated RB cell proliferation and drug sensitivity via inhibiting Notch1 expression.It could be concluded that overexpressed miR-515-5p suppressed proliferation and drug resistance of RB cells by targeting Notch1 expression, indicating that miR-515-5p might constitute a promising therapy target for RB.
2019-11-14 | Non-Coding RNAs in Retinoblastoma
Retinoblastoma (Rb) is the most common ocular pediatric malignancy that arises from the retina and is caused by a mutation of the two alleles of the tumor suppressor gene, RB1. Although early detection provides the opportunity of controlling the primary tumor with effective therapies, metastatic activity is fatal. Non-coding RNAs (ncRNAs) have emerged as important modifiers of a plethora of biological mechanisms including those involved in cancer. They are classified into short and long ncRNAs according to their length. Deregulation of all these molecules has also been shown to play a critical role in Rb pathogenesis and progression. It is believed that ncRNAs can provide new insights into novel regulatory mechanisms associated with clinical pathological characteristics, facilitating the development of therapeutic alternatives for the treatment of Rb. In this review we describe a variety of ncRNAs which, capable of regulating the most likely candidate genes involved in the tumorigenesis of Rb, could prove useful in analyzing different aspects of this cancer.
gene therapies
2025-08-13 | Retinoblastoma: Evolving Concepts and Future Challenges
Retinoblastoma is the most common ocular malignancy in children. It results from mutations in the RB1 gene or from MYCN oncogene amplification. We distinguish between the more common unilateral form and the rarer bilateral form. It is important to note that bilateral retinoblastoma is always hereditary. The most common and characteristic symptom is the white pupillary reflex. In addition, the child may develop strabismus or heterochromia. Treatment methods vary, ranging from those aimed at salvaging the eye to those involving total enucleation. Prognosis depends on the location and stage of the tumor. This review aims to explore the literature on new therapeutic methods and recent discoveries in the field of retinoblastoma.
2019-01-23 | Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01
Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1 VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.
2017-08-05 | Defective splicing of the RB1 transcript is the dominant cause of retinoblastomas
Defective splicing is a common cause of genetic diseases. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations with most mapping to the critical GT or AG nucleotides within the 5′ and 3′ splice sites. However, splicing mutations are underreported and the fraction of splicing mutations that compose all disease alleles varies greatly across disease gene. For example, there is a great excess (46%; ~threefold) of hereditary disease alleles that map to splice sites in RB1 that cause retinoblastoma. Furthermore, mutations in the exons and deeper intronic position may also affect splicing. We recently developed a high-throughput method that assays reported disease mutations for their ability to disrupt pre-mRNA splicing. Surprisingly, 27% of RB1-coding mutations tested also disrupt splicing. High-throughput in vitro spliceosomal assembly assay reveals heterogeneity in which stage of spliceosomal assembly is affected by splicing mutations. 58% of exonic splicing mutations were primarily blocked at the A complex in transition to the B complex and 33% were blocked at the B complex. Several mutants appear to reduce more than one step in the assembly. As RB1 splicing mutants are enriched in retinoblastoma disease alleles, additional priority should be allocated to this class of allele while interpreting clinical sequencing experiments. Analysis of the spectrum of RB1 variants observed in 60,706 exomes identifies 197 variants that have enough potential to disrupt splicing to warrant further consideration.
2007-11-13 | Pathogenic validation of unique germline intronic variants ofRB1 in retinoblastoma patients using minigenes
Precise identification of the pathogenic character of germline mutations in the retinoblastoma gene (RB1) is fundamental to provide genetic counselling to patients at risk of developing retinoblastoma. In contrast to bona fide oncogenic RB1 mutations like nonsense or frameshift mutations, and those affecting invariant dinucleotides at splice sites, intronic variants affecting less conserved splice motifs require additional analysis to ascertain whether splicing is altered. Although the frequency of these variations is low, their impact on genetic counselling is high, since they are usually associated with low penetrance phenotypes and unaffected carriers. In this work, we used minigene assays to study infrequent germline intronic variations for which functional data were not available. Using this approach, the aberrant splicing and the resulting oncogenic nature of three intronic RB1 mutations was established (c.501-15T>G, c.719-9C>G, c.2326-8T>A). Conversely, the intronic variant c.1961-12T>C was categorized by minigene assay as a very infrequent neutral polymorphism. To our knowledge this is the first report describing the use of minigene constructs to study the oncogenic character of intronic RB1 variants detected during mutational screening and show the utility of this approach to ascertain the oncogenic nature of unique RB1 intronic variants for which no previous functional and clinical data are available. Minigene assay can be especially useful when lymphocyte RNA is not available for study, or when aberrant mRNA can not be detected as a consequence of nonsense mediated decay. Since RB1 minigene are time-consuming assays, owing to the genomic organization of the RB1 gene, it should be welcome the design of new expression vectors that make this type of studies more straightforward. © 2007 Wiley-Liss, Inc.
2007-09-24 | Cell lineage-specific interactions between Men1 and Rb in neuroendocrine neoplasia
Inactivation of multiple endocrine neoplasia (MEN) type 1 gene (Men1) results in development of multiple endocrine tumors in Men1(+/-) mice and in humans. Intriguingly, loss of the wild-type retinoblastoma 1 (Rb) gene also leads to MEN-like phenotype in Rb(+/-) mice. To evaluate potential genetic interactions between these genes, we prepared and characterized Men1(+/-)Rb(+/-) compound mice in parallel with their parental genotypes. Men1 and Rb did not cooperate in tumor suppression, as demonstrated by comparable survival rates of Rb(+/-) and Men1(+/-)Rb(+/-) mice, absence of tumor growth acceleration and lack of novel neoplasms. Notably, the loss of the remaining copy of the wild-type Men1 and Rb was mutually exclusive in all tumors of Men1(+/-)Rb(+/-) mice, including pituitary anterior lobe and adrenal medulla neoplasms shared by Rb- and Men1-deficient phenotypes. Down-regulation of Men1 targets p18 and p27 and increased presence of phosphorylated-Rb were observed in Men1-deficient pheochromocytomas of Men1(+/-)Rb(+/-) and Men1(+/-) mice. At the same time, the RNA interference (RNAi) knock-down of Men1 mRNA resulted in increased apoptosis of Rb-deficient medullary thyroid carcinoma cells. These results demonstrate that, depending on cell lineage context, combined Men1 and Rb deficiency may be either redundant or detrimental to neoplastic growth. Identification of cell lineage-specific interactions between Men1 and Rb may have important implications for development of rationally designed therapeutic approaches.
antibodies
2024-01-19 | Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3
Abstract Background GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. Methods The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. Results We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro , significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. Conclusion Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.
2022-05-18 | Comprehensive Analysis of the Immune Cell Infiltration Landscape and Immune-Related Methylation in Retinoblastoma
Retinoblastoma is a common pediatric intraocular cancer, originating from cone precursors. The development of immunotherapies can help eradicate the tumor without vision loss, which would largely improve the quality of life of patients with retinoblastoma. Investigation of the tumor immune microenvironment provides knowledge for developing novel immunotherapies in cancer. However, the immune cell infiltrative landscape of retinoblastoma is unknown. Here, we compared the relative expression of immune gene signatures among 59 patients with retinoblastoma. The patients were divided into two subgroups according to the 28 types of immune cell infiltration (ICI) scores. We found that a subgroup with high ICI scores had increased expression levels of late cone markers, while the other subgroup exhibited larger tumor size and metastasis propensity. Furthermore, hypermethylated genes in the high-ICI subgroup were associated with immune regulation in the tumor microenvironment, suggesting that DNA methylation may play a vital regulatory role in retinoblastoma immunity. Our study provides a comprehensive framework for the systemic analysis of the influences of epigenetic events on the tumor immune microenvironment. We anticipate that our assay can not only provide insights into tumor immune regulation but also open up the perspectives for the identification of novel immunotherapy targets for retinoblastoma.
2018-04-01 | THE RECOGNITION OF CAVITARY RETINOBLASTOMA TUMORS
Purpose: To assess the role of consolidating adjuvant therapy for cavitary retinoblastoma and to understand if there is any phenotype–genotype correlation. Methods: Patients with retinoblastomas having ophthalmoscopically visible cavities between 2004 and 2014 in whom 4 to 6 cycles of systemic chemotherapy were given. Results: Eighteen eyes of 17 patients displayed cavitary retinoblastomas. This represented 6.8% of 250 patients. Mean age at diagnosis was 13 months; 5 unilateral (29%) and 12 bilateral (71%). The mean (median, range) number of retinoblastoma tumors per eye was 2 (2; 1–6). The number of cavities per tumor was 3 (2, 1–6). Intratumoral cavities were seen in the superficial portion of the tumor in 10 eyes (55%). The cavities became visible in eight eyes (44%) and collapsed in eight eyes (44%). Two eyes required enucleation because of relapse in noncavitary tumors. Germline mutations were detected in 14 patients (82%) of whom four demonstrated mosaicism (29%); only one had a low penetrant mutation. The mean follow-up period was 40 (35, 6–120) months. Conclusion: Cavitary retinoblastomas can be detected after systemic chemotherapy with cavities becoming visible after mean two cycles of chemotherapy (secondary cavitary retinoblastoma). The etiology is uncertain. They remain stable and do not require aggressive adjuvant therapy. There was no evident phenotype–genotype correlation with mosaicism noted in 29%.
2017-03-22 | DO MRPS18-2 AND RB PROTEINS COOPERATE TO CONTROL CELL STEMNESS AND DIFFERENTIATION, PREVENTING CANCER DEVELOPMENT?
In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule. These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1-encoded protein (RB) does not control the cell cycle in embryonic stem cells. It has not been yet well understood how RB controls cell stemness and differentiation. The question arises why “inactive” RB is required for the survival and stemness of cells? Recently, we have found that overexpression of the RB-binding protein MRPS18-2 (S18-2) in primary fibroblasts leads to their immortalization, which is accompanied by the induction of embryonic stem cell markers and, eventually, malignant transformation. We suggest that cell stemness may be associated with high expression levels of both proteins, RB and S18-2. There must be a strict regulation of the expression levels of S18-2 and RB during embryogenesis. Disturbances in the expression of these proteins would lead to the abnormalities in development. We think that the S18-2 protein, together with the RB, plays a crucial role in the control on cell stemness and differentiation. We hope to uncover the new mechanisms of the cell fate determination. The S18-2 may serve as a new target for anticancer medicines, which will help to improve human health.
2017-02-22 | HER2 Overexpression in Retinoblastoma: A Potential Therapeutic Target
Retinoblastoma (RB) is the most common primary intraocular malignancy. Current therapies are associated with high morbidity in the short- and long-term. Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein detected in 15-30% of breast cancers, but it has also been described in other malignancies. Recently, it has been claimed that a truncated version of this protein is expressed in RB, responsive to directed therapies in vitro. We scored HER2 overexpression in RB tissue samples and discussed its potential clinical utility.HER2 overexpression was investigated using immunohistochemistry; the overexpression was evaluated with a score ranging from 0 to 3+ according to the membranous staining pattern in archival formalin-fixed, paraffin-embedded RBs.A total of 60 RB cases and a RB cell line (Y79) were considered. The mean age at enucleation was 31.6 ± 31.5 months. The mean time from diagnosis to enucleation was 11.8 ± 11.2 months (range 1-44). Five (8%) cases were multifocal. HER2 overexpression was negative in all RB cases (49 cases scored 0 and 11 scored 1+) and in the Y79 cell line.Overall, we were not able to demonstrate the overexpression of HER2. Further studies should clarify and better elucidate the potential role of HER2-targeted therapies in RB.
small molecules
2025-04-25 | Epigenetic Reprogramming by Decitabine in Retinoblastoma
Introduction: Retinoblastoma (Rb) is a rare cancer, yet it is the most common eye tumor in children. It can occur in either a familial or sporadic form, with the sporadic variant being more prevalent, though its downstream effects on epigenetic markers remain largely unclear. Currently, the treatment for retinoblastoma typically involves aggressive chemotherapy and surgical resection. The identification of specific epigenetic characteristics of non-hereditary (sporadic) Rb has led to the development of advanced, high-throughput methods to explore its epigenetic profile. Our previous research demonstrated that treatment with the demethylating agent 5-Aza-2′-deoxycytidine (decitabine; DAC) induced cell cycle arrest and apoptosis in a well-characterized retinoblastoma model (WERI-Rb-1). Our analysis of time-dependent gene expression in WERI-Rb-1 cells following DAC exposure has led to the development of testable hypotheses to further investigate the epigenetic impact on the initiation and progression of retinoblastoma tumors. Methods: Gene expression analysis of publicly available datasets from patients’ primary tumors and normal retina have been compared with those found in WERI-Rb-1 cells to assess the relevance of DAC-driven genes as markers of primary retinoblastoma tumors. The effect of DAC treatment has been evaluated in vivo, both in subcutaneous xenografts and in orthotopic models. qPCR analysis of gene expression and Methylation-Specific PCR (MSP) was performed. Results: Our analysis of network maps for differentially expressed genes in primary tumors compared to DAC-driven genes identified 15 hub/driver genes that may play a pivotal role in the genesis and progression of retinoblastoma. DAC treatment induced significant tumor growth arrest in vivo in both subcutaneous and orthotopic xenograft retinoblastoma models. This was associated with changes in gene expression, either through the direct switching-on of epigenetically locked genes or through the indirect regulation of linked genes, suggesting the potential use of DAC as an epigenetic anti-cancer drug for the treatment of retinoblastoma patients. Conclusion: There is a pressing need to develop innovative treatments for retinoblastoma. Our research revealed that DAC can effectively suppress the growth and progression of retinoblastoma in in vivo models, offering a potential new therapeutic approach to battle this destructive disease. This discovery highlights the impact of this epigenetic therapy in reprogramming tumor dynamics, and thus its potential to preserve both the vision and lives of affected children.
2024-12-30 | Expression of Wnt signaling proteins LEF1, β-catenin, GSK3β, DVL1, and N-myc varies across retinoblastoma subtypes and pRb phosphorylation status
Retinoblastoma, a rare childhood eye cancer, has hereditary and non-hereditary forms. While TNM classification helps in prognosis, understanding molecular mechanisms is vital for the clinical behavior of retinoblastoma prediction. Our study aimed to analyze the expression levels of key Wnt pathway proteins, GSK3β, LEF1, β-catenin, and DVL1, and associate them to non-phosphorylated active form (pRb) and the phosphorylated inactive form (ppRb) and N-myc expression, in retinoblastoma cells and healthy retinal cells, in order to elucidate their roles in retinoblastoma and identify potential targets that could help to improve diagnostic and therapy. Specimens from 22 retinoblastoma cases (unilateral, bilateral, and trilateral) were analyzed. Immunohistochemistry assessed proteins' expressions, followed by semi-quantitative analysis using the Immunoreactivity Score (IRS). Bayesian statistical methods were employed for data analysis. The study revealed various expression patterns of Wnt signaling proteins across different retinoblastoma types. The high expression levels were observed for LEF1 and DVL1. Inactive GSK3β and nuclear localization of β-catenin indicated Wnt signaling activation. The levels of inactive ppRb were significantly higher in retinoblastoma compared to healthy retina, as well as the levels of inactive GSK3β. Positive correlations between DVL1 and N-myc, GSK3β Y216 and GSK3β S9 and non-P β-catenin and LEF1 were established. Retinoblastomas without germline mutations (RB1+/+) exhibited high pRb, N-myc, and LEF1 levels, while those in genetically predisposed children (RB1+/-) showed lower expression of these proteins. Trilateral retinoblastomas demonstrated especially high N-myc and LEF1, but low pRb and ppRb levels. The findings highlight the meaningful role of the Wnt signaling pathway in retinoblastoma pathogenesis, providing insights into potential therapeutic targets. Understanding molecular features may pave the way for personalized treatments and improve outcomes for retinoblastoma patients.
2024-03-18 | Therapeutic Strategies for RB1-Deficient Cancers: Intersecting Gene Regulation and Targeted Therapy
The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.
2024-03-15 | Advancement in the treatment, genetic understanding, and diagnostic approaches for retinoblastoma
The most common intraocular tumor in children is retinoblastoma. In developed countries, there has been an impressive rise in the survival rate and visual outcome of patients with retinoblastoma. This is clarified by developments in retinoblastoma treatment and early detection of tumors. The primary therapy remedy for intraocular retinoblastoma is now chemotherapy along with adjuvant consolidative treatment, instead of external beam radiation. Likewise, prophylactic chemotherapy is now allowed to treat potential micro metastases in enucleated eyes based on the identification of high-risk histopathological factors. Extra ocular retinoblastoma still has a poor future outcome; chances of survival have been reported to be between 50% and 70%. Retinoblastoma patients' overall survival is still struggling in developing countries, mostly because of delayed presentation and greater risk of extra ocular illness while compared to with the developed world, where intraocular disease contributes to majority of cases. To enhance the survival rate for those with retinoblastoma in developing countries, greater priority must be given to early detection of tumors. We provide a summary of the latest clinical management of retinoblastoma in this article.
2024-03-01 | Characterization of Retinoblastoma Patients in a Referral Center on the Colombian North Coast
Purpose: The purpose of the following study was to describe the sociodemographic, clini-cal, and therapeutic characteristics of patients with retinoblastoma (RB), the most common intraocular tumor in children, receiving medical care in an eyecare institution in the Carib-bean region of Colombia.Methods: A case series between 2016 and 2021 was carried out. Eyes of patients with RB, receiving medical care in a single health care institution, and in compliance with the esta-blished follow-up protocol, were included. Descriptive analyzes of relevant variables were performed.99Characterization of Retinoblastoma Patients in a Referral Center on the Colombian North CoastAna María Álvarez Castillo, Cesar Atencia Niño,Diana Cifuentes Zapata, Katia Gutiérrez Brun,Jaime Moreno Chaparro, Javier Antonio Amaya Nieto, Javier Vásquez RamírezVol. 40(1), 2024, 97-108Barranquilla (Col.) Results: In this study, a totalof 21 eyes of 16 patients were examined. The average age at the time of diagnosis was 17.7 months, and 50% of children were male. Using the Interna-tional Classification for Intraocular Retinoblastoma, 42.9% of the total cases were classi-fied as group D. Out of the 21 cases, 71.4% went into total remission without the necessity for enucleation, and the most common treatment was chemotherapy, using Melphalan® via intraarterial or intravitreal administration.Conclusion: Specific findings of patients with RB in the Caribbean Coast of Colombia were identified. These findings imply that, despite the obstacles to healthcare access, an early diagnosis and a treatment plan using intraarterial chemotherapy may provide a satisfac-tory clinical outcome (remission).
oligonucleotides
2023-02-23 | Intraocular siRNA Delivery Mediated by Penetratin Derivative to Silence Orthotopic Retinoblastoma Gene
Gene therapy brings a ray of hope for inherited ocular diseases that may cause severe vision loss and even blindness. However, due to the dynamic and static absorption barriers, it is challenging to deliver genes to the posterior segment of the eye by topical instillation. To circumvent this limitation, we developed a penetratin derivative (89WP)-modified polyamidoamine polyplex to deliver small interference RNA (siRNA) via eye drops to achieve effective gene silencing in orthotopic retinoblastoma. The polyplex could be spontaneously assembled through electrostatic and hydrophobic interactions, as demonstrated by isothermal titration calorimetry, and enter cells intactly. In vitro cellular internalization revealed that the polyplex possessed higher permeability and safety than the lipoplex composed of commercial cationic liposomes. After the polyplex was instilled in the conjunctival sac of the mice, the distribution of siRNA in the fundus oculi was significantly increased, and the bioluminescence from orthotopic retinoblastoma was effectively inhibited. In this work, an evolved cell-penetrating peptide was employed to modify the siRNA vector in a simple and effective way, and the formed polyplex interfered with intraocular protein expression successfully via noninvasive administration, which showed a promising prospect for gene therapy for inherited ocular diseases.
2022-03-05 | LncRNA HOTAIR facilitates proliferation and represses apoptosis of retinoblastoma cells through the miR-20b-5p/RRM2/PI3K/AKT axis
Retinoblastoma (RB) represents an adolescent eye malignancy. Long non-coding RNA (LncRNA) HOTAIR shows aberrant expression in many malignancies. This research investigated the mechanism of HOTAIR in RB.Normal retinal cell lines (ARPE-19 and RPE-1) and RB cell lines (ORB50, Y79, HXO-RB44, and WERI-RB) were selected for detection of HOTAIR expression by qRT-PCR. sh-HOTAIR was delivered into Y79 and HXO-RB44 cells. Cell-cycle distribution, proliferation, and apoptosis were detected by CCK-8 assay and flow cytometry. Binding relationships among HOTAIR, miR-20b-5p, and RRM2 were confirmed using dual-luciferase assay. Roles of miR-20b-5p and RRM2 in RB cell-cycle distribution, proliferation, and apoptosis were ascertained by functional rescue experiments. Murine model of xenograft tumor was established, followed by detection of tumor growth and counting of Ki67-positive cells. Expressions of proliferation- and apoptosis-associated proteins and PI3K/AKT pathway-related proteins were determined by Western blot.HOTAIR was elevated in RB cells relative to that in normal retinal cells and showed relatively high expression in Y79 and HXO-RB44 cells. sh-HOTAIR induced RB cell-cycle arrest, restrained proliferation, and strengthened apoptosis. HOTAIR functioned as the ceRNA of miR-20b-5p and targeted RRM2. RB cells had poorly-expressed miR-20b-5p and highly-expressed RRM2. miR-20b-5p downregulation or RRM2 overexpression facilitated RB cell-cycle and proliferation, suppressed apoptosis, and reversed the protective effect of sh-HOTAIR on RB. sh-HOTAIR reduced tumor growth and Ki67-positive cells in vivo and inactivated PI3K/AKT pathway.LncRNA HOTAIR upregulated RRM2 by competitively binding to miR-20b-5p and activated PI3K/AKT pathway, thereby facilitating proliferation and repressing apoptosis of RB cells.
2021-10-14 | Identification and functional annotation of differentially expressed long noncoding RNAs in retinoblastoma
Retinoblastoma (RB), the most common intraocular malignancy, typically occurs in pediatric patients under the age of 6 years. The present study aimed to explore the long noncoding RNA (lncRNA) expression profile in RB and identify novel lncRNA biomarkers to facilitate the investigation of molecular mechanisms of RB and improve clinical therapy. Raw microarray data for the comparison of gene expression between three RB and three adjacent normal tissue samples were downloaded from Gene Expression Omnibus (dataset no. GSE111168). After identification of differentially expressed lncRNAs (DELs) and differentially expressed mRNAs (DEMs) in RB, functional enrichment analyses and a DEL-DEM weighted correlation network analysis were performed. A total of 3,915 DELs (1,774 upregulated and 2,141 downregulated) and 3,715 DEMs (1,492 upregulated and 2,223 downregulated) were identified in RB. The DEL-targeted DEMs were highly enriched by genes involved in hexose transport, muscle tissue morphogenesis, the stereocilium membrane, endothelin B receptor binding and γ-filamin/ABP-L, α-actinin and telethonin binding protein of the Z-disc binding. Furthermore, associations of the DELs and DEMs with several pathways were determined, including PI3K/AKT, Hippo and cancer signaling, as well as extracellular matrix-receptor interaction pathways. Coexpression network analysis revealed that the top three DELs, lnc-DAZ1-161, lnc-HDAC7-21 and lnc-OR52A1-55, formed coexpression modules with 181, 156 and 210 DEMs, respectively. In addition, the top three DEMs, namely EIF1AY, GSTM1 and NLRP11, formed coexpression modules with 33, 50 and 41 DELs, respectively. Validation using reverse transcription-quantitative PCR indicated that the expression of representative lncRNAs (lnc-DAZ1-161 and lnc-HDAC7-21) in RB cells in vitro was consistent with that in RB tissues in the database, while the expression of lnc-OR52A1-55 was not consistent with the database. These results suggested that the aberrant lncRNA expression profile in RB is related to the differential regulation of numerous physiological and pathological processes. The lncRNA and mRNA profiles in RB identified may provide novel targets for the investigation of its molecular mechanisms and thus lead to improvements in clinical therapy for RB.
2020-11-01 | <p>Effect of miR-515-5p on Proliferation and Drug Sensitivity of Retinoblastoma Cells</p>
Retinoblastoma (RB) is a common malignancy in children eyes. Aberrant microRNA (miR) expression is observed in many cancer cases. miR-515-5p is reported to be concerned with the course of many cancers. This study explores the role of miR-515-5p in proliferation and drug sensitivity of RB cells.Human RB cell lines (WERI-RB1, SO-RB50 and Y79) and human retinal pigment epithelial cell line ARPE-19 were utilized in this study. Drug-resistant cells SO-RB50/VCR and SO-RB50/CBP were constructed for the following experiments. The expressions of miR-515-5p and Notch1 in RB cells were detected. Notch1 was significantly upregulated in RB cells while miR-515-5p was notably downregulated. Then, the binding relationship between miR-515-5p and Notch1 was predicted and verified.miR-515-5p negatively regulated Notch1 expression. In vitro and in vivo experiments revealed that overexpressed miR-515-5p inhibited RB cell proliferation and enhanced drug sensitivity. Functional rescue experiment suggested that miR-515-5p regulated RB cell proliferation and drug sensitivity via inhibiting Notch1 expression.It could be concluded that overexpressed miR-515-5p suppressed proliferation and drug resistance of RB cells by targeting Notch1 expression, indicating that miR-515-5p might constitute a promising therapy target for RB.
2019-11-14 | Non-Coding RNAs in Retinoblastoma
Retinoblastoma (Rb) is the most common ocular pediatric malignancy that arises from the retina and is caused by a mutation of the two alleles of the tumor suppressor gene, RB1. Although early detection provides the opportunity of controlling the primary tumor with effective therapies, metastatic activity is fatal. Non-coding RNAs (ncRNAs) have emerged as important modifiers of a plethora of biological mechanisms including those involved in cancer. They are classified into short and long ncRNAs according to their length. Deregulation of all these molecules has also been shown to play a critical role in Rb pathogenesis and progression. It is believed that ncRNAs can provide new insights into novel regulatory mechanisms associated with clinical pathological characteristics, facilitating the development of therapeutic alternatives for the treatment of Rb. In this review we describe a variety of ncRNAs which, capable of regulating the most likely candidate genes involved in the tumorigenesis of Rb, could prove useful in analyzing different aspects of this cancer.
gene therapies
2025-08-13 | Retinoblastoma: Evolving Concepts and Future Challenges
Retinoblastoma is the most common ocular malignancy in children. It results from mutations in the RB1 gene or from MYCN oncogene amplification. We distinguish between the more common unilateral form and the rarer bilateral form. It is important to note that bilateral retinoblastoma is always hereditary. The most common and characteristic symptom is the white pupillary reflex. In addition, the child may develop strabismus or heterochromia. Treatment methods vary, ranging from those aimed at salvaging the eye to those involving total enucleation. Prognosis depends on the location and stage of the tumor. This review aims to explore the literature on new therapeutic methods and recent discoveries in the field of retinoblastoma.
2019-01-23 | Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01
Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1 VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.
2017-08-05 | Defective splicing of the RB1 transcript is the dominant cause of retinoblastomas
Defective splicing is a common cause of genetic diseases. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations with most mapping to the critical GT or AG nucleotides within the 5′ and 3′ splice sites. However, splicing mutations are underreported and the fraction of splicing mutations that compose all disease alleles varies greatly across disease gene. For example, there is a great excess (46%; ~threefold) of hereditary disease alleles that map to splice sites in RB1 that cause retinoblastoma. Furthermore, mutations in the exons and deeper intronic position may also affect splicing. We recently developed a high-throughput method that assays reported disease mutations for their ability to disrupt pre-mRNA splicing. Surprisingly, 27% of RB1-coding mutations tested also disrupt splicing. High-throughput in vitro spliceosomal assembly assay reveals heterogeneity in which stage of spliceosomal assembly is affected by splicing mutations. 58% of exonic splicing mutations were primarily blocked at the A complex in transition to the B complex and 33% were blocked at the B complex. Several mutants appear to reduce more than one step in the assembly. As RB1 splicing mutants are enriched in retinoblastoma disease alleles, additional priority should be allocated to this class of allele while interpreting clinical sequencing experiments. Analysis of the spectrum of RB1 variants observed in 60,706 exomes identifies 197 variants that have enough potential to disrupt splicing to warrant further consideration.
2007-11-13 | Pathogenic validation of unique germline intronic variants ofRB1 in retinoblastoma patients using minigenes
Precise identification of the pathogenic character of germline mutations in the retinoblastoma gene (RB1) is fundamental to provide genetic counselling to patients at risk of developing retinoblastoma. In contrast to bona fide oncogenic RB1 mutations like nonsense or frameshift mutations, and those affecting invariant dinucleotides at splice sites, intronic variants affecting less conserved splice motifs require additional analysis to ascertain whether splicing is altered. Although the frequency of these variations is low, their impact on genetic counselling is high, since they are usually associated with low penetrance phenotypes and unaffected carriers. In this work, we used minigene assays to study infrequent germline intronic variations for which functional data were not available. Using this approach, the aberrant splicing and the resulting oncogenic nature of three intronic RB1 mutations was established (c.501-15T>G, c.719-9C>G, c.2326-8T>A). Conversely, the intronic variant c.1961-12T>C was categorized by minigene assay as a very infrequent neutral polymorphism. To our knowledge this is the first report describing the use of minigene constructs to study the oncogenic character of intronic RB1 variants detected during mutational screening and show the utility of this approach to ascertain the oncogenic nature of unique RB1 intronic variants for which no previous functional and clinical data are available. Minigene assay can be especially useful when lymphocyte RNA is not available for study, or when aberrant mRNA can not be detected as a consequence of nonsense mediated decay. Since RB1 minigene are time-consuming assays, owing to the genomic organization of the RB1 gene, it should be welcome the design of new expression vectors that make this type of studies more straightforward. © 2007 Wiley-Liss, Inc.
2007-09-24 | Cell lineage-specific interactions between Men1 and Rb in neuroendocrine neoplasia
Inactivation of multiple endocrine neoplasia (MEN) type 1 gene (Men1) results in development of multiple endocrine tumors in Men1(+/-) mice and in humans. Intriguingly, loss of the wild-type retinoblastoma 1 (Rb) gene also leads to MEN-like phenotype in Rb(+/-) mice. To evaluate potential genetic interactions between these genes, we prepared and characterized Men1(+/-)Rb(+/-) compound mice in parallel with their parental genotypes. Men1 and Rb did not cooperate in tumor suppression, as demonstrated by comparable survival rates of Rb(+/-) and Men1(+/-)Rb(+/-) mice, absence of tumor growth acceleration and lack of novel neoplasms. Notably, the loss of the remaining copy of the wild-type Men1 and Rb was mutually exclusive in all tumors of Men1(+/-)Rb(+/-) mice, including pituitary anterior lobe and adrenal medulla neoplasms shared by Rb- and Men1-deficient phenotypes. Down-regulation of Men1 targets p18 and p27 and increased presence of phosphorylated-Rb were observed in Men1-deficient pheochromocytomas of Men1(+/-)Rb(+/-) and Men1(+/-) mice. At the same time, the RNA interference (RNAi) knock-down of Men1 mRNA resulted in increased apoptosis of Rb-deficient medullary thyroid carcinoma cells. These results demonstrate that, depending on cell lineage context, combined Men1 and Rb deficiency may be either redundant or detrimental to neoplastic growth. Identification of cell lineage-specific interactions between Men1 and Rb may have important implications for development of rationally designed therapeutic approaches.
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Drug Discovery Landscape
2 orphan drug designations for Hereditary retinoblastoma.
2 orphan drug designations for Hereditary retinoblastoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
melphalan | small molecules | FDA | 2025-07-24 | — | Zhaoke Ophthalmology |
Genetically modified human adenovirus encoding human PH20 hyaluronidase | gene therapies | EMA | 2024-10-11 | — | Theriva Biologics S.L. |
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