Abstract
Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. These are important to establish reliable preclinical models to study the disease and develop therapies. Although retinoblastoma is the most curable pediatric cancer with a high survival rate, advanced tumors limit globe salvage and are often associated with high-risk histopathological features predictive of dissemination. The advent of chemotherapy has improved treatment outcomes, which is effective for globe preservation with new routes of targeted drug delivery. However, molecularly targeted therapeutics with more effectiveness and less toxicity are needed. Here, we review the current knowledge concerning retinoblastoma genesis with particular attention to the genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, as well as the retinoblastoma cell-of-origin and current disease models. We further discuss current treatments, clinicopathological correlations, which assist in guiding treatment and may facilitate globe preservation, and finally we discuss targeted therapeutics for future treatments.
Highlights
Retinoblastoma is a tumor that develops in the retina, which is diagnosed in the first few years of a child’s life, affecting approximately 1 in 16,000 live births [1,2]
This review provides the current knowledge on the etiology, modeling, and treatment of retinoblastoma with particular attention to (i) the molecular and cellular basis concerning genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, and the tumor cell-of-origin; (ii) disease models with the features and limitations of each model; and (iii) current treatments and clinicopathological correlations regarding histopathological risk features, which assist in guiding treatment and may facilitate globe preservation, and assessment of targeted therapeutics for future treatments
A cone-specific signal circuitry is linked with the pRB pathway pRB pathway through S-phase kinase associated protein 2 (SKP2), whose activity is suppressed through through S-phase kinase associated protein 2 (SKP2), whose activity is suppressed through an Nan N-terminal interaction with pRb [72]
Summary
Retinoblastoma is a tumor that develops in the retina, which is diagnosed in the first few years of a child’s life, affecting approximately 1 in 16,000 live births [1,2]. Hereditary retinoblastoma (40%) is associated with a RB1 germline-predisposing variant, and subsequent somatic inactivation of the other allele [2,7] For this reason, cases of non-heritable retinoblastoma have unilateral tumors, unlike heritable retinoblastoma that often develops bilaterally and multifocally. Chemotherapy is the standard of care for patients with a high risk of metastasis but has inevitable toxicity [10,11,12,13,14,15] Such treatment is commonly used for globe sparing with different routes of drug delivery depending on the clinical features and anticipated. Therapeutics that selectively target tumors, while sparing the normal retina, are desired with the expectation of improving treatment outcomes. This review provides the current knowledge on the etiology, modeling, and treatment of retinoblastoma with particular attention to (i) the molecular and cellular basis concerning genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, and the tumor cell-of-origin; (ii) disease models with the features and limitations of each model; and (iii) current treatments and clinicopathological correlations regarding histopathological risk features, which assist in guiding treatment and may facilitate globe preservation, and assessment of targeted therapeutics for future treatments
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