Each year, a total of 8000 cases of retinoblastoma representing 11% of tumours in the paediatric population under 1 year of age.
Despite the most current systemic and innovative drug delivery approachesBoth intravitreal and intra-ophthalmic routes have resulted in greater ocular preservation, some tumours progress to a chemo-resistant phenotype. In these cases, in order to prevent extra-ocular metastases that could prove fatal, enucleation (surgical removal of the eye) is necessary. Alternatively, a intensive local chemotherapy could preserve the eyes, but lead to a high visual impairment due to retinal toxicity of long-term administration.
Current research on retinoblastoma, for these reasons, focuses mainly on on the identification of new targeted therapies with increased anti-tumour activity and improved retinal safety profiles.
A new treatment for retinoblastoma
A recent paper, published in Science Translational Medicinepresented the results of a new treatment strategy for retinoblastoma based on the use of an oncolytic adenovirus (designed to replicate in cancer cells).
The study is based on the genetic characteristics of retinoblastoma: the disease is determined in the majority of cases, by bi-allelic inactivation of the retinoblastoma 1 (RB1) suppressor gene, located on chromosome 13. In 40% of cases, the retinoblastoma is hereditaryIt is determined by a single-allelic germline mutation of RB1 and presents clinically with bilateral multifocal disease.
In the remaining 60% of cases the pathology is not hereditary (sporadic), and is caused by bi-allelic inactivation of RB1, arising locally in the developing retina (unilateral disease).
In both cases, retinal cells reveal a non-functional state of RB1 resulting in uncontrolled cell division and oncogenesis of retinoblastoma.
Under normal conditions, functional RB1 binds to free E2F transcription factors, forming a complex that inhibits cell proliferation. E2Fs are, in fact, a family of transcription factors that, by binding to target promoters, control the expression of key cell cycle regulators.
In the case of retinoblastoma, inactivation of RB1 removes the constraint on cell cycle control and constitutively increases the expression of free E2F.
Understanding the genetic basis of retinoblastoma has enabled the team of researchers to identify in RB1 dysfunction and increased E2F expression of possible targets for a treatment strategy. To this end, it was designed VCN-01, an oncolytic adenovirus capable of selectively replicating in tumour cells with high abundance of free E2F-1, consequence of a dysfunctional RB1 pathway.
The study's conclusions
The study showed that, in mouse models, the intravitreal administration of VCN-01 in retinoblastoma-induced tumour necrosis by xenografts improved ocular preservation compared to standard chemotherapy treatments by preventing micrometastatic spread.
As for toxicity, VCN-01 tested in immunocompetent young rabbits, it did not replicate in the retinas, induced slight and local side effects and spread in the blood little and for a short time.
Data from the initial phase 1 study, conducted in the first paediatric patients, showed the feasibility of intravitreal administration of VCN-01 that replicates in tumour cells without any systemic inflammation.
The results of the study are encouraging and support the use of oncolytic adenoviruses as a treatment option for retinoblastoma, selective and independent of chemotherapy.
Source:
Guillem Pascual-Pasto et al. Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01. Science Translational Medicine. 2019.
Dr. Carmelo Chines
Direttore responsabile
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