HomeENGLISH MAGAZINERetinoblastoma gets "viewed" from within opening a widERR gamma of opportunities

Retinoblastoma gets “viewed” from within opening a widERR gamma of opportunities

Retinoblastoma is a rare cancer affecting the retina – the tissue in the back of the eye that receives light and converts it into signals to the brain. It is most often diagnosed in children under 2 and has been associated with mutations in the RB1 gene. However, there are currently no specific, targeted therapies; doctors rely on broad-acting chemotherapy drugs that carry numerous side effects and toxicities. The most commonly used drugs are carboplatin, vincristine ed etoposide; occasionally doxorubicin and topotecan are employed. Since the most represented patient range is pediatric, more timelapsed side effects may hit children in the future. Despite decades of medical advances, children who develop the pediatric eye cancer retinoblastoma often lose their vision or an eye due to a lack of specific, targeted therapies and a poor molecular understanding of this cancer.

Now researchers at UT Southwestern and the University of Miami, led by professor Horbour, have discovered that a celluar protein, estrogen-related receptor gamma or ERR-G, becomes hyperactive and promotes tumor cell survival in retinoblastoma. ERR-gamma is an orphan nuclear hormone receptor that belongs to the ERR subfamily of transcription factors. No endogenous ligand has been identified to date. Recent data from animal models have established ERR-G as a crucial mediator of multiple endocrine and metabolic signals, intervening in pathological conditions such as alcoholic liver injury, insulin resistance and cardiac hypertrophy. Past data discovered that it may also control energy metabolism in the heart, skeletal muscle, pancreas and certain brain areas. ERR-G is known to play a role in the early development of the retina and other nervous system areas but had never been linked to retinoblastoma before.

In this research, Dr. Harbour and his team analyzed genes and proteins in tumor cells from 103 retinoblastoma patients, representing the largest sequencing analysis of retinoblastoma reported to date. While 94% of the tumors contained RB1 mutations, many also contained other altered genes. When the scientists analyzed these other mutations, they discovered that many were involved in the same signaling pathway inside cells: a molecular network that regulates ERR-G. The team discovered that RB1 normally puts the brakes on ERR-G in normal retinal cells. However, in retinal cells that have transformed into retinoblastoma, ERR-G becomes activated and helps keep cells alive and proliferating, even as oxygen levels drop. This is due to direct RB1-ERRG interaction that suppresses ERR-G transcriptional activity. Blocking ERR-G causes cells to die under these low-oxygen conditions that are common in rapidly growing tumors and inside the eye.

The researchers noted that more studies are needed to prove that drugs targeting ERR-G could be used in humans to treat retinoblastoma. But their results are encouraging. As said earlier no endogenous ligand is known yet for ERR-G, even though scientists suspect it is an aromatic metabolite. An exogenous, notorious and infamous ligand of ERR-G is bisphenol A, a precursor of plastics and an aromatic endocrine disruptor as well. Another direct agonist of ERR-G is DY131, which is being studied to unravel the roles of this nuclear receptors in human disease. An inverse agonist called GSK5182 is a tamoxifen derivative able to bind ERR-G and hamper its binding to specific genome areas. But no direct ERR-G antagonists are still known to man. Nonetheless, scientists are satisfied since this knowledge represents the first opportuity to use a cellular protein directly involved in retinoblastoma pathogenesis as a drug target.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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