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 poor molecular understanding of the cancer. Now, researchers from UT Southwestern and the University of Miami have found that one molecule – estrogen-related receptor gamma, or ESRRG – becomes overactive and promotes tumor cell survival in retinoblastoma. By blocking the ESRRG, the team reported in Scientists progresskills retinoblastoma cells.
“Our discovery could lead to new, innovative treatments for this cancer that take advantage of this reliance of retinoblastoma on ESRRG,” said study leader J. William Harbour, MD, chairman and professor of ophthalmology at UT Southwestern. Prior to joining UTSW last year, Dr. Harbor served as Vice President of Translational Research at the University of Miami’s Bascom Palmer Eye Institute.
Retinoblastoma is a rare cancer affecting the retina – the tissue at the back of the eye that receives light and converts it into signals to the brain. It is most commonly diagnosed in children under 2 years of age and has been associated with mutations in RB1 embarrassed. However, there is currently no specific targeted therapy; doctors rely on broad-acting chemotherapy drugs that cause many side effects and toxicities.
In the new study, Dr. Harbor and his colleagues analyzed the genes and proteins of tumor cells from 103 retinoblastoma patients, representing the largest retinoblastoma sequencing analysis reported to date. While 94% of tumors contained RB1 mutations, many also contained other altered genes. When the scientists analyzed these other mutations, they found that many were involved in the same signaling pathway inside cells: a molecular network that regulates ESRRG. ESRRG is known to play a role in the early development of the retina and other components of the nervous system, but has never been linked to retinoblastoma before.
The team then showed that RB1 normally suppresses ESRRG in normal retinal cells. However, in retinal cells that have turned into retinoblastoma, ESRRG activates and helps keep cells alive and proliferating, even when oxygen levels drop – normally a signal that kills healthy cells. Blocking the ESRRG causes cells to die in those low oxygen conditions that are common in rapidly growing tumors and inside the eye.
“We found that when cells lose RB1ESRRG is triggered to allow continued tumor growth despite low oxygen conditions,” said Harold C. Simmons Comprehensive Cancer Center Fellow Dr. Harbour.
The researchers noted that more studies are needed to prove that drugs targeting the ESRRG could be used in humans to treat retinoblastoma. But their results are encouraging.
“Retinoblastoma is the most common eye cancer in children, and it’s incredibly exciting to finally have a potential drug target,” said Dr Harbor.
Ce travail a été soutenu par la subvention d’innovation Alex’s Lemonade Stand/Tap Cancer Out, University of Miami Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Center for Computational Science Fellowship, University of Miami Lois Pope LIFE Fellowship Award, Alcon Research Award , NIH/NCI (R01CA248890 et P30CA240139), NIH/NEI (P30EY014801), Research to Prevent Blindness Unrestricted Grant, et un don philanthropique de MJ Daily.
Dr. Harbor holds the David Bruton, Jr. Professorship in Ophthalmology.
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Material provided by UT Southwestern Medical Center. Note: Content may be edited for style and length.