New molecular drivers of retinoblastoma

Despite decades of medical advances, children with childhood eye cancer retinoblastoma often lose sight or one eye, due to the lack of specific, targeted treatments and a lack
of molecular understanding of cancer.
Now, researchers at the University of Texas at Southwestern and the University of Miami have found that in retinoblastoma, a molecule called estrogen-associated receptor γ (ESRRG) becomes abnormally active and promotes tumor cell survival
.
The team reported in the journal Science Advances that blocking ESRRG can kill retinoblastoma cells
.

J.
William Harbour, M.
D

"Our findings could lead to innovative new therapies for this cancer, harnessing retinoblastoma's dependence on ESRRG," said study lead J.
Thompson.
Dr.
William Harbour said he is the director and professor
of ophthalmology at the University of Texas Southwest.
Prior to joining UTSW last year, Dr.
Harbour served as associate director of translational research at the Bascomb Palmer Institute of Ophthalmology at the University of
Miami.

Retinoblastoma is a rare cancer
that affects the retina.
The retina is the tissue at the back of the eye that receives light and converts it into signals that are transmitted to the brain
.
It is usually diagnosed in children under 2 years of age and is associated
with mutations in the RB1 gene.
However, there is currently no concrete, targeted treatment; Doctors rely on extensive, extensive chemotherapy drugs
with a large number of side effects and toxicity.

In the new study, Dr.
Harbour and his colleagues analyzed genes and proteins in tumor cells in 103 retinoblastoma patients, the largest sequencing analysis
of retinoblastoma reported to date.
While 94 percent of tumors contain the RB1 mutation, many also contain other altered genes
.
When the scientists analyzed these other mutations, they found that many of them were related to the same signaling pathway within the cell: the 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.

Inactivated retinoblastoma residue after successful arterial chemotherapy

The team further showed that in normal retinal cells, RB1 typically inhibits ESRRG
.
However, in retinal cells that have been transformed into retinoblastoma, ESRRG is activated and helps maintain cell survival and proliferation, even as oxygen levels drop — often a signal
to kill healthy cells.
Clogging ESRRG can cause cells to die under these hypoxic conditions, which is common
in fast-growing tumors and inside the eye.

Dr Harbour said: "We found that when cells lose RB1, ESRRG is released, allowing tumors to continue growing
under low-oxygen conditions.
" The researchers note that more research is needed to prove that ESRRG-targeted drugs can be used to treat retinoblastoma
in humans.
But their findings are encouraging
.
"Retinoblastoma is the most common eye cancer in children, and finally finding a potential drug target is incredibly exciting," said
Dr.
Harbour.