Combination Therapy May Offer Better Outcomes for Patients with Retinoblastoma

Use of Chemotherapy with a Survivin Inhibitor Improves Treatment
Responses in Retinoblastoma Cells and Ocular Tumor Models


LOS ANGELES–(BUSINESS WIRE)–Researchers at The Saban Research Institute of Children’s Hospital Los
Angeles (CHLA) have demonstrated that targeting survivin – a protein
that inhibits apoptosis or cell death – enhances the effectiveness of
chemotherapy in cells and mouse models of retinoblastoma (Rb), the most
common malignant tumor of the eye in children.

The study – led by Charles Gomer, PhD, of the Children’s
Center for Cancer and Blood Diseases
at CHLA and Jonathan Kim, MD,
director of the retinoblastoma program at The Vision Center at CHLA –
demonstrates for the first time that the combination of a survivin
inhibitor called YM155 and chemotherapy provides a therapeutic advantage
for Rb cells and tumors. The results were recently published online in
PLOS One.

While treatments for retinoblastoma vary depending on size and location
of the lesions, most therapy includes chemotherapy agents such as
carboplatin and topotecan. The CHLA researchers examined whether such
agents induced a pro-survival phenotype associated with increased
expression of survivin in Rb cells and Rb tumors growing in mouse models.

They found that exposure to chemotherapy resulted in elevated levels of
survivin in two human Rb cell lines, but not in normal ocular retinal
pigmented epithelial (RPE) cells. They also documented that cellular
levels of survivin were significantly decreased in Rb cells, but not in
RPE cells, when exposed to YM155. The combination of YM155 and
chemotherapy agents was also most effective in enhancing Rb cell death
when compared to either alone.

The investigators next evaluated the combined modality approach using Rb
tumors growing in mouse eyes. Their study demonstrated the same positive
results using YM155 combined with carboplatin, increasing long term Rb
tumor responsiveness when compared to single agents.

“Our study shows proof of concept, that we can enhance chemotherapeutic
approaches to retinoblastoma while using the same dosage,” said Gomer,
who is also a professor in the Departments of Pediatrics and Radiation
Oncology at Keck School of Medicine of the University of Southern
California. “We’re hopeful that following additional preclinical studies
that this combination therapy will offer better outcomes to children
with retinoblastoma and perhaps the possibility of reduced chemotherapy,
reducing long-term adverse effects.”

Jonathan Kim is also an associate professor in the Department of
Ophthalmology and the Roski Eye Institute at USC. Additional
contributors include co-first authors Angela Ferrario and Marian Luna;
Natalie Rucker, Sam Wong and Ariel Lederman of The Saban Research
Institute of Children’s Hospital Los Angeles. The study was supported in
part by National Institutes of Health grant UL1TR000130, a grant from
ThinkCure and by the Las Madrinas Endowment for Experimental
Therapeutics in Ophthalmology.

About Children’s Hospital Los Angeles

Children’s Hospital Los Angeles has been named the best children’s
hospital on the West Coast and among the top five in the nation for
clinical excellence with its selection to the prestigious U.S. News &
World Report Honor Roll. Children’s Hospital is home to The Saban
Research Institute, one of the largest and most productive pediatric
research facilities in the United States. Children’s Hospital is also
one of America’s premier teaching hospitals through its affiliation
since 1932 with the Keck School of Medicine of the University of
Southern California. For more information, visit CHLA.org
or visit our blog at ResearCHLAblog.org.

Contacts

Children’s Hospital Los Angeles
Debra Kain, 323-361-7628 or
323-361-1812
dkain@chla.usc.edu

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