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Drug Target Identified for Potential Treatment of Aggressive Eye Cancer

By BiotechDaily International staff writers
Posted on 01 Mar 2012
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The protein target for a drug already being developed to treat other diseases has now been identified with high potential as an effective target for treating childhood retinoblastoma.

The potential target was identified using an approach that also helped characterize how this eye tumor becomes particularly aggressive. The mechanism was found to involve epigenetic factors and surprisingly few genetic mutations.

The only known genetic mutations associated with childhood retinoblastoma are loss-of-function mutations in the tumor suppressor gene RB1. Bi-allelic RB1 inactivation seems to trigger retinoblastoma during fetal development. Tumors then progress very quickly, but other major factors involved were unknown.

The study, reported in the January 11, 2012, advance online edition of the journal Nature, initially involved sequencing of the complete normal and cancer genomes of four retinoblastoma patients at St. Jude's University Hospital (Memphis, TN, USA). The retinoblastoma tumor genomes contained about 15-fold fewer mutations than have been found in nearly all other cancers sequenced so far. In one patient’s tumor, RB1 was the only mutation.

These findings prompted the next part of the study: to integrate the sequencing results with tests that looked at differences in gene activity patterns in tumor versus normal tissue.

“To our surprise and excitement, what we found was that instead of cancer genes having genetic mutations, they were being epigenetically regulated differently than normal cells,” said Michael Dyer, PhD, member of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute Early Career Scientist.

The genes included the proto-oncogene SYK, a known target of drugs already in clinical trials for adults with leukemia and rheumatoid arthritis.

Surprisingly, SYK has no role in normal eye development. When SYK protein levels were checked in normal and retinoblastoma tissue, they found high levels in tumor samples but absence in normal tissue. Changes observed in the SYK gene activity probably give the retinoblastoma cell "a growth advantage or provide other key factors,” said Richard Wilson, PhD, director of The Genome Institute at Washington University (St. Louis, MO, USA) and head of the team that collaborated with the St. Jude's team led by Dyer.

When the experimental drugs were used to block SYK in human retinoblastoma cells in tissue culture or in mouse eyes, the cells died. Dr. Dyer said work is now underway to reformulate one of the experimental drugs, a SYK-inhibitor called R406, so it can be delivered directly into the eye. If successful, those efforts are expected to lead to a Phase I trial in patients.

The effort was part of a PCGP project launched in 2010 in expectation that the results will provide a foundation for the next generation of clinical care for children and adolescents battling some of the most challenging cancers.

Related Links:
St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP)


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